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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
EXALGO (NDA-021217)
(HYDROMORPHONE HYDROCHLORIDE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
10/07/2019 (SUPPL-25)
5 Warnings and Precautions
5.3 Life-Threatening Respiratory Depression
Newly added information to end of subsection:
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.
Additions and/or revisions underlined:
5.12 Withdrawal
Do not abruptly discontinue EXALGO in a patient physically dependent on opioids. When discontinuing EXALGO in a physically dependent patient, gradually taper the dosage. Rapid tapering of hydromorphone in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain.
Additionally, avoid the use of mixed agonist/antagonist …
7 Drug Interactions
Table 4. Clinically Significant Drug Interactions with EXALGO
Serotonergic Drugs
Additions and/or revisions underlined:
Example: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDEAdditions and/or revisions underlined in bulleted information:
Important information about EXALGO:
Store EXALGO securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home.
When taking EXALGO:
Dispose of expired, unwanted, or unused EXALGO by promptly flushing down the toilet, if a drug take-back option is not readily available. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.
Storage and Disposal:
Additions and/or revisions underlined:
Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store EXALGO securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving EXALGO unsecured can pose a deadly risk to others in the home.
Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused EXALGO should be disposed of by flushing the unused medication down the toilet if a drug take-back option is not readily available. Inform patients that they can visit
www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines.
Newly added titled section:
Important Discontinuation Instructions
In order to avoid developing withdrawal symptoms, instruct patients not to discontinue EXALGO without first discussing a tapering plan with the prescriber.
09/18/2018 (SUPPL-24)
Boxed Warning
(Additions and/or revisions are underlined)
WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS):
To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a 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
complete a REMS-compliant education program,
counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products,
emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and
consider other tools to improve patient, household, and community safety.
5 Warnings and Precautions
5.2 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)(Additions and/or revisions are underlined)
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.
12/16/2016 (SUPPL-19)
Boxed Warning
(Additions and/or revisions are underlined)
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE- THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death
- Reserve concomitant prescribing of EXALGO 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.
4 Contraindications
(Additions and/or revisions are underlined)
EXALGO is contraindicated in:
- Known or suspected gastrointestinal obstruction, including paralytic ileus
5 Warnings and Precautions
5.1 Addiction, Abuse, and Misuse(Additions and/or revisions are underlined)
Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing EXALGO, and monitor all patients receiving EXALGO for the development of these behaviors and conditions…
(Revised subsection title; Additions and/or revisions are underlined)
The hydromorphone in EXALGO 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…
(Revised subsection title)
(Revised subsection title)
(Additions and/or revisions are underlined)
…Closely monitor patients for respiratory depression, especially within the first 24-72 hours of initiating therapy with EXALGO and following dosage increases.
(Additions and/or revisions are underlined)
…Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly…
(Revised subsection title; Additions and/or revisions are underlined)
Profound sedation, respiratory depression, coma, and death may result from the concomitant use of EXALGO 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.
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 EXALGO 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.
(Revised subsection title; Additions and/or revisions are underlined)
The use of EXALGO 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: EXALGO 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 EXALGO.
(Newly added subsection)
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.
(Revised subsection title; Additions and/or revisions are underlined)
…In patients with circulatory shock, EXALGO may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of EXALGO in patients with circulatory shock.
(Revised subsection title)
(Revised subsection title; Additions and/or revisions are underlined)
EXALGO is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus…
…Opioids may cause increases in serum amylase…
6 Adverse Reactions
6 ADVERSE REACTIONS(Additions and/or revisions are underlined)
The following serious adverse reactions are discussed elsewhere in the labeling:
- Interactions with Benzodiazepine or Other CNS Depressants
- Adrenal Insufficiency
- Severe Hypotension
- Gastrointestinal Adverse Reactions
- Withdrawal
(Additions and/or revisions are underlined)
…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: Anaphylactic reaction has been reported with ingredients contained in EXALGO
Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids
7 Drug Interactions
(Additions and/or revisions are underlined)
Table 4 includes clinically significant drug interactions with EXALGO. (Table has been added; please refer to label)
8 Use in Specific Populations
8.1 Pregnancy(Additions and/or revisions are underlined; Pregnancy and Lactation Labeling Rule (PLLR) Conversion)
Risk Summary
Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome
There are no adequate and well-controlled studies in pregnant women. Based on animal data, advise pregnant women of the potential risk to a fetus.
In animal reproduction studies, reduced postnatal survival of pups, developmental delays, and altered behavioral responses were noted following oral treatment of pregnant rats with hydromorphone during gestation and through lactation at doses 2.1 times the human daily dose of 32 mg/day (HDD), respectively. In published studies, neural tube defects were noted following subcutaneous injection of hydromorphone to pregnant hamsters at doses 4.8 times the HDD and soft tissue and skeletal abnormalities were noted following subcutaneous continuous infusion of 2.3 times the HDD to pregnant mice. No malformations were noted at 2.1 or 17 times the HDD in pregnant rats or rabbits, respectively. Based on animal data, advise pregnant women of the potential risk 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 2-4% 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.
Labor or 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. EXALGO 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 EXALGO 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
Pregnant rats were treated with hydromorphone hydrochloride from Gestation Day 6 to 17 via oral gavage doses of 1.75, 3.5, or 7 mg/kg/day (0.5, 1.1, or 2.1 times the HDD of 32 mg/day based on body surface area, respectively). Maternal toxicity was noted in all treatment groups (reduced food consumption and body weights in the two highest dose groups). There was no evidence of malformations or embryotoxicity reported.
Pregnant rabbits were treated with hydromorphone hydrochloride from Gestation Day 6 to 20 via oral gavage doses of 10, 25, or 50 mg/kg/day (4.3, 8.5, or 17 times the HDD of 32 mg/day based on body surface area, respectively). Maternal toxicity was noted in the highest dose group (reduced food consumption and body weights). There was no evidence of malformations or embryotoxicity reported.
In a published study, neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of hydromorphone hydrochloride (19 to 258 mg/kg) on Gestation Day 8 to pregnant hamsters (4.8 to 65.4 times the HDD of 32 mg/day based on body surface area). The findings cannot be clearly attributed to maternal toxicity. No neural tube defects were noted at 14 mg/kg (3.5 times the human daily dose of 32 mg/day). In a published study, CF-1 mice were treated subcutaneously with continuous infusion of 7.5, 15, or 30 mg/kg/day hydromorphone hydrochloride (1.1, 2.3, or 4.6 times the human daily dose of 32 mg based on body surface area) via implanted osmotic pumps during organogenesis (Gestation Days 7 to 10). Soft tissue malformations (cryptorchidism, cleft palate, malformed ventricles and retina), and skeletal variations (split supraoccipital, checkerboard and split sternebrae, delayed ossification of the paws and ectopic ossification sites) were observed at doses 2.3 times the human dose of 32 mg/day based on body surface area. The findings cannot be clearly attributed to maternal toxicity.
Pregnant rats were treated with hydromorphone hydrochloride from Gestation Day 6 to Lactation Day 21 via oral gavage doses of 1.75, 3.5, or 7 mg/kg/day (0.5, 1.1, or 2.1 times the HDD of 32 mg/day based on body surface area, respectively). Reduced pup weights were noted at 1.1 and 2.1 times the human daily dose of 32 mg/day and increased pup deaths, delayed ear opening, reduced auditory startle reflex, and reduced open-field activity were also noted at 2.1 times the HDD. Maternal toxicity was noted in all treatment groups (reduced food consumption and body weights in all groups) and decreased maternal care in the high dose group.
(Additions and/or revisions are underlined; Pregnancy and Lactation Labeling Rule (PLLR) Conversion)
Risk Summary
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 EXALGO…
Clinical Considerations
Monitor infants exposed to EXALGO 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 breast-feeding is stopped.
(Additions and/or revisions are underlined; Pregnancy and Lactation Labeling Rule (PLLR) Conversion)
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.
(Additions and/or revisions are underlined)
Elderly patients (aged 65 years or older) may have increased sensitivity to hydromorphone. 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 EXALGO slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression.
Hydromorphone 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.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Additions and/or revisions are underlined)
Interactions with Benzodiazepines and Other CNS Depressants
Inform patients and caregivers that potentially fatal additive effects may occur if EXALGO is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a health care provider.
Serotonin Syndrome
Inform patients that EXALGO 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 healthcare providers if they are taking, or plan to take serotonergic medications.
MAOI Interaction
Inform patients to avoid taking EXALGO while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking EXALGO.
Adrenal Insufficiency
Inform patients that EXALGO 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.
Important Administration Instructions
Instruct patients how to properly take EXALGO, including the following:
- EXALGO is designed to work properly only if swallowed intact. Taking cut, broken, chewed, crushed, or dissolved EXALGO tablets can result in a fatal overdose
Pregnancy
Embryo-Fetal Toxicity
Inform female patients of reproductive potential that EXALGO can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy.
Lactation
Advise patients that breastfeeding is not recommended during treatment with EXALGO.
Infertility
Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible.
Disposal Of Unused EXALGO
Advise patients to flush the unused tablets down the toilet when EXALGO is no longer needed.
(Additions and/or revisions are underlined)
Important information about EXALGO:
- Taking EXALGO with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.
Tell your healthcare provider if you are:
- breastfeeding. Not recommended during treatment with EXALGO.
When taking EXALGO:
- Do not change your dose. Take EXALGO exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed.
Get emergency medical help if you have:
- trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.