Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING DURAMORPH (morphine sulfate injection, USP) is a preservative-free solution, available as 5 mg/10 mL (0.5 mg/mL) and 10 mg/10 mL (1 mg/mL), in amber ampuls, for single use administration. NDC 0641-6020-10 5 mg/10 mL (0.5 mg/mL) Single Use amber ampuls packaged in 10s NDC 0641-6019-10 10 mg/10 mL (1 mg/mL) Single Use amber ampuls packaged in 10s DURAMORPH is supplied in sealed ampuls. Accidental dermal exposure should be treated by the removal of any contaminated clothing and rinsing the affected area with water. PROTECT FROM LIGHT. Keep stored in carton until time of use. Store at 20˚‑25˚C (68˚‑77˚F), excursions permitted to 15˚‑30˚C (59˚‑86˚F) [See USP Controlled Room Temperature]. DO NOT FREEZE. DURAMORPH contains no preservative or antioxidant. Each 10 mL ampul of DURAMORPH is intended for SINGLE USE ONLY. Discard any unused portion. Do not heat-sterilize. To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . For Product Inquiry call 1-877-845-0689.; PRINCIPAL DISPLAY PANEL NDC 0641- 6020 -01 10 mL Ampul Rx only Duramorph (Morphine Sulfate Injection, USP) CII 5 mg per 10 mL (0.5 mg/mL) Preservative Free For Intravenous, Epidural, or Intrathecal Use NDC 0641- 6020 -10 Rx only Duramorph (Morphine Sulfate Injection, USP) CII 5 mg per 10 mL (0.5 mg/mL) Preservative Free For Intravenous, Epidural, or Intrathecal Use 10 x 10 mL Ampuls amp sp; PRINCIPAL DISPLAY PANEL NDC 0641- 6019 -01 10 mL Ampul Rx only Duramorph (Morphine Sulfate Injection, USP) CII 10 mg per 10 mL (1 mg/mL) Preservative Free For Intravenous, Epidural, or Intrathecal Use NDC 0641- 6019 -10 Rx only Duramorph (Morphine Sulfate Injection, USP) CII 10 mg per 10 mL (1 mg/mL) Preservative Free For Intravenous, Epidural, or Intrathecal Use 10 x 10 mL Ampuls amp sp
- 16 HOW SUPPLIED/STORAGE AND HANDLING DURAMORPH (morphine sulfate injection, USP) is a preservative-free solution, available as 5 mg/10 mL (0.5 mg/mL) and 10 mg/10 mL (1 mg/mL), in amber ampuls, for single use administration. NDC 0641-6020-10 5 mg/10 mL (0.5 mg/mL) Single Use amber ampuls packaged in 10s NDC 0641-6019-10 10 mg/10 mL (1 mg/mL) Single Use amber ampuls packaged in 10s DURAMORPH is supplied in sealed ampuls. Accidental dermal exposure should be treated by the removal of any contaminated clothing and rinsing the affected area with water. PROTECT FROM LIGHT. Keep stored in carton until time of use. Store at 20˚‑25˚C (68˚‑77˚F), excursions permitted to 15˚‑30˚C (59˚‑86˚F) [See USP Controlled Room Temperature]. DO NOT FREEZE. DURAMORPH contains no preservative or antioxidant. Each 10 mL ampul of DURAMORPH is intended for SINGLE USE ONLY. Discard any unused portion. Do not heat-sterilize. To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . For Product Inquiry call 1-877-845-0689.
- PRINCIPAL DISPLAY PANEL NDC 0641- 6020 -01 10 mL Ampul Rx only Duramorph (Morphine Sulfate Injection, USP) CII 5 mg per 10 mL (0.5 mg/mL) Preservative Free For Intravenous, Epidural, or Intrathecal Use NDC 0641- 6020 -10 Rx only Duramorph (Morphine Sulfate Injection, USP) CII 5 mg per 10 mL (0.5 mg/mL) Preservative Free For Intravenous, Epidural, or Intrathecal Use 10 x 10 mL Ampuls amp sp
- PRINCIPAL DISPLAY PANEL NDC 0641- 6019 -01 10 mL Ampul Rx only Duramorph (Morphine Sulfate Injection, USP) CII 10 mg per 10 mL (1 mg/mL) Preservative Free For Intravenous, Epidural, or Intrathecal Use NDC 0641- 6019 -10 Rx only Duramorph (Morphine Sulfate Injection, USP) CII 10 mg per 10 mL (1 mg/mL) Preservative Free For Intravenous, Epidural, or Intrathecal Use 10 x 10 mL Ampuls amp sp
Overview
DURAMORPH (morphine sulfate injection) is an opioid agonist, available as a sterile, nonpyrogenic isobaric solution of morphine sulfate in strengths of 0.5 mg or 1 mg morphine sulfate per mL, free of antioxidants, preservatives or other potentially neurotoxic additives, and is intended for intravenous, epidural, or intrathecal administration. Morphine is the most important alkaloid of opium and is a phenanthrene derivative. It is available as the sulfate salt, chemically identified as 7,8-Didehydro-4,5-epoxy-17-methyl-(5α,6α)-morphinan-3,6-diol sulfate (2:1) (salt), pentahydrate, with the following structural formula: (C 17 H 19 NO 3 ) 2 • H 2 SO 4 • 5H 2 O Molecular Weight is 758.83 Morphine sulfate USP is an odorless, white crystalline powder with a bitter taste. It has a solubility of 1 in 21 parts of water and 1 in 1000 parts of alcohol, but is practically insoluble in chloroform or ether. The octanol:water partition coefficient of morphine is 1.42 at physiologic pH and the pKa is 7.9 for the tertiary nitrogen (the majority is ionized at pH 7.4). Each mL of DURAMORPH contains morphine sulfate, USP 0.5 mg (5 mg/10 mL) or 1 mg (10 mg/10 mL) and sodium chloride 9 mg in Water for Injection. The pH range is 2.5 – 6.5. Contains no preservative. Each 10 mL ampul of DURAMORPH is intended for SINGLE USE ONLY. structure
Indications & Usage
DURAMORPH is indicated for: the management of pain severe enough to require use of an opioid analgesic by intravenous administration, and for which alternative treatments are not expected to be adequate. the epidural or intrathecal management of pain without attendant loss of motor, sensory, or sympathetic function. Limitation of Use DURAMORPH is not for use in continuous microinfusion devices. 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 (5.2) ] , reserve opioid analgesiscs, including DURAMORPH for use in patients for whom alternative treatment options are ineffective, not tolerated or would be otherwise inadequate to provide sufficient management of pain. DURAMORPH is an opioid agonist, indicated for: the management of pain severe enough to require use of an opioid analgesic by intravenous administration and for which alternative treatments are not expected to be adequate. the epidural or intrathecal management of pain without attendant loss of motor, sensory, or sympathetic function. ( 1) Limitation of Use DURAMORPH is not for use in Continuous Microinfusion Devices. 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 DURAMORPH 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 , 5.2 )
Dosage & Administration
DURAMORPH should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. ( 2.1 ) Should be administered by or under the direction of a physician experienced in the techniques of epidural or intrathecal administration. ( 2.1 ) Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of DURAMORPH for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. ( 2.2 , 5 ) Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. ( 2.1 , 5.2 ) Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with DURAMORPH. Consider this risk when selecting an initial dose and when making dose adjustments. ( 2 , 5.3 ) Dosage for Intravenous Administration: 2 mg to 10 mg/70 kg of body weight. ( 2.3 ) Dosage for Epidural Administration: Initial injection of 5 mg in the lumbar region may provide satisfactory pain relief for up to 24 hours. If adequate pain relief is not achieved within one hour, carefully administer incremental doses of 1 to 2 mg at intervals sufficient to assess effectiveness. Administer no more than 10 mg/24 hr. ( 2.4 ) Dosage for Intrathecal Administration: A single injection of 0.2 to 1 mgmayprovidesatisfactorypainreliefforupto24hours.Repeated intrathecal injections of DURAMORPH are not recommended. ( 2.5 ) Periodically reassess patients receiving DURAMORPH to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and the development of addiction, abuse or misuse.( 2.6 ) Do not rapidly reduce or abruptly discontinue DURAMORPH abruptly in a physically-dependent patient. ( 2.6 , 5.16 ) 2.1 Important Dosage and Administration Instructions Do Not Use DURAMORPH in Continuous Microinfusion Devices. DURAMORPH should be administered by or under the direction of a physician experienced in the techniques of epidural or intrathecal administration and familiar with the patient management problems associated with epidural or intrathecal drug administration and the labeling, and should take place only in settings where adequate patient monitoring is possible. DURAMORPHshouldbeprescribedonlybyhealthcareprofessionalswhoareknowledgeable about the use of opioids and how to mitigate the associated risks. Because of the risk of delayed respiratory depression, patients should be observed in a fully equipped and staffed environment for at least 24 hours. Respiratory depression (both early and late onset)hasoccurredmorefrequentlyfollowingintrathecaladministrationthanepidural administration. Becauseepiduraladministrationhasbeenassociatedwithlesspotentialforimmediateorlate adverse effects than intrathecal administration, the epidural route should be used whenever possible. Forsafetyreasons,itisrecommendedthatadministrationofDURAMORPHbytheepiduralor intrathecal routes be limited to the lumbar area. Have resuscitative equipment and an opioid overdose reversal agent (e.g., naloxone, nalmefene) immediately available for the management of respiratory depression as well as complicationswhichmightresultfrominadvertentintrathecalorintravascularinjection(note: intrathecal dosage is usually 1/10 that of epidural dosage). Epidural Administration Verify proper placement of a needle or catheter in the epidural space before DURAMORPH is injected. Acceptable techniques for verifying proper placement include: a) aspiration to check for absence of blood or cerebrospinal fluid, or b) administration of 5 mL (3 mL in obstetric patients) of 1.5% PRESERVATIVE-FREE Lidocaine and Epinephrine (1:200,000) Injection and then observe the patient for lack of tachycardia (this indicates that vascular injection has not been made) and lack of sudden onset of segmental anesthesia (this indicates that intrathecal injection has not been made). Safety and Handling Instructions: DURAMORPH is supplied in sealed ampuls. Accidental dermal exposure should be treated by the removal of any contaminated clothing and rinsing the affected area with water. Inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if color is darker than pale yellow, if it is discolored in any other way, or if it contains a precipitate . DURAMORPH is intended for single use only. Protect from light, discard any unused portion. Do not heat-sterilize. 2.2 Initial Dosage The starting dose of DURAMORPH must be individualized. Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions (5) ] . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of DURAMORPH for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.2) ]. Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with DURAMORPH. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions (5) ] . 2.3 Dosage for Intravenous Administration Adult Dosage : The initial dose of morphine should be 2 mg to 10 mg/70 kg of body weight, and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of DURAMORPH 2.4 Dosage for Epidural Administration Adult Dosage: Initial injection of 5 mg in the lumbar region may provide satisfactory pain relief for up to 24 hours. If adequate pain relief is not achieved within one hour, careful administration of incremental doses of 1 to 2 mg at intervals sufficient to assess effectiveness may be given. Do not administer more than 10 mg per 24 hours. 2.5 Dosage for Intrathecal Administration Adult Dosage: Intrathecal dosage is usually 1/10 that of epidural dosage. A single injection of 0.2 to 1 mg may provide satisfactory pain relief for up to 24 hours. (Caution: this is only 0.4 to 2 mL of the 5 mg/10 mL ampul or 0.2 to 1 mL of the 10 mg/10 mL ampul of DURAMORPH). Do not inject intrathecally more than 2 mL of the 5 mg/10 mL ampul or 1 mL of the 10 mg/10 mL ampul. Repeated intrathecal injections of DURAMORPH are not recommended. If pain recurs, consider alternative routes of administration A constant intravenous infusion of naloxone, 0.6 mg/hr, for 24 hours after intrathecal injection may be used to reduce the incidence of potential side effects. 2.6 Safe Reduction and Discontinuation of DURAMORPH When a patient who has been treated with a regimen of opioid analgesics including DURAMORPH regularly and may be physically dependent or no longer requires therapy with DURAMORPH, taper the dose gradually while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. Do not rapidly reduce or abruptly discontinue DURAMORPH in patients who may be physically dependant on opioids. [see Warnings and Precautions (5.16 ), Drug Abuse and Dependence (9.3 )] .
Warnings & Precautions
Risk of Tolerance and Myoclonic Activity: Monitor patients for unusual acceleration of neuraxial morphine, which may cause myoclonic-like spasm of lower extremities. Detoxification maybe required. ( 5.6 ) Chest Wall Rigidity: Rapid intravenous administration may result in chest wall rigidity. ( 5.7 ) Opioid Induced Hyperalgesia and Allodynia : Opioid Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation (safety switching the patient to a different opioid moiety). ( 5.8 ) Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation and titration. ( 5.9 ) Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.11 ) Severe Hypotension: Monitor during dosage initiation and titration. AvoiduseofDURAMORPHinpatientswithcirculatoryshock.( 5.12 ) Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of DURAMORPH in patients with impaired consciousness or coma. ( 5.13 ) 5.1 Risks with Neuraxial Administration Control of pain by neuraxial opioid delivery is always accompanied by considerable risk to the patient and requires a high level of skill to be successfully accomplished. The task of treating these patients must be undertaken by experienced clinical teams, well-versed in patient selection, evolving technology and emerging standards of care. In the case of epidural or intrathecal administration, DURAMORPH should be administered by or under the direction of a physician experienced in the techniques and familiar with the patient management problems associated with epidural or intrathecal drug administration. The physician should be familiar with patient conditions (such as infection at the injection site, bleeding diathesis, anticoagulant therapy, etc.) which call infection at the injection site, bleeding diathesis, anticoagulant therapy, etc.) which call for special evaluation of the benefit versus risk potential. Because epidural administration has been associated with less potential for immediate or late adverse effects than intrathecal administration, the epidural route should be used whenever possible. For safety reasons, it is recommended that administration of DURAMORPH by the epidural or intrathecal routes be limited to the lumbar area. Thoracic epidural administration has been shown to dramatically increase the incidence of early and late respiratory depression even with doses of 1 to 2 mg. Because of the risk of severe adverse effects when the epidural or intrathecal route of administration is employed, patients must be observed in a fully equipped and staffed environment for at least 24 hours after the initial dose. The facility must be equipped to resuscitate patients with severe opiate overdosage, and the personnel must be familiar with the use and limitations of specific opioid overdose reversal agents in (naloxone, naltrexone) in such cases. Parenteral administration of narcotics in patients receiving epidural or intrathecal morphine may result in overdosage. 5.2 Addiction, Abuse, and Misuse DURAMORPH contains morphine, a Schedule II controlled substance. As an opioid, DURAMORPH exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9) ]. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed DURAMORPH. Addiction can occur at recommended dosages and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see Adverse Reactions (6.2 ) ]. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing DURAMORPH, and monitor all patients receiving DURAMORPH 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 abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as DURAMORPH but use in such patients necessitates intensive counseling about the risks and proper use of DURAMORPH along with intensive monitoring for signs of addiction, abuse, and misuse. Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing DURAMORPH. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity. 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. 5.3 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 overdose reversal agents (e.g., naloxone, nalmefene), depending on the patient’s clinical status [see Overdosage (10) ]. Carbon dioxide (CO) 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 DURAMORPH, the risk is greatest during the initiation of therapy or following a dosage increase. This respiratory depression and/or respiratory arrest may be severe and could require intervention. Because of delay in maximum CNS effect with intravenously administered drug (30 min), rapid administration may result in overdosing. Single-dose neuraxial administration may result in acute or delayed respiratory depression for periods at least as long as 24 hours. Severe respiratory depression up to 24 hours following epidural or intrathecal administration has been reported. Intrathecal use has been associated with a higher incidence of respiratory depression than epidural use. Thoracic administration has been shown to dramatically increase the incidence of early and late respiratory depression even at doses of 1 to 2 mg. Because of the risk of severe adverse effects when the epidural or intrathecal route of administration is employed, patients must be observed in a fully equipped and staffed environment for at least 24 hours after the initial dose. The facility must be equipped to resuscitate patients with severe opiate overdosage, and the personnel must be familiar with the use and limitations of specific narcotic antagonists (naloxone, naltrexone) in such cases. To reduce the risk of respiratory depression, proper dosing and titration of DURAMORPH are essential [see Dosage and Administration (2) ] . Overestimating the DURAMORPH dosage can result in a fatal overdose with the first dose. Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.6) ] 5.4 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from concomitant use of DURAMORPH with benzodiazepines and/or other CNS depressants, including alcohol (e.g., nonbenzodiazepine sedatives/ hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Use of neuroleptics in conjunction with neuraxial morphine may increase the risk of respiratory depression. 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. Monitor patients closely for signs and symptoms of respiratory depression and sedation. 5.5 Neonatal Opioid Withdrawal Syndrome Prolonged use of DURAMORPH 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 management by neonatology experts will be available at delivery [see Use in Specific Populations (8.1) ]. 5.6 Risk of Tolerance and Myoclonic Activity Patients sometimes manifest unusual acceleration of neuraxial morphine requirements, which may cause concern regarding systemic absorption and the hazards of large doses; these patients may benefit from hospitalization and detoxification. Two cases of myoclonic-like spasm of the lower extremities have been reported in patients receiving more than 20 mg/day of intrathecal morphine. After detoxification, it might be possible to resume treatment at lower doses, and some patients have been successfully changed from continuous epidural morphine to continuous intrathecal morphine. Repeat detoxification may be indicated at a later date. The upper daily dosage limit for each patient during continuing treatment must be individualized. 5.7 Chest Wall Rigidity Rapid intravenous administration may result in chest wall rigidity. 5.8 Opioid-Induced Hyperalgesia and Allodynia Opioid Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [ see Dependence (9.3) ]. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily nonpainful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior. Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see Dosage and Administration (2.6) , Warnings and Precautions (5.16) ] . 5.9 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of DURAMORPH 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: 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 doses of DURAMORPH [see Warnings and Precautions (5.3) ] . 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 (5.3) ] . Monitor such patients closely, particularly when initiating and titrating DURAMORPH and when DURAMORPH is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.3 , 5.4 ), Drug Interactions (7) ] . Alternatively, consider the use of non-opioid analgesics in these patients. 5.10 Interaction with Monoamine Oxidase Inhibitors Monoamine oxidase inhibitors (MAOIs) may potentiate the effects of morphine, including respiratory depression, coma, and confusion. DURAMORPH should not be used in patients taking MAOIs or within 14 days of stopping such treatment [see Drug Interactions (7) ] . 5.11 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 nonspecific 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. 5.12 Severe Hypotension DURAMORPH may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or 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 DURAMORPH. In patients with circulatory shock, DURAMORPH may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of DURAMORPH in patients with circulatory shock. 5.13 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), DURAMORPH 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 DURAMORPH. DURAMORPH should be used with extreme caution in patients with head injury or increased intracranial pressure. Pupillary changes (miosis) from morphine may obscure the existence, extent and course of intracranial pathology. High doses of neuraxial morphine may produce myoclonic events [see Warnings and Precautions (5.6) ] . Clinicians should maintain a high index of suspicion for adverse drug reactions when evaluating altered mental status or movement abnormalities in patients receiving this modality of treatment. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of DURAMORPH in patients with impaired consciousness or coma. 5.14 Risks of Gastrointestinal Complications DURAMORPH is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The morphine in DURAMORPH 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. As significant morphine is released into the systemic circulation from neuraxial administration, the ensuing smooth muscle hypertonicity may result in biliary colic. Cases of opioid-induced esophageal dysfunction (OIED) have been reported in patients taking opioids. The risk of OIED may increase as the dose and/or duration of opioids increases. Regularly evaluate patients for signs and symptoms of OIED (e.g., dysphagia, regurgitation, non-cardiac chest pain) and, if necessary, adjust opioid therapy as clinically appropriate [see Clinical Pharmacology (12.2) ] . 5.15 Risk of Seizures The morphine in DURAMORPH may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical setting associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during DURAMORPH therapy. Excitation of the central nervous system, resulting in convulsions, may accompany high doses of morphine given intravenously. 5.16 Withdrawal Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including DURAMORPH. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see Drug Interactions (7) ] . When discontinuing DURAMORPH, gradually taper the dosage [see Dosage and Administration (2.6) ] . Do not rapidly reduce or abruptly discontinue DURAMORPH [see Drug Abuse and Dependence (9.3) ] . 5.17 Risks of Use in Patients with Urinary System Disorders Urinary retention, which may persist 10 to 20 hours following single epidural or intrathecal administration, is frequently associated with neuraxial opioid administration and must be anticipated, more frequently in male patients than female patients. Urinary retention may also occur during the first several days of hospitalization for the initiation of continuous intrathecal or epidural morphine therapy. Early recognition of difficulty in urination and prompt intervention in cases of urinary retention is indicated. Patients who develop urinary retention have responded to cholinomimetic treatment and/or judicious use of catheters. 5.18 Risks of Use in Ambulatory Patients Patients with reduced circulating blood volume, impaired myocardial function or on sympatholytic drugs should be monitored for the possible occurrence of orthostatic hypotension, a frequent complication in single-dose neuraxial morphine analgesia.
Boxed Warning
SERIOUS AND LIFE-THREATENING RISKS FROM USE OF DURAMORPH Risks with Neuraxial Administration Single-dose neuraxial administration may result in acute or delayed respiratory depression up to 24 hours. Because of the risk of severe adverse reactions when DURAMORPH is administered by the epidural or intrathecal route of administration, patients must be observed in a fully equipped and staffed environment for at least 24 hours after the initial dose [see Warnings and Precautions (5.1) ]. Addiction, Abuse, and Misuse Because the use of DURAMORPH 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 and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.2) ]. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of DURAMORPH, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of DURAMORPH are essential [see Warnings and Precautions (5.3) ]. Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of DURAMORPH and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see Warnings and Precautions (5.4) , Drug Interactions (7) ]. Neonatal Opioid Withdrawal Syndrome (NOWS) Advise pregnant women using opioids for an extended period of time of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see Warnings and Precautions (5.5) ]. WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF DURAMORPH See full prescribing information for complete boxed warning. Single-dose neuraxial administration may result in acute or delayed respiratory depression up to 24 hours. Because of the risk of severe adverse reactions when DURAMORPH is administered by the epidural or intrathecal route of administration, patients must be observed in a fully equippedandstaffedenvironmentforatleast24hoursafter the initial dose. ( 5.1 ) DURAMORPH exposes users to risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess patient’s risk before prescribing and reassess regularly for these behaviors and conditions. ( 5.2 ) Serious, life-threatening, or fatal respiratory depression may occur with use of DURAMORPH, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of DURAMORPH are essential. ( 5.3 ) 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 for use in patients for whom alternative treatment options are inadequate. ( 5.4 , 7 ) Advise pregnant women using opioids for an extended period of time of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery ( 5.5 )
Contraindications
DURAMORPH is contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions (5.3) ] Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.9) ] Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Warnings and Precautions (5.10) , Drug Interactions (7) ] Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.14) ] Hypersensitivity to morphine (e.g., anaphylaxis) [see Adverse Reactions (6) ] Neuraxial administration of DURAMORPH is contraindicated in patients with: Infection at the injection microinfusion site [see Warnings and Precautions (5.1) ] Concomitant anticoagulant therapy [see Warnings and Precautions (5.1) ] Uncontrolled bleeding diathesis [see Warnings and Precautions (5.1) ] The presence of any other concomitant therapy or medical condition which would render epidural or intrathecal administration of medication especially hazardous. DURAMORPH is contraindicated in patients with: Significant respiratory depression (4) Acute or severe bronchial asthma in an unmonitored setting in absence of resuscitative equipment (4) Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days (4) Known or suspected gastrointestinal obstruction, including paralytic ileus (4) Hypersensitivity or intolerance to morphine (4) Neuraxial administration of DURAMORPH is contraindicated in patients with: Infection at the injection microinfusion site (4) Concomitant anticoagulant therapy (4) Uncontrolled bleeding diathesis (4) The presence of any other concomitant therapy or medical condition which would render epidural or intrathecal administration of medication especially hazardous. (4)
Adverse Reactions
The following serious adverse reactions are described, or described in greater detail, in other sections: Addiction, Abuse, and Misuse [see Warnings and Precautions (5.2) ] Life-Threatening Respiratory Depression [see Warnings and Precautions (5.3) ] Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.4)] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.5) ] Myoclonic Activity [see Warnings and Precautions (5.6) ] Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.8) ] Adrenal Insufficiency [see Warnings and Precautions (5.11) ] Severe Hypotension [see Warnings and Precautions (5.12)] Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.14) ] Seizures [see Warnings and Precautions (5.15) ] Withdrawal [see Warnings and Precautions (5.16) ] Urinary Retention [see Warnings and Precautions (5.17) ] Orthostatic Hypotension [see Warnings and Precautions (5.18)] The following adverse reactions associated with the use of morphine were identified in clinical studies or postmarketing reports. Because some of these reactions were 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. The most serious adverse reactions encountered during administration of DURAMORPH were respiratory depression and/or respiratory arrest. Cardiovascular System: While low doses of intravenously administered morphine have little effect on cardiovascular stability, high doses are excitatory, resulting from sympathetic hyperactivity and increase in circulating catecholamines. Central Nervous System: myoclonus, seizures, dysphoric reactions, toxic psychosis, dizziness, euphoria, anxiety, confusion, headache. Lumbar puncture-type headache is encountered in a significant minority of cases for several days following intrathecal catheter implantation and generally responds to bed rest and/or other conventional therapy. Gastrointestinal System: Nausea, vomiting, constipation Skin: Generalized pruritus, urticaria, wheals, and/or local tissue irritation. Single-dose epidural or intrathecal administration is accompanied by a high incidence of dose-related generalized pruritus. Urinary System: Urinary retention, oliguria. Peripheral edema: There are several reports of peripheral edema Other: Other adverse reactions reported following morphine therapy include depression of cough reflex, interference with thermal regulation, peripheral edema. Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis: Anaphylaxis has been reported with ingredients contained in DURAMORPH. 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 (5.8) ]. 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 (5.14) ]. 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 disorderbasedonDiagnosticandStatisticalManualofMentalDisorders,FifthEdition(DSM-5) criteria, and approximately9%and22%ofparticipantsacrossthetwocohortsnewlymetcriteriafor 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 opioidinvolved 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. Most serious adverse reactions were respiratory depression and/or respiratory arrest. (6) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
Drug Interactions
Table 1 includes clinically significant drug interactions with DURAMORPH. Table 1 Clinically Significant Drug Interactions with DURAMORPH Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. The depressant effects of morphine are potentiated by the presence of other CNS depressants. Use of neuroleptics in conjunction with neuraxial morphine may increase the risk of respiratory depression [see Warnings and Precautions (5.4) ] . Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4) ] . Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, psychotropic drugs, antihistamines, neuroleptics, gabapentinoids (gabapentin or pregabalin), other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention : If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue DURAMORPH if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.10) ] . Do not use DURAMORPH in patients taking MAOIs or within 14 days of stopping such treatment. Intervention: If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of other opioids (such as oxycodone, hydromorphone, oxymorphone, hydrocodone, or buprenorphine) to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: Clinical Impact: May reduce the analgesic effect of DURAMORPH and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: Butorphanol, nalbuphine, pentazocine, buprenorphine. Muscle Relaxants Clinical Impact: Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of DURAMORPH and/or the muscle relaxant as necessary. Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralyticileus. Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when DURAMORPH is used concomitantly with anticholinergic drugs. Oral P2Y 12 Inhibitors Clinical Impact: The co-administration of oral P2Y 12 inhibitors and intravenous morphine sulfate can decrease the absorption and peak concentration of oral P2Y 12 inhibitors and delay the onset of the antiplatelet effect. Intervention: Consider the use of a parenteral antiplatelet agent in the setting of acute coronary syndrome requiring co-administration of intravenous morphine sulfate. Examples: clopidogrel, prasugrel, ticagrelor Serotonergic Drugs : Concomitant use may result in serotonin syndrome. Discontinue DURAMORPH if serotonin syndrome is suspected. (7) Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics : Avoid use with DURAMORPH because they may reduce the analgesic effect of DURAMORPH or precipitate withdrawal symptoms. (7)
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