Morphin: Fachinformation – Dosierung, Gegenanzeigen, Wechselwirkungen, Nebenwirkungen

Für Fachkreise

Anwendungsgebiete

Morphine Sulfate Tablets sind angezeigt zur Behandlung von:

•Erwachsenen und Kindern und Jugendlichen mit einem Körpergewicht von mindestens 50 kg mit akuten Schmerzen, die so stark sind, dass ein Opioid-Analgetikum erforderlich ist, und für die alternative Behandlungen unzureichend sind.
•Erwachsenen mit chronischen Schmerzen, die so stark sind, dass ein Opioid-Analgetikum erforderlich ist, und für die alternative Behandlungen unzureichend sind.

Anwendungsbeschränkungen:

Aufgrund der Risiken von Abhängigkeit, Missbrauch, Fehlgebrauch, Überdosierung und Tod, die bei jeder Dosierung und Behandlungsdauer auftreten können und über den gesamten Therapieverlauf bestehen bleiben [siehe Warnhinweise und Vorsichtsmaßnahmen (5.1)], sind Opioid-Analgetika, einschließlich Morphine Sulfate Tablets, Patienten vorzubehalten, bei denen alternative Behandlungsoptionen unwirksam sind, nicht vertragen werden oder anderweitig für eine ausreichende Schmerzbehandlung unzureichend wären.

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Morphine Sulfate Tablets are indicated for the management of:

•adult and pediatric patients weighing at least 50 kg and above with acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.
•adults with chronic pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

Limitations of Use:

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

Dosierung und Art der Anwendung

2.1 Wichtige Hinweise zur Dosierung und Anwendung

Morphine Sulfate Tablets sollten nur von Angehörigen der Gesundheitsberufe verordnet werden, die mit der Anwendung von Opioiden und der Minderung der damit verbundenen Risiken vertraut sind.

Die niedrigste wirksame Dosis über den kürzesten mit den individuellen Behandlungszielen des Patienten vereinbaren Zeitraum anwenden [siehe Warnhinweise und Vorsichtsmaßnahmen (5)]. Da das Risiko einer Überdosierung mit steigender Opioiddosis zunimmt, ist die Titration auf höhere Dosen von Morphine Sulfate Tablets Patienten vorzubehalten, bei denen niedrigere Dosen nicht ausreichend wirksam sind und bei denen der erwartete Nutzen einer höheren Opioiddosis die erheblichen Risiken eindeutig überwiegt.

Viele akute Schmerzzustände (z. B. Schmerzen nach einer Reihe chirurgischer Eingriffe oder bei akuten muskuloskelettalen Verletzungen) erfordern ein Opioid-Analgetikum für nicht mehr als einige Tage. Für einige akute Schmerzzustände sind klinische Leitlinien zur Verordnung von Opioiden verfügbar.

Die zur angemessenen Schmerzbehandlung erforderliche Dosis und Dauer eines Opioid-Analgetikums variieren sowohl in Abhängigkeit von der Schmerzursache als auch von individuellen Patientenfaktoren. Das Dosierungsschema für jeden Patienten individuell festlegen und dabei die zugrunde liegende Ursache und den Schweregrad der Schmerzen, die vorherige analgetische Behandlung und das Ansprechen darauf sowie Risikofaktoren für Abhängigkeit, Missbrauch und Fehlgebrauch berücksichtigen [siehe Warnhinweise und Vorsichtsmaßnahmen (5.1)].

Eine Atemdepression kann jederzeit während einer Opioidtherapie auftreten, insbesondere zu Beginn der Behandlung mit Morphine Sulfate Tablets und nach Dosiserhöhungen. Dieses Risiko bei der Wahl der Anfangsdosis und bei Dosisanpassungen berücksichtigen [siehe Warnhinweise und Vorsichtsmaßnahmen (5)].

2.2 Zugang des Patienten zu einem Antidot bei Opioidüberdosierung zur Notfallbehandlung einer Opioidüberdosierung

Patienten und Betreuungspersonen über Antidote bei Opioidüberdosierung (z. B. Naloxon, Nalmefen) informieren. Die Bedeutung des Zugangs zu einem Antidot bei Opioidüberdosierung besprechen, insbesondere wenn der Patient Risikofaktoren für eine Überdosierung aufweist (z. B. gleichzeitige Anwendung ZNS-dämpfender Mittel, Opioidgebrauchsstörung in der Vorgeschichte oder frühere Opioidüberdosierung) oder wenn Haushaltsmitglieder (einschließlich Kinder) oder andere enge Kontaktpersonen dem Risiko einer versehentlichen Einnahme oder einer Opioidüberdosierung ausgesetzt sind. Das Vorliegen von Risikofaktoren für eine Überdosierung sollte bei keinem Patienten die Schmerzbehandlung verhindern [siehe Warnhinweise und Vorsichtsmaßnahmen (5.1, 5.2, 5.3)].

Die Möglichkeiten zur Beschaffung eines Antidots bei Opioidüberdosierung besprechen (z. B. auf Verschreibung, rezeptfrei oder im Rahmen eines gemeindebasierten Programms) [siehe Warnhinweise und Vorsichtsmaßnahmen (5.2)].

Zwischen den Antidoten bei Opioidüberdosierung bestehen wichtige Unterschiede, etwa hinsichtlich Art der Anwendung, Wirkstärke, zugelassener Altersgruppe und Pharmakokinetik. Vor der Empfehlung oder Verordnung eines solchen Mittels mit diesen Unterschieden, wie sie in der zugelassenen Produktinformation dieser Arzneimittel beschrieben sind, vertraut sein.

2.3 Anfangsdosis

Anwendung von Morphine Sulfate Tablets als erstes Opioid-Analgetikum (opioidnaive oder nicht opioidtolerante Patienten):

Erwachsene: Die empfohlene Dosis zu Behandlungsbeginn bei Erwachsenen beträgt 15 mg bis 30 mg alle 4 Stunden nach Bedarf gegen Schmerzen, und zwar in der niedrigsten Dosis, die zur Erzielung einer ausreichenden Analgesie erforderlich ist. Die Dosis auf Grundlage des individuellen Ansprechens des Patienten auf die Anfangsdosis von Morphine Sulfate Tablets titrieren.

Kinder und Jugendliche mit einem Körpergewicht von mindestens 50 kg: Die empfohlene Dosis zu Behandlungsbeginn bei Kindern und Jugendlichen mit einem Körpergewicht von mindestens 50 kg, die Tabletten schlucken können, beträgt 15 mg alle 4 Stunden nach Bedarf gegen Schmerzen, und zwar die niedrigste Dosis, die zur Erzielung einer ausreichenden Analgesie erforderlich ist. Die Dosis auf Grundlage des individuellen Ansprechens des Patienten auf die Anfangsdosis von Morphine Sulfate Tablets titrieren. Als Anfangsdosis 30 mg nicht überschreiten.

Morphine Sulfate Tablets werden zur Anwendung bei Kindern und Jugendlichen mit einem Körpergewicht unter 50 kg nicht empfohlen, da die empfohlene Dosierung mit den verfügbaren Tablettenstärken nicht erreicht werden kann. Bei Patienten, die keine Tabletten schlucken können oder weniger als 50 kg wiegen, die Anwendung eines anderen Morphinsulfat-Präparats in Betracht ziehen.

Umstellung von parenteralem Morphin auf Morphine Sulfate Tablets

Bei der Umstellung von parenteralem Morphin auf Morphine Sulfate Tablets können 3 bis 6 mg orales Morphinsulfat erforderlich sein, um eine Schmerzlinderung zu erzielen, die 1 mg parenteralem Morphin entspricht.

Umstellung von anderen Opioiden auf Morphine Sulfate Tablets

Die Wirkstärke von Opioid-Arzneimitteln und Opioid-Formulierungen variiert zwischen Patienten. Daher wird bei der Festlegung der täglichen Gesamtdosis von Morphine Sulfate Tablets ein vorsichtiges Vorgehen empfohlen. Es ist sicherer, die 24-Stunden-Dosis von Morphine Sulfate Tablets eines Patienten zu unterschätzen, als die 24-Stunden-Dosis von Morphine Sulfate Tablets zu überschätzen und eine Nebenwirkung infolge einer Überdosierung behandeln zu müssen. Die Behandlung mit Morphine Sulfate Tablets 15 mg bis 30 mg alle 4 Stunden beginnen.

Umstellung von Morphine Sulfate Tablets auf retardiertes Morphin

Bei gegebener Dosis steht aus Morphine Sulfate Tablets und retardierten Morphin-Formulierungen dieselbe Gesamtmenge an Morphinsulfat zur Verfügung. Die verlängerte Freisetzungsdauer von Morphinsulfat aus retardierten Formulierungen führt im Vergleich zu kürzer wirksamen Morphinsulfat-Präparaten zu niedrigeren maximalen und höheren minimalen Plasmakonzentrationen von Morphinsulfat. Eine Umstellung von Morphine Sulfate Tablets auf dieselbe tägliche Gesamtdosis einer retardierten Formulierung könnte bei Spitzenserumspiegeln zu übermäßiger Sedierung führen. Daher kann eine Umstellung auf retardiertes Morphin zu einem erhöhten Risiko übermäßiger Sedierung und einer Atemdepression führen.

2.4 Titration und Erhaltungstherapie

Morphine Sulfate Tablets individuell auf eine Dosis titrieren, die eine ausreichende Analgesie bewirkt und Nebenwirkungen minimiert. Patienten, die Morphine Sulfate Tablets erhalten, kontinuierlich neu beurteilen, um die Aufrechterhaltung der Schmerzkontrolle, Anzeichen und Symptome eines Opioidentzugs und andere Nebenwirkungen zu bewerten sowie erneut auf die Entwicklung von Abhängigkeit, Missbrauch oder Fehlgebrauch zu prüfen [siehe Warnhinweise und Vorsichtsmaßnahmen (5.1, 5.14)]. Während Phasen eines sich ändernden Analgetikabedarfs, einschließlich der initialen Titration, ist eine häufige Kommunikation zwischen dem verordnenden Arzt, anderen Mitgliedern des Behandlungsteams, dem Patienten und der Betreuungsperson/Familie wichtig.

Nehmen die Schmerzen nach Stabilisierung der Dosis zu, vor einer Erhöhung der Dosis von Morphine Sulfate Tablets versuchen, die Ursache der verstärkten Schmerzen zu ermitteln. Werden nach einer Dosiserhöhung inakzeptable opioidbedingte Nebenwirkungen beobachtet (einschließlich einer Zunahme der Schmerzen nach Dosiserhöhung), eine Dosisreduktion in Betracht ziehen [siehe Warnhinweise und Vorsichtsmaßnahmen (5)]. Die Dosis so anpassen, dass ein angemessenes Gleichgewicht zwischen Schmerzbehandlung und opioidbedingten Nebenwirkungen erreicht wird.

2.5 Sichere Dosisreduktion oder sicheres Absetzen von Morphine Sulfate Tablets

Morphine Sulfate Tablets bei Patienten, die möglicherweise körperlich von Opioiden abhängig sind, nicht rasch reduzieren oder abrupt absetzen. Eine rasche Reduktion oder ein abruptes Absetzen von Opioid-Analgetika bei körperlich opioidabhängigen Patienten hat zu schweren Entzugssymptomen, unkontrollierten Schmerzen und Suizid geführt. Eine rasche Reduktion oder ein abruptes Absetzen wurde außerdem mit Versuchen in Verbindung gebracht, andere Bezugsquellen für Opioid-Analgetika zu finden, was mit einer Arzneimittelsuche zu Missbrauchszwecken verwechselt werden kann. Patienten können außerdem versuchen, ihre Schmerzen oder Entzugssymptome mit illegalen Opioiden wie Heroin und anderen Substanzen zu behandeln.

Wurde entschieden, bei einem opioidabhängigen Patienten, der Morphine Sulfate Tablets einnimmt, die Dosis zu verringern oder die Therapie abzusetzen, sind verschiedene Faktoren zu berücksichtigen, darunter die tägliche Gesamtdosis der Opioide (einschließlich Morphine Sulfate Tablets), die der Patient eingenommen hat, die Behandlungsdauer, die Art der behandelten Schmerzen sowie die körperlichen und psychischen Merkmale des Patienten. Es ist wichtig, die fortlaufende Versorgung des Patienten sicherzustellen und einen geeigneten Ausschleichplan sowie einen Nachsorgeplan zu vereinbaren, damit die Ziele und Erwartungen von Patient und Behandler klar und realistisch sind. Werden Opioid-Analgetika wegen einer vermuteten Substanzgebrauchsstörung abgesetzt, den Patienten untersuchen und behandeln oder zur Untersuchung und Behandlung der Substanzgebrauchsstörung überweisen. Die Behandlung sollte evidenzbasierte Ansätze umfassen, wie eine medikamentengestützte Behandlung der Opioidgebrauchsstörung. Komplexe Patienten mit komorbiden Schmerzen und Substanzgebrauchsstörungen können von einer Überweisung an einen Spezialisten profitieren.

Es gibt keine Standard-Ausschleichpläne für Opioide, die für alle Patienten geeignet sind. Gute klinische Praxis erfordert einen patientenspezifischen Plan zur schrittweisen Reduktion der Opioiddosis. Bei Patienten unter Morphine Sulfate Tablets, die körperlich opioidabhängig sind, das Ausschleichen mit einem ausreichend kleinen Reduktionsschritt beginnen (z. B. nicht mehr als 10 % bis 25 % der täglichen Gesamtdosis), um Entzugssymptome zu vermeiden, und die Dosisreduktion in Abständen von jeweils 2 bis 4 Wochen fortsetzen. Patienten, die Opioide über kürzere Zeiträume eingenommen haben, vertragen möglicherweise ein schnelleres Ausschleichen.

Um ein erfolgreiches Ausschleichen zu erreichen, kann es erforderlich sein, dem Patienten niedrigere Dosisstärken zur Verfügung zu stellen. Den Patienten häufig neu beurteilen, um Schmerzen und gegebenenfalls auftretende Entzugssymptome zu behandeln. Häufige Entzugssymptome sind Unruhe, Tränenfluss, Rhinorrhö, Gähnen, Schwitzen, Schüttelfrost, Myalgie und Mydriasis. Es können sich auch andere Anzeichen und Symptome entwickeln, darunter Reizbarkeit, Angst, Rückenschmerzen, Gelenkschmerzen, Schwäche, Bauchkrämpfe, Schlaflosigkeit, Übelkeit, Anorexie, Erbrechen, Durchfall oder ein Anstieg von Blutdruck, Atemfrequenz oder Herzfrequenz. Treten Entzugssymptome auf, kann es erforderlich sein, das Ausschleichen für eine gewisse Zeit zu unterbrechen oder die Dosis des Opioid-Analgetikums auf die vorherige Dosis zu erhöhen und anschließend langsamer auszuschleichen. Darüber hinaus die Patienten auf Stimmungsänderungen, das Auftreten suizidaler Gedanken oder den Gebrauch anderer Substanzen untersuchen.

Bei der Behandlung von Patienten, die Opioid-Analgetika einnehmen, insbesondere solchen, die über einen längeren Zeitraum und/oder mit hohen Dosen wegen chronischer Schmerzen behandelt wurden, sicherstellen, dass vor Beginn des Ausschleichens eines Opioid-Analgetikums ein multimodaler Ansatz der Schmerzbehandlung, einschließlich psychischer Unterstützung (falls erforderlich), etabliert ist. Ein multimodaler Ansatz der Schmerzbehandlung kann die Behandlung chronischer Schmerzen optimieren und zum erfolgreichen Ausschleichen des Opioid-Analgetikums beitragen [siehe Warnhinweise und Vorsichtsmaßnahmen (5.14), Arzneimittelmissbrauch und Abhängigkeit (9.3)].

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2.1 Important Dosage and Administration Instructions

Morphine Sulfate Tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks.

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 Morphine Sulfate Tablets 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 (5.1)].

Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Morphine Sulfate Tablets. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions (5)].

2.2 Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose

Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient [see Warnings and Precautions ( 5.1 , 5.2 , 5.3 )].

Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program) [see Warnings and Precautions ( 5.2 )].

There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent.

2.3 Initial Dosage

Use of Morphine Sulfate Tablets as the First Opioid Analgesic (Opioid-naïve or Opioid-non-tolerant Patients):

Adults: The recommended dosage to initiate treatment in adults is 15 mg to 30 mg every 4 hours as needed for pain, 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 Morphine Sulfate Tablets.

Pediatric Patients Weighing at Least 50 kg: The recommended dosage to initiate treatment in pediatric patients weighing at least 50 kg and who are able to swallow oral tablets is 15 mg every 4 hours as needed for pain, and the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of Morphine Sulfate Tablets. Do not exceed 30 mg as an initial dose.

Morphine Sulfate Tablets are not recommended for use in pediatric patients who weigh less than 50 kg as the recommended dosage cannot be achieved with available tablet strengths. Consider use of another morphine sulfate product in patients who cannot swallow oral tablets or who weigh less than 50 kg.

Conversion from Parenteral Morphine to Morphine Sulfate Tablets

For conversion from parenteral morphine to Morphine Sulfate Tablets, anywhere from 3 to 6 mg of oral morphine sulfate may be required to provide pain relief equivalent to 1 mg of parenteral morphine.

Conversion from Other Opioids to Morphine Sulfate Tablets

There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of Morphine Sulfate Tablets. It is safer to underestimate a patient’s 24-hour Morphine Sulfate Tablets dosage than to overestimate the 24-hour Morphine Sulfate Tablets dosage and manage an adverse reaction due to overdose. Initiate dosing using Morphine Sulfate Tablets 15 mg to 30 mg every 4 hours.

Conversion from Morphine Sulfate Tablets to Extended-Release Morphine

For a given dose, the same total amount of morphine sulfate is available from Morphine Sulfate Tablets, and extended-release morphine formulations. The extended duration of release of morphine sulfate from extended-release formulations results in reduced maximum and increased minimum plasma morphine sulfate concentrations than with shorter acting morphine sulfate products. Conversion from Morphine Sulfate Tablets to the same total daily dose of an extended-release formulation could lead to excessive sedation at peak serum levels. Therefore, conversion to extended-release morphine may lead to increased risk of excessive sedation and respiratory depression.

2.4 Titration and Maintenance of Therapy

Individually titrate Morphine Sulfate Tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Morphine Sulfate Tablets to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions as well as to reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1, 5.14)]. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration.

If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the Morphine Sulfate Tablets dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase), consider reducing the dosage [see Warnings and Precautions (5)]. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

2.5 Safe Reduction or Discontinuation of Morphine Sulfate Tablets

Do not rapidly reduce or abruptly discontinue Morphine Sulfate Tablets in patients who may be physically dependent on opioids. Rapid reduction or abrupt discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid reduction or abrupt discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.

When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking Morphine Sulfate Tablets, there are a variety of factors that should be considered, including the total daily dose of opioids (including Morphine Sulfate Tablets) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication-assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist.

There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on Morphine Sulfate Tablets who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.

It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.

When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions (5.14), Drug Abuse and Dependence (9.3)].

Darreichungsformen und Stärken

•15 mg: Each tablet contains 15 mg morphine sulfate, USP (equivalent to 11.25 mg morphine) and is a white, biconvex tablet scored on one side and product identification "54" over "733" debossed on the other side.
•30 mg: Each tablet contains 30 mg morphine sulfate, USP (equivalent to 22.5 mg morphine) and is a white, biconvex tablet scored on one side and product identification "54" over "262" debossed on the other side.

Gegenanzeigen

Morphine Sulfate Tablets sind kontraindiziert bei Patienten mit:

•Signifikanter Atemdepression [siehe Warnhinweise und Vorsichtsmaßnahmen (5.2)].
•Akutem oder schwerem Asthma bronchiale in einer nicht überwachten Umgebung oder bei fehlender Ausrüstung zur Wiederbelebung [siehe Warnhinweise und Vorsichtsmaßnahmen (5.7)].
•Gleichzeitiger Anwendung von Monoaminoxidase-Hemmern (MAO-Hemmern) oder Anwendung von MAO-Hemmern innerhalb der letzten 14 Tage [siehe Warnhinweise und Vorsichtsmaßnahmen (5.8) und Wechselwirkungen (7)].
•Bekannter oder vermuteter gastrointestinaler Obstruktion, einschließlich paralytischem Ileus [siehe Warnhinweise und Vorsichtsmaßnahmen (5.12)].
•Überempfindlichkeit gegen Morphin (z. B. Anaphylaxie) [siehe Nebenwirkungen (6)].

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Morphine Sulfate Tablets are 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 (5.7)].
•Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Warnings and Precautions (5.8) and Drug Interactions (7)].
•Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.12)].
•Hypersensitivity to morphine (e.g., anaphylaxis) [see Adverse Reactions (6)].

Nebenwirkungen

The following serious adverse reactions are described, or described in greater detail, in other sections:

•Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]
•Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)]
•Interactions with Benzodiazepine or Other CNS Depressants [see Warnings and Precautions (5.3)]
•Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4)]
•Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.6)]
•Adrenal Insufficiency [see Warnings and Precautions (5.9)]
•Severe Hypotension [see Warnings and Precautions (5.10)]
•Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.12)]
•Seizures [see Warnings and Precautions (5.13)]
•Withdrawal [see Warnings and Precautions (5.14)]

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.

Serious adverse reactions associated with morphine use included: respiratory depression, apnea, and to a lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest.

The common adverse reactions seen on initiation of therapy with morphine in adults were dose-dependent and were typical opioid-related adverse reactions. The most frequent of these included: constipation, nausea, and somnolence. Other commonly observed adverse reactions included: lightheadedness, dizziness, sedation, vomiting, and sweating. The frequency of these events depended upon several factors including clinical setting, the patient’s level of opioid tolerance, and host factors specific to the individual.

Other less frequently observed adverse reactions from opioid analgesics, including morphine sulfate included:

Body as a Whole: malaise, withdrawal syndrome

Cardiovascular System: bradycardia, hypertension, hypotension, palpitations, syncope, tachycardia

Digestive System: biliary pain, dyspepsia, dysphagia, gastroenteritis, abnormal liver function tests, rectal disorder, thirst

Endocrine: hypogonadism

Hemic and Lymphatic System: anemia, thrombocytopenia

Metabolic and Nutritional Disorders: edema, weight loss

Musculoskeletal: skeletal muscle rigidity, decreased bone mineral density

Nervous System: abnormal dreams, abnormal gait, agitation, amnesia, anxiety, ataxia, confusion, convulsions, coma, delirium, depression, dry mouth, euphoria, hallucinations, lethargy, nervousness, abnormal thinking, tremor, vasodilation, vertigo, headache

Respiratory System: hiccup, hypoventilation, voice alteration

Skin and Appendages: dry skin, urticaria, pruritus

Special Senses: amblyopia, eye pain, taste perversion

Urogenital System: abnormal ejaculation, dysuria, impotence, decreased libido, oliguria, urinary retention or hesitancy, anti-diuretic effect, amenorrhea

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 Morphine Sulfate Tablets.

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

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

Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

Clinical Trial Experience in Pediatric Patients

The safety of morphine sulfate was evaluated in 81 pediatric patients with acute pain [see Use in Specific Populations (8.4)]. Morphine Tablets are not recommended for use in pediatric patients weighing less than 50 kg. The adverse reaction profile in pediatric patients is similar to adults. The most common adverse reactions reported on initiation of therapy in at least 5% of patients were: nausea (17%), vomiting (10%), constipation (6%), decreased oxygen saturation (5%), and flatulence (5%).

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 ( 5.12 )].

Adverse Reactions from Observational Studies

A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021. Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90-day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n=1,244). Those included also had no dispensing of the qualifying opioids in the previous 6 months.

Over 12 months:

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

A retrospective, observational cohort study estimated the risk of opioid involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249). Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months. New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days’ supply over the 3 months prior to study entry and none during the preceding 6 months. Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry. Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database. The 5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose-related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up. Approximately 17% of first opioid overdoses observed over the entire study period (5-11 years, depending on the study site) were fatal. Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death. Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow up (approximately 80%) also may have biased estimates.

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

Warnhinweise und Vorsichtsmaßnahmen

5.1 Addiction, Abuse, and Misuse

Morphine Sulfate Tablets contain morphine, a Schedule II controlled substance. As an opioid, Morphine Sulfate Tablets expose 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 morphine sulfate. 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)].

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Morphine Sulfate Tablets, and reassess all patients receiving Morphine Sulfate Tablets for the development of these behaviors or 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 Morphine Sulfate Tablets but use in such patients necessitates intensive counseling about the risks and proper use of Morphine Sulfate Tablets along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2) and Warnings and Precautions (5.2)].

Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing Morphine Sulfate Tablets. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and proper disposal of unused drug. 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.

5.2 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, 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 Morphine Sulfate Tablets, the risk is greatest during the initiation of therapy or following a dosage increase.

To reduce the risk of respiratory depression, proper dosing and titration of Morphine Sulfate Tablets are essential [see Dosage and Administration ( 2.3 , 2.4 )]. Overestimating the Morphine Sulfate Tablets dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.

Accidental ingestion of even one dose of Morphine Sulfate Tablets, especially by children, can result in respiratory depression and death due to an overdose of morphine.

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose.

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 ( 2.5 )].

Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose

Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).

Educate patients and caregivers on how to recognize respiratory depression, and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 , 5.3 ), Overdosage (10)].

5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Morphine Sulfate Tablets with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine 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.

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. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2), Warnings and Precautions ( 5.2 ), Overdosage (10)].

Advise both patients and caregivers about the risks of respiratory depression and sedation when Morphine Sulfate Tablets are 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)].

5.4 Neonatal Opioid Withdrawal Syndrome

Use of Morphine Sulfate Tablets for an extended period of time 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 an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1)].

5.5 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 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: https://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.

5.6 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 non-painful 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 (2.5), Warnings and Precautions (5.14)].

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

The use of Morphine Sulfate Tablets 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:

Morphine Sulfate Tablets-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 Morphine Sulfate Tablets [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)].

Regularly evaluate patients, particularly when initiating and titrating Morphine Sulfate Tablets and when Morphine Sulfate Tablets are given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2), Drug Interactions (7)]. Alternatively, consider the use of non-opioid analgesics in these patients.

5.8 Interaction with Monoamine Oxidase Inhibitors

Monoamine oxidase inhibitors (MAOIs) may potentiate the effects of morphine, including respiratory depression, coma, and confusion. Morphine Sulfate Tablets should not be used in patients taking MAOIs or within 14 days of stopping such treatment.

5.9 Adrenal Insufficiency

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

5.10 Severe Hypotension

Morphine Sulfate Tablets 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)]. Regularly evaluate patients for signs of hypotension after initiating or titrating the dosage of Morphine Sulfate Tablets. In patients with circulatory shock, Morphine Sulfate Tablets may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Morphine Sulfate Tablets in patients with circulatory shock.

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

In patients who may be susceptible to the intracranial effects of CO₂ retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Morphine Sulfate Tablets may reduce respiratory drive, and the resultant CO₂ retention can further increase intracranial pressure. Monitor patients for signs of sedation and respiratory depression, particularly when initiating therapy with Morphine Sulfate Tablets.

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

5.12 Risks of Gastrointestinal Complications

Morphine Sulfate Tablets are contraindicated in patients with gastrointestinal obstruction, including paralytic ileus.

The morphine in Morphine Sulfate Tablets may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis for worsening symptoms.

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)].

5.13 Increased Risk of Seizures in Patients with Seizure Disorders

The morphine in Morphine Sulfate Tablets 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. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during Morphine Sulfate Tablets therapy.

5.14 Withdrawal

Do not rapidly reduce or abruptly discontinue Morphine Sulfate Tablets in a patient physically dependent on opioids. When discontinuing Morphine Sulfate Tablets in a physically dependent patient, gradually taper the dosage. Rapid tapering of morphine in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration (2.5) and Drug Abuse and Dependence (9.3)].

Additionally, 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 Morphine Sulfate Tablets. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms [see Drug Interactions (7)].

5.15 Risks of Driving and Operating Machinery

Morphine Sulfate Tablets may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Morphine Sulfate Tablets and know how they will react to the medication.

Wechselwirkungen

Table 1 includes clinically significant drug interactions with Morphine Sulfate Tablets.

Table 1: Clinically Significant Drug Interactions with Morphine Sulfate Tablets

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 [see Warnings and Precautions (5.3)].
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. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.2, 5.3)].
Examples: | Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, 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, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue Morphine Sulfate Tablets 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 (MAO) 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 (5.8)].
Intervention: | Do not use Morphine Sulfate Tablets in patients taking MAOIs or within 14 days of stopping such treatment.
Examples: | Phenelzine, tranylcypromine, linezolid.
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: | May reduce the analgesic effect of Morphine Sulfate Tablets 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: | Because respiratory depression may be greater than otherwise expected, decrease the dosage of Morphine Sulfate Tablets and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2), Warnings and Precautions (5.2, 5.3 )].
Examples: | Cyclobenzaprine, metaxalone
Cimetidine
Clinical Impact: | The concomitant use of morphine and cimetidine has been reported to precipitate apnea, confusion, and muscle twitching in an isolated report.
Intervention: | Evaluate patients for increased respiratory and CNS depression when Morphine Sulfate Tablets are used concomitantly with cimetidine.
Diuretics
Clinical Impact: | Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: | Evaluate 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 paralytic ileus.
Intervention: | Evaluate patients for signs of urinary retention or reduced gastric motility when Morphine Sulfate Tablets are used concomitantly with anticholinergic drugs.
P-Glycoprotein (P-gp) Inhibitors
Clinical Impact: | The concomitant use of P-gp inhibitors can increase the exposure to morphine by two-fold and can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: | Evaluate patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Morphine Sulfate Tablets and/or the P-gp inhibitor as necessary.
Examples: | Quinidine, verapamil.

Schwangerschaft, Stillzeit, Kinder, ältere Menschen

8.1 Pregnancy

Risk Summary:

Use of opioid analgesics for an extended period of time during pregnancy can cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.4)]. There are no available data with Morphine Sulfate Tablets in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Published studies with morphine use during pregnancy have not reported a clear association with morphine and major birth defects [see Human Data]. In published animal reproduction studies, morphine administered subcutaneously during the early gestational period produced neural tube defects (i.e., exencephaly and cranioschisis) at 5 and 16 times the human daily dose of 60 mg based on body surface area (HDD) in hamsters and mice, respectively, lower fetal body weight and increased incidence of abortion at 0.4 times the HDD in the rabbit, growth retardation at 6 times the HDD in the rat, and axial skeletal fusion and cryptorchidism at 16 times the HDD in the mouse. Administration of morphine sulfate to pregnant rats during organogenesis and through lactation resulted in cyanosis, hypothermia, decreased brain weights, pup mortality, decreased pup body weights, and adverse effects on reproductive tissues at 3 to 4 times the HDD; and long-term neurochemical changes in the brain of offspring which correlate with altered behavioral responses that persist through adulthood at exposures comparable to and less than the HDD [see Animal Data]. Based on animal data, advise pregnant women of the potential risk to a fetus.

The 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% to 4% and 15% to 20%, respectively.

Clinical Considerations:

Fetal/Neonatal Adverse Reactions: Use of opioid analgesics for an extended period of time 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 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 signs of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.4)].

Labor or Delivery: Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agent, such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate. Morphine Sulfate Tablets are not recommended for use in women during and immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including Morphine Sulfate Tablets, can prolong labor through actions that 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 dilatation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data:

Human Data: The results from a population-based prospective cohort, including 70 women exposed to morphine during the first trimester of pregnancy and 448 women exposed to morphine at any time during pregnancy, indicate no increased risk for congenital malformations. However, these studies cannot definitely establish the absence of any risk because of methodological limitations, including small sample size and non-randomized study design.

Animal Data: Formal reproductive and developmental toxicology studies for morphine have not been conducted. Exposure margins for the following published study reports are based on human daily dose of 60 mg morphine using a body surface area comparison (HDD).

Neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of morphine sulfate (35 to 322 mg/kg) on Gestation Day 8 to pregnant hamsters (4.7 to 43.5 times the HDD). A no adverse effect level was not defined in this study and the findings cannot be clearly attributed to maternal toxicity. Neural tube defects (exencephaly), axial skeletal fusions, and cryptorchidism were reported following a single subcutaneous (SC) injection of morphine sulfate to pregnant mice (100 to 500 mg/kg) on Gestation Day 8 or 9 at 200 mg/kg or greater (16 times the HDD) and fetal resorption at 400 mg/kg or higher (32 times the HDD). No adverse effects were noted following 100 mg/kg morphine in this model (8 times the HDD). In one study, following continuous subcutaneous infusion of doses greater than or equal to 2.72 mg/kg to mice (0.2 times the HDD), exencephaly, hydronephrosis, intestinal hemorrhage, split supraoccipital, malformed sternebrae, and malformed xiphoid were noted. The effects were reduced with increasing daily dose; possibly due to rapid induction of tolerance under these infusion conditions. The clinical significance of this report is not clear.

Decreased fetal weights were observed in pregnant rats treated with 20 mg/kg/day morphine sulfate (3.2 times the HDD) from Gestation Day 7 to 9. There was no evidence of malformations despite maternal toxicity (10% mortality). In a second rat study, decreased fetal weight and increased incidences of growth retardation were noted at 35 mg/kg/day (5.7 times the HDD) and there was a reduced number of fetuses at 70 mg/kg/day (11.4 times the HDD) when pregnant rats were treated with 10, 35, or 70 mg/kg/day morphine sulfate via continuous infusion from Gestation Day 5 to 20. There was no evidence of fetal malformations or maternal toxicity.

An increased incidence of abortion was noted in a study in which pregnant rabbits were treated with 2.5 (0.8 times the HDD) to 10 mg/kg morphine sulfate via subcutaneous injection from Gestation Day 6 to 10. In a second study, decreased fetal body weights were reported following treatment of pregnant rabbits with increasing doses of morphine (10 to 50 mg/kg/day) during the pre-mating period and 50 mg/kg/day (16 times the HDD) throughout the gestation period. No overt malformations were reported in either publication; although only limited endpoints were evaluated.

In published studies in rats, exposure to morphine during gestation and/or lactation periods is associated with: decreased pup viability at 12.5 mg/kg/day or greater (2 times the HDD); decreased pup body weights at 15 mg/kg/day or greater (2.4 times the HDD); decreased litter size, decreased absolute brain and cerebellar weights, cyanosis, and hypothermia at 20 mg/kg/day (3.2 times the HDD); alteration of behavioral responses (play, social-interaction) at 1 mg/kg/day or greater (0.2 times the HDD); alteration of maternal behaviors (e.g., decreased nursing and pup retrievals) in mice at 1 mg/kg or higher (0.08 times the HDD) and rats at 1.5 mg/kg/day or higher (0.2 times the HDD); and a host of behavioral abnormalities in the offspring of rats, including altered responsiveness to opioids at 4 mg/kg/day (0.7 times the HDD) or greater.

Fetal and/or postnatal exposure to morphine in mice and rats has been shown to result in morphological changes in fetal and neonatal brain and neuronal cell loss, alteration of a number of neurotransmitter and neuromodulator systems, including opioid and non-opioid systems, and impairment in various learning and memory tests that appear to persist into adulthood. These studies were conducted with morphine treatment usually in the range of 4 to 20 mg/kg/day (0.7 to 3.2 times the HDD).

Additionally, delayed sexual maturation and decreased sexual behaviors in female offspring at 20 mg/kg/day (3.2 times the HDD), and decreased plasma and testicular levels of luteinizing hormone and testosterone, decreased testes weights, seminiferous tubule shrinkage, germinal cell aplasia, and decreased spermatogenesis in male offspring were also observed at 20 mg/kg/day (3.2 times the HDD). Decreased litter size and viability were observed in the offspring of male rats that were intraperitoneally administered morphine sulfate for 1 day prior to mating at 25 mg/kg/day (4.1 times the HDD) and mated to untreated females. Decreased viability and body weight and/or movement deficits in both first and second generation offspring were reported when male mice were treated for 5 days with escalating doses of 120 to 240 mg/kg/day morphine sulfate (9.7 to 19.5 times the HDD) or when female mice treated with escalating doses of 60 to 240 mg/kg/day (4.9 to 19.5 times the HDD) followed by a 5-day treatment-free recovery period prior to mating. Similar multigenerational findings were also seen in female rats pre-gestationally treated with escalating doses of 10 to 22 mg/kg/day morphine (1.6 to 3.6 times the HDD).

8.2 Lactation

Risk Summary:

Morphine is present in breast milk. Published lactation studies report variable concentrations of morphine in breast milk with administration of immediate-release morphine to nursing mothers in the early postpartum period with a milk-to-plasma morphine AUC ratio of 2.5:1 measured in one lactation study. However, there is insufficient information to determine the effects of morphine on the breastfed infant and the effects of morphine on milk production. Lactation studies have not been conducted with Morphine Sulfate Tablets and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Morphine Sulfate Tablets and any potential adverse effects on the breastfed infant from Morphine Sulfate Tablets or from the underlying maternal condition.

Clinical Considerations:

Monitor infants exposed to Morphine Sulfate Tablets through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of morphine is stopped, or when breastfeeding is stopped.

8.3 Females and Males of Reproductive Potential

Infertility:

Use of opioids for an extended period of time 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) and Clinical Pharmacology (12.2)].

In published animal studies, morphine administration adversely effected fertility and reproductive endpoints in male rats and prolonged estrus cycle in female rats [see Nonclinical Toxicology (13)].

8.4 Pediatric Use

The safety and effectiveness of Morphine Sulfate Tablets have been established for the management of pediatric patients weighing at least 50 kg with acute pain severe enough to require an opioid analgesic when alternative treatments are inadequate. Use of Morphine Sulfate Tablets in this age group is supported by clinical evidence in adults and supportive data from an open-label, safety and pharmacokinetic study in pediatric patients 2 through 17 years of age with post-operative acute pain. Patients were excluded if they had used opioids for more than 7 days within the previous 30 days prior to surgery or had received opioids in any form in the previous 7 days prior to surgery. Initial dosing was approximately 0.15 mg/kg to 0.3 mg/kg. Pharmacokinetic modeling and simulation indicate that an initial dose of 15 mg Morphine Sulfate Tablets to pediatric patients weighing at least 50 kg is expected to produce a maximum systemic exposure (Cmax) similar to that achieved after single dose administration of 10 mg morphine sulfate oral solution to adults [see Clinical Pharmacology (12.3)]. Safety data were available in 81 patients who received single and multiple doses (63 patients aged 2 to 17 years received the oral solution; 18 patients aged 12 years to 17 years received the tablets). The median duration of treatment was 20 hours (range 4 hours to 36 hours). Opioid and non-opioid rescue analgesics were allowed. The safety profile in pediatric patients consisted primarily of opioid-related adverse reactions and is similar to that observed in adults [see Adverse Reactions (6)].

The safety and effectiveness of Morphine Sulfate Tablets have not been established for the management of pediatric patients weighing less than 50 kg with acute pain severe enough to require an opioid analgesic when alternative treatments are inadequate because the recommended dosage cannot be achieved with available tablet strengths. Consider use of another morphine sulfate product in patients who cannot swallow oral tablets or who weigh less than 50 kg [see Dosage and Administration (2.3)].

The safety and effectiveness of Morphine Sulfate Tablets have not been established for the management of pediatric patients with chronic pain severe enough to require an opioid analgesic when alternative treatments are inadequate.

8.5 Geriatric Use

Elderly patients (aged 65 years or older) may have increased sensitivity to morphine. In general, use caution when selecting a dose 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 Morphine Sulfate Tablets slowly in geriatric patients and frequentlyreevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.7)].

Morphine 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 regularly evaluate renal function.

8.6 Hepatic Impairment

Morphine pharmacokinetics have been reported to be significantly altered in patients with cirrhosis. Start these patients with a lower than usual dosage of Morphine Sulfate Tablets and titrate slowly while regularly evaluating for signs of respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3)].

8.7 Renal Impairment

Morphine sulfate pharmacokinetics are altered in patients with renal failure. Start these patients with a lower than usual dosage of Morphine Sulfate Tablets and titrate slowly while regularly evaluating for signs of respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3)].

Überdosierung

Clinical Presentation

Acute overdose with morphine can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2)]. Toxic leukoencephalopathy has been reported after opioid overdose and can present hours, days, or weeks after apparent recovery from the initial intoxication.

Treatment of Overdose

In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support measures.

For clinically significant respiratory or circulatory depression secondary to opioid overdose, administer an opioid overdose reversal agent such as naloxone or nalmefene.

Because the duration of opioid reversal is expected to be less than the duration of action of morphine in Morphine Sulfate Tablets, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an opioid overdose reversal agent is suboptimal or only brief in nature, administer additional reversal agent as directed by the product’s prescribing information.

In an individual physically dependent on opioids, administration of the recommended usual dosage of the opioid overdose reversal agent will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the reversal agent administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the reversal agent should be initiated with care and by titration with smaller than usual doses of the reversal agent.

Klinische Pharmakologie

12.1 Mechanism of Action

Morphine is a full opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of morphine is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with morphine. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression.

The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.

12.2 Pharmacodynamics

Effects on the Central Nervous System:

Morphine produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.

Morphine causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and Other Smooth Muscle:

Morphine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, transient elevations in serum amylase, and opioid-induced esophageal dysfunction (OIED).

Effects on the Cardiovascular System:

Morphine produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Effects on the Endocrine System:

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions ( 6)]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Auszug – vollständiger Text im Originaldokument. Original auf DailyMed (FDA/NLM)

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