Morphabond ER

Morphine is used to relieve moderate to severe pain. It belongs to the group of medicines called narcotic analgesics (pain medicines). Morphine acts on the central nervous system (CNS) to relieve pain.

Morphine extended-release capsules or tablets should not be used if you need pain medicine for just a short time, such as when recovering from surgery. Do not use this medicine to relieve mild pain, or in situations when non-narcotic medication is effective. This medicine should not be used to treat pain that you only have once in a while or "as needed".

When morphine is used for a long time, it may become habit-forming, causing mental or physical dependence. However, people who have continuing pain should not let the fear of dependence keep them from using narcotics to relieve their pain. Mental dependence (addiction) is not likely to occur when narcotics are used for this purpose. Physical dependence may lead to withdrawal side effects if treatment is stopped suddenly. However, severe withdrawal side effects can usually be prevented by gradually reducing the dose over a period of time before treatment is stopped completely.

This medicine is available only with your doctor's prescription.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Abdominal or stomach pain
• blurred vision
• bulging soft spot on the head of an infant
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• change in the ability to see colors, especially blue or yellow
• chest pain or discomfort
• confusion
• cough
• decreased urination
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• fainting
• fast, pounding, or irregular heartbeat or pulse
• headache
• hives, itching, or skin rash
• increased sweating
• loss of appetite
• nausea or vomiting
• nervousness
• pounding in the ears
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• severe constipation
• severe vomiting
• shakiness in the legs, arms, hands, or feet
• slow heartbeat
• sweating or chills

• Black, tarry stools
• cold, clammy skin
• feeling of warmth or heat
• flushing or redness of the skin, especially on the face and neck
• irregular, fast or slow, or shallow breathing
• lightheadedness
• loss of consciousness
• low blood pressure or pulse
• painful urination
• pale or blue lips, fingernails, or skin
• pale skin
• pinpoint red spots on the skin
• pounding in the ears
• shakiness and unsteady walk
• unsteadiness, trembling, or other problems with muscle control or coordination
• unusual bleeding or bruising
• very slow heartbeat

Get emergency help immediately if any of the following symptoms of overdose occur:

• Constricted, pinpoint, or small pupils (black part of the eye)
• decreased awareness or responsiveness
• extreme drowsiness
• fever
• increased blood pressure
• increased thirst
• lower back or side pain
• muscle cramps or spasms
• muscle pain or stiffness
• no muscle tone or movement
• severe sleepiness
• swelling of the face, fingers, or lower legs
• weight gain

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Cramps
• difficulty having a bowel movement (stool)
• drowsiness
• false or unusual sense of well-being
• relaxed and calm feeling
• sleepiness or unusual drowsiness
• weight loss

• Absent, missed, or irregular menstrual periods
• agitation
• bad, unusual, or unpleasant (after) taste
• change in vision
• depression
• dry mouth
• face is warm or hot to touch
• floating feeling
• halos around lights
• heartburn or indigestion
• loss in sexual ability, desire, drive, or performance
• muscle stiffness or tightness
• night blindness
• overbright appearance of lights
• problems with muscle control
• redness of the skin
• skin rash
• stomach discomfort or upset
• trouble sleeping
• uncontrolled eye movements

• Abnormal dreams
• change in walking and balance
• change or problem with discharge of semen
• clumsiness or unsteadiness
• confusion as to time, place, or person
• delusions
• dementia
• feeling of constant movement of self or surroundings
• general feeling of discomfort or illness
• holding false beliefs that cannot be changed by fact
• problems with memory
• seeing, hearing, or feeling things that are not there
• sensation of spinning
• unusual excitement, nervousness, or restlessness

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Extended-release tablets: 15 mg, 30 mg, 60 mg, 100 mg.

• 15 mg extended-release tablets (round, blue-colored, coated tablets ink-printed with “IDT/M15” on one side; and plain on the other)
• 30 mg extended-release tablets (round, purple-colored, coated tablets ink-printed with “IDT/M30” on one side; and plain on the other)
• 60 mg extended-release tablets (round, orange-colored, coated tablets ink-printed with “IDT/M60” on one side; and plain on the other)
• 100 mg extended-release tablets* (round, gray-colored, coated tablets ink-printed with “IDT/M100” on one side; and plain on the other)

*100 mg tablets are for use in opioid-tolerant patients only

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)]
• Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.3)]
• Interactions with Benzodiazepine or Other CNS Depressants [see Warnings and Precautions (5.4)]
• Adrenal Insufficiency [see Warnings and Precautions (5.7)]
• Severe Hypotension [see Warnings and Precautions (5.8)]
• Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.10)]
• Seizures [see Warnings and Precautions (5.11)]
• Withdrawal [see Warnings and Precautions (5.12)]

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Morphabond ER may increase the risk of serious adverse reactions such as those observed with other opioid analgesics, including respiratory depression, apnea, respiratory arrest, circulatory depression, hypotension, or shock [see Overdosage (10)].

Most Frequently Observed Reactions

In clinical trials, the most common adverse reactions with morphine sulfate extended-release were constipation, dizziness, sedation, nausea, vomiting, sweating, dysphoria, and euphoric mood.

Some of these effects seem to be more prominent in ambulatory patients and in those not experiencing severe pain.

Less Frequently Observed Reactions

Cardiovascular disorders: tachycardia, bradycardia, palpitations

Eye disorders: visual impairment, vision blurred, diplopia, miosis

Gastrointestinal disorders: dry mouth, diarrhea, abdominal pain, constipation, dyspepsia

General disorders and administration site conditions: chills, feeling abnormal, edema, edema peripheral, weakness

Hepatobiliary disorders: biliary colic

Metabolism and nutrition disorders: anorexia

Musculoskeletal and connective tissue disorders: muscle rigidity, muscle twitching

Nervous system disorders: presyncope, syncope, headache, tremor, uncoordinated muscle movements, convulsion, intracranial pressure increased, taste alteration, paresthesia, nystagmus

Psychiatric disorders: agitation, mood altered, anxiety, depression, abnormal dreams, hallucination, disorientation, insomnia

Renal and urinary disorders: urinary retention, urinary hesitation, antidiuretic effect

Reproductive system and breast disorders: reduced libido and/or potency

Respiratory, thoracic and mediastinal disorders: laryngospasm

Skin and subcutaneous tissue disorders: pruritus, urticaria, rash

Vascular disorders: flushing, hypotension, hypertension

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of morphine sulfate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

amenorrhea, asthenia, bronchospasm, confusional state, drug hypersensitivity, fatigue, hyperalgesia, hypertonia, ileus, increased hepatic enzymes, intestinal obstruction, lethargy, malaise, pulmonary edema, thinking disturbances, somnolence, and vertigo.

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 Morphabond ER.

Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2)].

Controlled Substance

Morphabond ER contains morphine, a Schedule II controlled substance.

Abuse

Morphabond ER contains morphine, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, oxycodone, oxymorphone, and tapentadol. Morphabond ER can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1)].

The high drug content in extended-release formulations adds to the risk of adverse outcomes from abuse and misuse.

All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

"Drug seeking" behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.

Morphabond ER, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help limit abuse of opioid drugs.

Risks Specific to Abuse of Morphabond ER

Morphabond ER is for oral use only. Abuse of Morphabond ER poses a risk of overdose and death. This risk is increased with concurrent abuse of Morphabond ER with alcohol and other central nervous system depressants. Taking cut, broken, chewed, crushed, or dissolved Morphabond ER enhances drug release and increases the risk of overdose and death.

Parenteral abuse of Morphabond ER can be expected to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

Abuse Deterrence Studies

Morphabond ER is formulated with inactive ingredients that make the tablet more difficult to adulterate for misuse and abuse while maintaining extended-release characteristics even if the tablet is subjected to physical manipulation, and/or chemical extraction. To evaluate the ability of the abuse-deterrent technology to reduce the potential for abuse of Morphabond ER, a series of in vitro laboratory manipulation, extraction, and syringeability, studies was conducted. An in vivo clinical abuse potential study was also conducted. The results of these studies are summarized below. Overall, the results indicate that Morphabond ER has properties that are expected to reduce abuse or misuse via injection or insufflation; however, abuse by these routes is still possible.

In Vitro Testing

Morphabond ER has been tested in vitro using methods of manipulation that drug abusers commonly use for preparation of extended-release opioids for administration by various routes, including oral consumption, intranasal insufflation, injection, and smoking.

Abusers may manipulate extended-release opioids in order to prepare the tablets for oral, intranasal, or intravenous administration. The laboratory test data demonstrated that, relative to morphine sulfate extended-release tablet, Morphabond ER has increased resistance to cutting, crushing, or breaking using a variety of tools. When subjected to a liquid environment the manipulated Morphabond ER formulation forms a viscous material that resists passage through a needle.

Clinical Studies

A randomized, double-blind, double-dummy, placebo-controlled, single-dose four-way crossover study in 25 non-dependent recreational opioid users with a history of intranasal drug abuse was performed to determine the relative bioavailability and abuse potential of crushed intranasal Morphabond ER 60 mg tablets compared with crushed intranasal morphine sulfate extended-release tablet 60 mg tablets, and intact orally administered Morphabond ER 60 mg tablets. The intact oral tablets were included as a reference for evaluating abuse potential after manipulation and administration via an unintended route.

Drug liking was measured on a 100 mm bipolar visual analog scale (VAS) where 50 represents a neutral response of neither liking nor disliking, 0 represents maximum disliking, and 100 represents maximum liking. Response to whether the subject would take the study drug again was also measured on a bipolar scale of 0 to 100 where 50 represents a neutral response, 0 represents the strongest negative response (‘definitely would not take drug again’) and 100 represents the strongest positive response (‘definitely would take drug again’).

Intranasal administration of crushed Morphabond ER was associated with statistically significantly lower drug liking (Emax) scores (P < 0.0001), and significantly lower willingness to take the drug again (Emax) scores (P = 0.034), compared to crushed extended-release morphine (Table 2). Drug liking and take drug again scores for crushed intranasal Morphabond ER were not significantly different from those of Morphabond ER taken orally intact. These data are consistent with the similar relative bioavailability after crushed intranasal and intact oral administration of Morphabond ER that support retention of its extended release properties when manipulated compared to morphine sulfate extended-release tablets [see Clinical Pharmacology (12.3)].

Figure 1 demonstrates a comparison of peak drug liking scores for crushed Morphabond ER compared to crushed extended-release morphine in subjects who received both treatments intranasally. Seventy-six percent of subjects (n = 19) experienced some reduction in Emax of Drug Liking VAS with crushed Morphabond ER compared with crushed extended-release morphine, 48%; (n = 12) experienced at least a 30% reduction in Emax and 32% (n = 8) experienced at least a 50% reduction in Emax of drug liking.

Figure 1. Percent Reduction Profiles for Emax of Drug Liking for Morphabond ER vs. Morphine Sulfate ER Tablets (n=25), Following Intranasal Administration

Summary

The in vitro data demonstrate that Morphabond ER has physiochemical properties expected to make abuse via injection difficult. The data from the clinical study, along with support from in vitro data, also indicate that Morphabond ER has physicochemical properties that are expected to reduce abuse by the intranasal route of administration. However, abuse by intranasal, intravenous, and oral routes is still possible.

Additional data, including epidemiological data, when available, may provide further information on the impact of the current formulation of Morphabond ER on the abuse liability of the drug. Accordingly, this section may be updated in the future as appropriate.

Dependence

Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

Morphabond ER should not be abruptly discontinued [see Dosage and Administration (2.4)]. If Morphabond ER is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: 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.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)].

Morphabond ER™ (morphine sulfate) extended-release tablets 15 mg are round, blue-colored, coated tablets ink-printed with IDT/M15 on one side; and plain on the other. They are supplied as opaque plastic bottles containing 100 tablets (NDC 65597-301-10).

Morphabond ER™ (morphine sulfate) extended-release tablets 30 mg are round, purple-colored, coated tablets ink-printed with IDT/M30 on one side; and plain on the other. They are supplied as opaque plastic bottles containing 100 tablets (NDC 65597-302-10).

Morphabond ER™ (morphine sulfate) extended-release tablets 60 mg are round, orange-colored, coated tablets ink-printed with IDT/M60 on one side; and plain on the other. They are supplied as opaque plastic bottles containing 100 tablets (NDC 65597-303-10).

Morphabond ER™ (morphine sulfate) extended-release tablets 100 mg are round, gray-colored, coated tablets ink-printed with IDT/M100 on one side; and plain on the other. They are supplied as opaque plastic bottles containing 100 tablets (NDC 65597-304-10).

Store at 25ºC (77ºF); excursions permitted between 15º-30ºC (59º-86ºF)[see USP Controlled Room Temperature].

Dispense in a tight, light-resistant container.