Morphabond

Name: Morphabond

What are some things I need to know or do while I take Morphabond?

  • Tell all of your health care providers that you take Morphabond. This includes your doctors, nurses, pharmacists, and dentists.
  • Avoid driving and doing other tasks or actions that call for you to be alert until you see how this medicine affects you.
  • To lower the chance of feeling dizzy or passing out, rise slowly if you have been sitting or lying down. Be careful going up and down stairs.
  • Do not take Morphabond with other strong pain drugs or if you are using a pain patch without talking to your doctor first.
  • Have your blood work checked if you are on this medicine for a long time. Talk with your doctor.
  • Do not take more than what your doctor told you to take. Taking more than you are told may raise your chance of very bad side effects.
  • If you have been taking Morphabond for a long time or at high doses, it may not work as well and you may need higher doses to get the same effect. This is known as tolerance. Call your doctor if this medicine stops working well. Do not take more than ordered.
  • Do not stop taking Morphabond all of a sudden without calling your doctor. You may have a greater risk of signs of withdrawal. If you need to stop this medicine, you will want to slowly stop it as ordered by your doctor.
  • For some brands, you may see the tablet shell in your stool. For these brands, this is normal and not a cause for concern. If you have questions, talk with your doctor.
  • Some products may cause choking, gagging, or trouble swallowing. These products must be taken with a full glass of water. Ask your pharmacist if you need to take your product with a full glass of water.
  • Long-term use of an opioid drug like Morphabond may lead to lower sex hormone levels. This may lead to signs like change in sex ability in men, no menstrual period in women, lowered interest in sex, or fertility problems. Call your doctor if you have any of these signs.
  • This medicine may raise the chance of seizures in some people, including people who have had seizures in the past. Talk to your doctor to see if you have a greater chance of seizures while taking this medicine.
  • If you are 65 or older, use Morphabond with care. You could have more side effects.
  • This medicine may cause harm to the unborn baby if you take it while you are pregnant. If you are pregnant or you get pregnant while taking this medicine, call your doctor right away.

Morphabond Dosage and Administration

Important Dosage and Administration Instructions

Morphabond ER should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

Morphabond ER 100 mg tablets, a single dose greater than 60 mg, or a total daily dose greater than 120 mg, are only for use in patients in whom tolerance to an opioid of comparable potency has been established. Patients who are opioid tolerant are those receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.

  • Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)].
  • Initiate the dosing regimen for each patient individually; taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)].
  • Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases with Morphabond ER and adjust the dosage accordingly [see Warnings and Precautions (5.2)].

Instruct patients to swallow Morphabond ER tablets whole [see Patient Counseling Information (17)]. Crushing, chewing, or dissolving Morphabond ER tablets will result in uncontrolled delivery of morphine and can lead to overdose or death [see Warnings and Precautions (5.1)].

Morphabond ER is administered orally every 12 hours.

Initial Dosage

Use of Morphabond ER as the First Opioid Analgesic (opioid-naïve patients)

Initiate treatment with Morphabond ER with 15 mg tablets orally every 12 hours.

Use of Morphabond ER in Patients who are not Opioid Tolerant (opioid non-tolerant patients)

The starting dosage for patients who are not opioid tolerant is Morphabond ER 15 mg orally every 12 hours.

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression [see Warnings and Precautions (5.2)].

Conversion from Other Oral Morphine to Morphabond ER

Patients receiving other oral morphine formulations may be converted to Morphabond ER by administering one-half of the patient's 24-hour requirement as Morphabond ER on an every-12-hour schedule.

Conversion from Other Opioids to Morphabond ER

Discontinue all other around-the-clock opioid drugs when Morphabond ER therapy is initiated.

There are no established conversion ratios for conversion from other opioids to Morphabond ER defined by clinical trials. Initiate dosing using Morphabond ER 15 mg orally every 12 hours.

It is safer to underestimate a patient’s 24-hour oral morphine dosage and provide rescue medication (e.g., immediate-release morphine) than to overestimate the 24-hour oral morphine dosage and manage an adverse reaction due to an overdose. While useful tables of opioid equivalents are readily available, there is inter-patient variability in the relative potency of opioid drugs and formulations.

Close observation and frequent titration are warranted until pain management is stable on the new opioid. Monitor patients for signs and symptoms of opioid withdrawal and for signs of oversedation/toxicity after converting patients to Morphabond ER.

Conversion from Parenteral Morphine or Other Opioids (Parenteral or Oral) to Morphabond ER

When converting from parenteral morphine or other non-morphine opioids (parenteral or oral) to Morphabond ER, consider the following general points:

Parenteral to oral morphine ratio: Between 2 to 6 mg of oral morphine may be required to provide analgesia equivalent to 1 mg of parenteral morphine. Typically, a dose of morphine that is approximately three times the previous daily parenteral morphine requirement is sufficient.

Other parenteral or oral non-morphine opioids to oral morphine Ratios: Specific recommendations are not available because of a lack of systematic evidence for these types of analgesic substitutions. Published relative potency data are available, but such ratios are approximations. In general, begin with half of the estimated daily morphine requirement as the initial dose, managing inadequate analgesia by supplementation with immediate-release morphine.

Conversion from Methadone to Morphabond ER

Close monitoring is of particular importance when converting methadone to other opioid agonists. The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and can accumulate in the plasma.

Titration and Maintenance of Therapy

Individually titrate Morphabond ER to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Morphabond ER to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1)]. 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. During chronic therapy periodically reassess the continued need for the use of opioid analgesics.

Patients who experience breakthrough pain may require a dosage adjustment of Morphabond ER, or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the Morphabond ER dosage. Because steady-state plasma concentrations are approximated in 1 day, Morphabond ER dosage adjustments may be done every 1 to 2 days.

If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

Discontinuation of Morphabond ER

When the patient no longer requires therapy with Morphabond ER tablets, taper the dosage gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal. If a patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. Do not abruptly discontinue Morphabond ER [see Warnings and Precautions (5.12), Drug Abuse and Dependence (9.3)].

Use in specific populations

Pregnancy

Risk Summary

Prolonged use of opioid analgesics during pregnancy can cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.3)]. There are no available data with Morphabond ER 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 3-4 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 estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.3)].

Labor or Delivery

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Morphabond ER is not recommended for use in women during and immediately prior to labor, when shorter acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including Morphabond ER, 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 a 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 (35-322 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 (100-500 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 (10-50 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).

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 extended-release morphine, including Morphabond ER. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with Morphabond ER.

Clinical Considerations

Monitor infants exposed to Morphabond ER 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.

Females and Males of Reproductive Potential

Infertility

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2), 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)].

Pediatric Use

The safety and effectiveness in pediatric patients below the age of 18 have not been established.

Geriatric Use

The pharmacokinetics of Morphabond ER have not been studied in elderly patients. Clinical studies of morphine sulfate extended-release did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Elderly patients (aged 65 years or older) may have increased sensitivity to morphine. In general, dosage selection for an elderly patient should be cautious, 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 Morphabond ER slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.5)].

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 monitor renal function.

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 Morphabond ER and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3)].

Renal Impairment

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

Drug Abuse and Dependence

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)].

Table 2. Summary of Maximum Drug Liking (Emax) and Take Drug Again (Emax) Following Administration of Morphabond ER, morphine sulfate extended-release tablet, and Placebo in Recreational Opioid Users (n=25)
Crushed Intranasal Morphabond ER 60 mg Crushed Intranasal morphine sulfate extended-release tablet 60 mg Placebo Crushed Intranasal morphine sulfate extended-release tablet vs. Crushed Intranasal Morphabond ER Difference of LS Means (95% CI)
  Drug Liking (Emax)  Mean (SEM) 71.7 (2.87) 85.3 (2.42) 54.3 (1.63) 13.65 (7.80, 19.51)
 Median (Range) 72 (50-100) 85 (56-100) 51 (50-80)
  Take Drug Again (Emax)  Mean (SEM) 66.4 (3.76) 76.4 (4.17) 49.1 (2.21) 9.96 (0.77, 19.14)
 Median (Range) 64.0 (38-100) 75.0 (17-100) 50.0 (0-64)

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)].

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Addiction, Abuse, and Misuse

Inform patients that the use of Morphabond ER, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1)]. Instruct patients not to share Morphabond ER with others and to take steps to protect Morphabond ER from theft or misuse.

Life-Threatening Respiratory Depression

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Morphabond ER or when the dosage is increased, and that it can occur even at recommended dosages [see Warnings and Precautions (5.2)]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

Accidental Ingestion

Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.2)]. Instruct patients to take steps to store Morphabond ER securely and to dispose of unused Morphabond ER by flushing the tablets down the toilet.

Interactions with Benzodiazepines and other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if Morphabond ER is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a health care provider [see Warnings and Precautions (5.4), Drug Interactions (7)].

Serotonin Syndrome

Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications [see Drug Interactions 7].

MAOI Interaction

Inform patients not to take Morphabond ER while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking Morphabond ER [see Warnings and Precautions (5.6), Drug Interactions (7)].

Adrenal Insufficiency

Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.7)].

Important Administration Instructions [see Dosage and Administration (2.1, 2.4), Warnings and Precautions (5.2)]

Instruct patients how to properly take Morphabond ER, including the following:

  • Swallowing Morphabond ER tablets whole [see Dosage and Administration (2.1)]
  • Not crushing, chewing, or dissolving the tablets [see Dosage and Administration (2.1)]
  • Using Morphabond ER exactly as prescribed to reduce the risk of life-threatening adverse reactions (e.g., respiratory depression) [see Warnings and Precautions (5.2)]
  • Not discontinuing Morphabond ER without first discussing the need for a tapering regimen with the prescriber [see Dosage and Administration (2.4)]

Hypotension

Inform patients that Morphabond ER may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.8).

Anaphylaxis

Inform patients that anaphylaxis has been reported with ingredients contained in Morphabond ER. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4), Adverse Reactions (6)].

Pregnancy

Neonatal Opioid Withdrawal Syndrome
Inform female patients of reproductive potential that prolonged use of Morphabond ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.3), Use in Specific Populations (8.1)].

Embryo-Fetal Toxicity
Inform female patients of reproductive potential that Morphabond ER can cause fetal harm and to inform the healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)].

Lactation

Advise patients that breastfeeding is not recommended during treatment with Morphabond ER [see Use in Specific Populations (8.2)].

Infertility

Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations (8.3)].

Driving or Operating Heavy Machinery

Inform patients that Morphabond ER may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions (5.13)].

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6), Clinical Pharmacology (12.2)].

Disposal of Unused Morphabond ER

Advise patients to flush the unused tablets down the toilet when Morphabond ER is no longer needed.

Healthcare professionals can telephone Daiichi Sankyo, Inc. (1-877-437-7763) for information on this product.

Manufactured for: Daiichi Sankyo, Inc.
Parsippany, NJ 07054

©2017, Daiichi Sankyo, Inc.

This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: 2/2017

  Medication Guide

  Morphabond ER™ ('môr-'fa-'bänd ē-r) (morphine sulfate) extended-release tablets, CII

  Morphabond ER is:

  • A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage pain severe enough to require daily around-the-clock, long-term treatment with an opioid, when other pain treatments such as non-opioid pain medicines or immediate-release opioid medicines do not treat your pain well enough or you cannot tolerate them.
  • A long-acting (extended-release) opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.
  • Not for use to treat pain that is not around-the-clock.

  Important information about Morphabond ER:

  • Get emergency help right away if you take too much Morphabond ER (overdose). When you first start taking Morphabond ER, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur.
  • Taking Morphabond ER with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.
  • Never give anyone your Morphabond ER. They could die from taking it. Store Morphabond ER away from children and in a safe place to prevent stealing or abuse. Selling or giving away Morphabond ER is against the law.

  Do not take Morphabond ER if you have:

  • severe asthma, trouble breathing, or other lung problems.
  • a bowel blockage or have narrowing of the stomach or intestines.

  Before taking Morphabond ER, tell your healthcare provider if you have a history of:

  • head injury, seizures
  • problems urinating
  • abuse of street or prescription drugs, alcohol addiction, or mental health problems
  • liver, kidney, thyroid problems
  • pancreas or gallbladder problems

  Tell your healthcare provider if you are:

  • pregnant or planning to become pregnant. Prolonged use of Morphabond ER during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.
  • breastfeeding. Not recommended during treatment with Morphabond ER. It may harm your baby.
  • taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking Morphabond ER with certain other medicines can cause serious side effects and could lead to death.

  When taking Morphabond ER:

  • Do not change your dose. Take Morphabond ER exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed.
  • Take your prescribed dose every 12 hours, as directed by your healthcare provider. Do not take more than your prescribed dose. If you miss a dose, take your next dose at the usual time.
  • Swallow Morphabond ER whole. Do not cut, break, chew, crush, dissolve, snort, or inject Morphabond ER because this may cause you to overdose and die.
  • Call your healthcare provider if the dose you are taking does not control your pain.
  • Do not stop taking Morphabond ER without talking to your healthcare provider.
  • After you stop taking Morphabond ER, flush any unused tablets down the toilet.

  While taking Morphabond ER DO NOT:

  • Drive or operate heavy machinery, until you know how Morphabond ER affects you. Morphabond ER can make you sleepy, dizzy, or lightheaded.
  • Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with Morphabond ER may cause you to overdose and die.

  The possible side effects of Morphabond ER are:

  • constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe.

Get emergency medical help if you have:

trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.

These are not all the possible side effects of Morphabond ER. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov

Manufactured for Daiichi Sankyo, Inc.


For Healthcare Professionals

Applies to morphine: compounding powder, injectable solution, injectable tablet soluble, intravenous solution, oral capsule, oral capsule extended release, oral concentrate, oral liquid, oral solution, oral tablet, oral tablet extended release, rectal suppository, spinal solution

Nervous system

Central nervous system side effects may be either depressant or excitatory. Excitatory symptoms are sometimes ignored as possible side effects of morphine (the active ingredient contained in MorphaBond) Severe adverse effects such as respiratory depression can be treated with the opioid antagonist naloxone.

Patients receiving continuous infusion of morphine sulfate via indwelling intrathecal catheter should be monitored for new neurologic signs or symptoms. Further assessment or intervention should be based on the clinical condition of the individual patient.

Myoclonic spasms may occur in patients receiving high dose morphine, particularly in the setting of renal dysfunction. Hyperalgesia has also been reported with high doses.[Ref]

Very common (10% or more): Drowsiness (28%)
Common (1% to 10%): Dizziness, sedation, fever, anxiety, confusion, tremor, diaphoresis, lethargy, feeling of warmth
Uncommon (0.1% to 1%): Withdrawal symptoms after either abrupt cessation or fast tapering of the drug, headache, chills, flu syndrome, malaise, withdrawal syndrome, pallor, facial flushing, syncope, loss of concentration, insomnia, amnesia, paresthesia, agitation, vertigo, foot drop, ataxia, hypesthesia, slurred speech, hallucinations, euphoria, apathy, seizures, myoclonus
Frequency not reported: Inflammatory masses including granulomas (some of which have resulted in serous neurologic impairment including paralysis) in patients receiving continuous infusion of opioids via indwelling intrathecal catheter[Ref]

Respiratory

Common (1% to 10%): Respiratory depression
Uncommon (0.1% to 1%): Hiccup, rhinitis, atelectasis, asthma, hypoxia, voice alteration, depressed cough reflex, noncardiogenic pulmonary edema, bronchospasm[Ref]

Gastrointestinal

Morphine may cause constriction of the common bile duct and spasm of the sphincter of Oddi, thereby increasing intrabiliary pressure and worsening, rather than relieving, biliary colic.

In addition, morphine (the active ingredient contained in MorphaBond) may cause intense but uncoordinated duodenal contraction and decreased gastric emptying.[Ref]

Common (1% to 10%): Dry mouth, constipation, nausea, diarrhea, anorexia, abdominal pain, vomiting
Uncommon (0.1% to 1%): Dysphagia, dyspepsia, stomach atony disorder, gastroesophageal reflux, delayed gastric emptying, biliary colic, increased gastroesophageal reflux, intestinal obstruction[Ref]

Cardiovascular

Common (1% to 10%): Chest pain
Uncommon (0.1% to 1%): Tachycardia, atrial fibrillation, hypertension, hypotension, palpitations, bradycardia, vasodilation[Ref]

Psychiatric

Uncommon (0.1% to 1%): Abnormal thinking, abnormal dreams, depression, fearfulness, agitation, paranoia, psychosis, hypervigilance, hallucinations, delirium
Frequency not reported: Withdrawal symptoms after abrupt cessation of therapy[Ref]

Genitourinary

Uncommon (0.1% to 1%): Urinary abnormality, urinary retention, urinary hesitancy[Ref]

The risk of acute urinary retention is very high when morphine is administered by epidural or intrathecal injection. Clinicians should be attentive to the increased risk of urosepsis in this setting, particularly if instrumentation of the urinary tract is necessary.[Ref]

Hematologic

Common (1% to 10%): Anemia, leukopenia
Uncommon (0.1% to 1%): Thrombocytopenia[Ref]

Endocrine

Uncommon (0.1% to 1%): Hyponatremia due to inappropriate ADH secretion, gynecomastia, amenorrhea, reduced libido, reduced potency, prolonged labor[Ref]

Musculoskeletal

Common (1% to 10%): Asthenia, accidental injury
Uncommon (0.1% to 1%): Back pain, bone pain, arthralgia
Frequency not reported: Opioid-induced involuntary muscle hyperactivity with chronic high doses[Ref]

Dermatologic

Common (1% to 10%): Rash
Uncommon (0.1% to 1%): Decubitus ulcer, pruritus, skin flush[Ref]

Ocular

Uncommon (0.1% to 1%): Amblyopia, conjunctivitis, miosis, blurred vision, nystagmus, diplopia[Ref]

Hypersensitivity

Very rare (less than 0.01%): Hypersensitivity reactions, anaphylaxis[Ref]

Hepatic

Uncommon (0.1% to 1%): Increases in hepatic enzymes[Ref]

Metabolic

Common (1% to 10%): Peripheral edema
Uncommon (0.1% to 1%): Hyponatremia

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

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