MS CONTIN- morphine sulfate tablet

Country: United States

Language: English

Source: NLM (National Library of Medicine)

Active ingredient:

morphine sulfate (UNII: X3P646A2J0) (morphine - UNII:76I7G6D29C)

Available from:

Rhodes Pharmaceuticals L.P.

INN (International Name):

morphine sulfate

Composition:

morphine sulfate 15 mg

Administration route:

ORAL

Prescription type:

PRESCRIPTION DRUG

Therapeutic indications:

MS CONTIN is indicated for the management of severe and persistent pain that requires an extended treatment period with a daily opioid analgesic and for which alternative treatment options are inadequate. Limitations of Use - Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration, and because of the greater risks of overdose and death with extended- release/long-acting opioid formulations [see Warnings and Precautions (5.1)] , reserve MS CONTIN for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. - MS CONTIN is not indicated as an as-needed (prn) analgesic. MS CONTIN is 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), Drug Interactions (7)] . - Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.12)] - Hypersensitivity (e.g., anaphylaxis) to morphine [see Adverse Reactions (6.2)] Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal withdrawal syndrome [see Warnings and Precautions (5.4)]. There are no available data with MS CONTIN 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 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 (5.4)] . 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. MS CONTIN is not recommended for use in pregnant women during or immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including MS CONTIN, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data 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). 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 MS Contin. 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 MS CONTIN. Clinical Considerations Monitor infants exposed to MS CONTIN through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breastfeeding is stopped. 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 (6.2), Clinical Pharmacology (12.2), Nonclinical Toxicology (13.1)]] . 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) ]. The safety and effectiveness in pediatric patients below the age of 18 have not been established. The pharmacokinetics of MS CONTIN have not been studied in elderly patients. Clinical studies of MS CONTIN 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, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of MS CONTIN slowly in geriatric patients and frequently reevaluate 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. Morphine pharmacokinetics have been reported to be significantly altered in patients with cirrhosis. Start these patients with a lower than usual dosage of MS CONTIN and titrate slowly while regularly evaluating for signs of respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3)]. Morphine pharmacokinetics are altered in patients with renal failure. Start these patients with a lower than usual dosage of MS CONTIN and titrate slowly while regularly evaluating for signs of respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3)]. MS CONTIN contains morphine, a Schedule II controlled substance. MS CONTIN contains morphine, a substance with a high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions (5.1)] . Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than to other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of MS CONTIN increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of MS CONTIN with alcohol and/or other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction. All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of MS CONTIN abuse include those with a history of prolonged use of any opioid, including products containing morphine, those with a history of drug or alcohol abuse, or those who use MS CONTIN in combination with other abused drugs. "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 people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. MS CONTIN, like other opioids, can be diverted for nonmedical 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 reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of MS CONTIN Abuse of MS CONTIN poses a risk of overdose and death. This risk is increased with concurrent use of MS CONTIN with alcohol and/or other CNS depressants [see Warning and Precautions (5.1, 5.3), Drug Interactions (7)]. Taking cut, broken, chewed, crushed, or dissolved MS CONTIN enhances drug release and increases the risk of overdose and death. MS CONTIN is approved for oral use only. Due to the presence of talc as one of the excipients in MS CONTIN, parenteral abuse can be expected to result in local tissue necrosis, infection, pulmonary granulomas, embolism and death, 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. Both tolerance and physical dependence can develop during use of opioid therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity, (e.g., naloxone), 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 use. Do not abruptly discontinue MS CONTIN in a patient physically dependent on opioids. Rapid tapering of MS CONTIN in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. When discontinuing MS CONTIN, gradually taper the dosage using a patient-specific plan that considers the following: the dose of MS CONTIN the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration (2.6), Warnings and Precautions (5.14)]. 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)] .

Product summary:

MS CONTIN® (morphine sulfate extended-release tablets) are supplied as follows: 15 mg - round, blue-colored, film-coated tablets bearing the symbol PF on one side and M 15 on the other. 30 mg - round, lavender-colored, film-coated tablets bearing the symbol PF on one side and M 30 on the other. 60 mg - round, orange-colored, film-coated tablets bearing the symbol PF on one side and M 60 on the other. 100 mg - round, gray-colored, film-coated tablets bearing the symbol PF on one side and 100 on the other. 200 mg - capsule-shaped, green-colored, film-coated tablets bearing the symbol PF on one side and M 200 on the other. Store at 25°C (77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Store MS CONTIN securely and dispose of properly [see Patient Counseling Information (17)] . Dispense in a tight, light-resistant container.

Authorization status:

New Drug Application

Patient Information leaflet

Rhodes Pharmaceuticals L.P.
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MEDICATION GUIDE
MS CONTIN® (MS-KON-TIN) (MORPHINE SULFATE EXTENDED-RELEASE TABLETS),
CII
This Medication Guide has been approved by the U.S.
Food and Drug Administration.
Revised: 12/2023
MS CONTIN is:
•
A strong prescription pain medicine that contains an opioid (narcotic)
that is used to manage
severe and persistent pain that required an extended treatment period
with a daily opioid pain
medicine, when other pain 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 to be taken on an "as needed" basis.
Important information about MS CONTIN:
•
Get emergency help or call 911 right away if you take too much MS
CONTIN (overdose). When
you first start taking MS CONTIN, 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. Talk
to your healthcare provider about naloxone, a medicine for the
emergency treatment of an opioid
overdose.
•
Taking MS CONTIN 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 else your MS CONTIN. They could die from taking it.
Selling or giving away
MS CONTIN is against the law.
•
Store MS CONTIN securely, out of sight and reach of children, and in a
location not accessible
by others, including visitors to the home.
Do not take MS CONTIN if you have:
•
severe asthma, trouble breathing, or other lung problems.
•
a bowel blockage or have narrowing of the stomach or intestines.
Before taking MS CONTIN, tell your healthcare provider if you have a
history of:
•
Head injury, seizures
•
problems urinating
•
liver,

Summary of Product characteristics

MS CONTIN- MORPHINE SULFATE TABLET
RHODES PHARMACEUTICALS L.P.
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HIGHLIGHTS OF PRESCRIBING INFORMATION
THESE HIGHLIGHTS DO NOT INCLUDE ALL THE INFORMATION NEEDED TO USE MS
CONTIN SAFELY AND
EFFECTIVELY. SEE FULL PRESCRIBING INFORMATION FOR MS CONTIN.
MS CONTIN (MORPHINE SULFATE EXTENDED-RELEASE TABLETS), FOR ORAL USE
CII
INITIAL U.S. APPROVAL: 1941
WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF MS CONTIN
_SEE FULL PRESCRIBING INFORMATION FOR COMPLETE BOXED WARNING_.
MS CONTIN EXPOSES USERS TO RISKS OF ADDICTION, ABUSE, AND MISUSE,
WHICH CAN LEAD
TO OVERDOSE AND DEATH. ASSESS PATIENT'S RISK BEFORE PRESCRIBING AND
REASSESS
REGULARLY FOR THESE BEHAVIORS AND CONDITIONS. (5.1)
SERIOUS, LIFE-THREATENING, OR FATAL RESPIRATORY DEPRESSION MAY OCCUR,
ESPECIALLY
DURING INITIATION OR FOLLOWING A DOSAGE INCREASE. TO REDUCE THE RISK
OF RESPIRATORY
DEPRESSION, PROPER DOSING AND TITRATION OF MS CONTIN ARE ESSENTIAL.
INSTRUCT
PATIENTS TO SWALLOW MS CONTIN TABLETS WHOLE TO AVOID EXPOSURE TO A
POTENTIALLY FATAL
DOSE OF MORPHINE. (5.2)
ACCIDENTAL INGESTION OF MS CONTIN, ESPECIALLY BY CHILDREN, CAN RESULT
IN A FATAL
OVERDOSE OF MORPHINE. (5.2)
CONCOMITANT USE OF OPIOIDS WITH BENZODIAZEPINES OR OTHER CENTRAL
NERVOUS SYSTEM
(CNS) DEPRESSANTS, INCLUDING ALCOHOL, MAY RESULT IN PROFOUND SEDATION,
RESPIRATORY
DEPRESSION, COMA, AND DEATH. RESERVE CONCOMITANT PRESCRIBING FOR USE
IN PATIENTS
FOR WHOM ALTERNATIVE TREATMENT OPTIONS ARE INADEQUATE. (5.3, 7)
IF OPIOID USE IS REQUIRED FOR AN EXTENDED PERIOD OF TIME IN A PREGNANT
WOMAN,
ADVISE THE PATIENT OF THE RISK OF NEONATAL OPIOID WITHDRAWAL SYNDROME
WHICH MAY
BE LIFE-THREATENING IF NOT RECOGNIZED AND TREATED. ENSURE THAT
MANAGEMENT BY
NEONATOLOGY EXPERTS WILL BE AVAILABLE AT DELIVERY. (5.4)
HEALTHCARE PROVIDERS ARE STRONGLY ENCOURAGED TO COMPLETE A REMS
COMPLIANT
EDUCATION PROGRAM AND TO COUNSEL PATIENTS AND CAREGIVERS ON SERIOUS
RISKS, SAFE
USE, AND THE IMPORTANCE OF READING THE MEDICATION GUIDE WITH EACH
PRESCRIPTION.
(5.5)
RECENT MAJOR CHANGES
Boxed Warning
12/2023
Indica