Morphine Sulfate

Par Pharmaceutical Inc.
Par Pharmaceutical Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use Morphine Sulfate Extended-Release Capsules, USP safely and effectively. See full prescribing information for Morphine Sulfate Extended-release Capsules, USP.Morphine Sulfate Extended-release Capsules, USP, for oral use, CIIInitial U.S. Approval: 1941 RECENT MAJOR CHANGESBoxed Warning                                               7/2012Indications and Usage (1)                                7/2012Dosage and Administration (2)                         7/2012Contraindications (4)                                       7/2012Warnings and Precautions (5)                          7/2012BOXED WARNINGWARNING: ABUSE POTENTIAL, LIFE-THREATENING RESPIRATORY DEPRESSION, AND ACCIDENTAL EXPOSURE See full prescribing information for complete boxed warning. • Morphine sulfate extended-release capsules contain pellets of morphine sulfate, a Schedule II controlled substance. Monitor for signs of misuse, abuse, and addiction during morphine sulfate extended-release capsules therapy. ( 5.1 , 9 ) • Fatal respiratory depression may occur, with highest risk at initiation and with dose increases. Instruct patients on proper administration of morphine sulfate extended-release capsules to reduce the risk. ( 5.2 ) • Accidental ingestion of morphine sulfate extended-release capsules can result in fatal overdose of morphine, especially in children. ( 5.3 ) INDICATIONS AND USAGEMorphine sulfate extended-release capsules, USP are an opioid agonist product indicated for the management of moderate to severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time (1) Limitations of Use • Morphine sulfate extended-release capsules are not for use: ∘As an as-needed (prn) analgesic (1) ∘For pain that is mild or not expected to persist for an extended period of time (1) ∘For acute pain (1) ∘For postoperative pain, unless the patient is already receiving chronic opioid therapy prior to surgery, or if the postoperative pain is expected to be moderate to severe and persist for an extended period of time (1) •Morphine sulfate extended-release capsules USP, 100 mg are only for patients in whom tolerance to an opioid of comparable potency is established. (1) DOSAGE AND ADMINISTRATION •Individualize dosing based on patient’s prior analgesic treatment experience, and titrate as needed to provide adequate analgesia and minimize adverse reactions. (2.1, 2.2) •Instruct patients to swallow morphine sulfate extended-release capsules, USP intact, or to sprinkle the capsule contents on applesauce and immediately swallow. (2.4) •Do not abruptly discontinue morphine sulfate extended-release capsules, USP in a physically dependent patient. (2.3, 5.11) DOSAGE FORMS AND STRENGTHSCapsules (morphine sulfate) 20 mg , 30 mg, 50 mg, 60 mg, 80 mg, 100 mg (3)CONTRAINDICATIONS •Significant respiratory depression (4) •Acute or severe bronchial asthma (4) •Known or suspected paralytic ileus (4) •Hypersensitivity to morphine (4) WARNINGS AND PRECAUTIONS •Elderly, cachectic, and debilitated patients and patients with chronic pulmonary disease: Monitor closely because of increased risk of respiratory depression. (5.4, 5.5) •Interaction with CNS depressants: Consider dose reduction of one or both drugs because of additive effects. (5.6, 7.2) •Hypotensive effect: Monitor during dose initiation and titration (5.7) •Patients with head injury or increased intracranial pressure: Monitor for sedation and respiratory depression and avoid use of morphine sulfate extended-release in patients with impaired consciousness or coma susceptible to intracranial effects of CO2 retention. (5.8) Side EffectsMost common adverse reactions (>10%): constipation, nausea, and somnolence. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Par Pharmaceutical Companies, Inc. at 1-800-828-9393 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS •Mixed agonist/antagonist opioid analgesics: Avoid use with morphine sulfate extended-release because they may reduce analgesic effect of morphine sulfate extended-release or precipitate withdrawal symptoms. (5.11, 7.3) •Muscle relaxants: Avoid use with morphine sulfate extended-release because of increased risk of respiratory depression. (7.4) •Monoamine oxidase inhibitors (MAOIs): Avoid morphine sulfate extended-release in patients taking MAOIs or within 14 days of stopping such treatment. (7.5) USE IN SPECIFIC POPULATIONSPregnancy: Based on animal data, may cause fetal harm. (8.1) •Nursing mothers: Morphine has been detected in human milk. Closely monitor infants of nursing women receiving morphine sulfate extended-release. (8.3)

FULL PRESCRIBING INFORMATION: CONTENTS*

• WARNING: ABUSE POTENTIAL, LIFE-THREATENING RESPIRATORY DEPRESSION, AND ACCIDENTAL EXPOSURE
• 1 MORPHINE SULFATE INDICATIONS AND USAGE
• 2 MORPHINE SULFATE DOSAGE AND ADMINISTRATION
  • 2.1 Initial Dosing
  • 2.2 Titration and Maintenance of Therapy
  • 2.3 Discontinuation of Morphine Sulfate Extended-release Capsules, USP 
  • 2.4 Administration of Morphine Sulfate Extended-release Capsules, USP
• 3 DOSAGE FORMS AND STRENGTHS
• 4 MORPHINE SULFATE CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Abuse Potential
  • 5.2 Life Threatening Respiratory Depression
  • 5.3 Accidental Exposure
  • 5.4 Elderly, Cachectic, and Debilitated Patients
  • 5.5 Use in Patients with Chronic Pulmonary Disease
  • 5.6 Interactions with CNS Depressants and Illicit Drugs
  • 5.7 Hypotensive Effect
  • 5.8 Use in Patients with Head Injury or Increased Intracranial Pressure
  • 5.9 Use in Patients with Gastrointestinal Conditions
  • 5.10 Use in Patients with Convulsive or Seizure Disorders
  • 5.11 Avoidance of Withdrawal
  • 5.12 Driving and Operating Machinery
• 6 MORPHINE SULFATE ADVERSE REACTIONS
  • 6.1 Clinical Studies Experience
  • 6.2 Post-marketing Experience
• 7 DRUG INTERACTIONS
  • 7.1 Alcohol
  • 7.2 CNS Depressants
  • 7.3 Mixed Agonist/Antagonist Opioid Analgesics
  • 7.4 Muscle Relaxants
  • 7.5 Monoamine Oxidase Inhibitors (MAOIs)
  • 7.6 Cimetidine
  • 7.7 Diuretics
  • 7.8 Anticholinergics
  • 7.9 P-Glycoprotein (PGP) Inhibitors
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.2 Labor and Delivery
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Neonatal Opioid Withdrawal Syndrome
• 9 DRUG ABUSE AND DEPENDENCE
  • 9.1 Controlled Substance
  • 9.2 Abuse
  • 9.3 Dependence
• 10 OVERDOSAGE
• 11 MORPHINE SULFATE DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION
• Package/Label Display Panel
• Package/Label Display Panel
• Package/Label Display Panel
• Package/Label Display Panel
• Package/Label Display Panel
• Package/Label Display Panel

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Morphine sulfate extended-release capsules, USP are indicated for the management of moderate to severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time.

Limitations of Use

Morphine sulfate extended-release capsules, USP are not for use:

• •As an as-needed (prn) analgesic
  
• •For pain that is mild or not expected to persist for an extended period of time
  
• •For acute pain
  
• •For postoperative pain unless the patient is already receiving chronic opioid therapy prior to surgery or if the postoperative pain is expected to be moderate to severe and persist for an extended period of time.

Morphine sulfate extended-release capsules USP, 100 mg are only for patients in whom tolerance to an opioid of comparable potency is established. Patients considered opioid-tolerant are those taking at least 60 mg of morphine daily, at least 30 mg of oral oxycodone daily, at least 8 mg of oral hydromorphone daily, or an equianalgesic dose of another opioid for a week or longer.

2 DOSAGE AND ADMINISTRATION

2.1 Initial Dosing

Initiate the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment experience. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with morphine sulfate extended-release capsules [see Warnings and Precautions (5.2)].

Consider the following factors when selecting an initial dose of morphine sulfate extended-release capsules:

• •Total daily dose, potency, and any prior opioid the patient has been taking previously;
  
• •Reliability of the relative potency estimate used to calculate the equivalent dose of morphine needed (Note: potency estimates may vary with the route of administration);
  
• •Patient's degree of opioid experience and opioid tolerance;
  
• •General condition and medical status of the patient;
  
• •Concurrent medication;
  
• •Type and severity of the patient's pain.

Morphine sulfate extended-release capsules are administered at a frequency of either once daily (every 24 hours) or twice daily (every 12 hours).

Use of Morphine Sulfate Extended-release Capsules as the First Opioid Analgesic

There has been no evaluation of morphine sulfate extended-release capsules as an initial opioid analgesic in the management of pain. Because it may be more difficult to titrate a patient to adequate analgesia using an extended-release morphine, begin treatment using an immediate-release morphine formulation and then convert patients to morphine sulfate extended-release capsules as described below.

Conversion from Other Oral Morphine Formulations to Morphine Sulfate Extended-release Capsules

Patients receiving other oral morphine formulations may be converted to morphine sulfate extended-release capsules by administering one-half of the patient's total daily oral morphine dose as morphine sulfate extended-release capsules twice daily or by administering the total daily oral morphine dose as morphine sulfate extended-release capsules once daily. There are no data to support the efficacy or safety of prescribing morphine sulfate extended-release capsules more frequently than every 12 hours.

Morphine sulfate extended-release capsules are not bioequivalent to other extended-release morphine preparations. Conversion from morphine sulfate extended-release capsules to the same total daily dose of another extended-release morphine product may lead to either excessive sedation at peak or inadequate analgesia at trough. Therefore, monitor patients closely when initiating morphine sulfate extended-release capsules therapy and adjust the dosage of morphine sulfate extended-release capsules as needed.

Conversion from Parenteral Morphine, or Other Opioids to Morphine Sulfate Extended-release Capsules

While there are useful tables of oral and parenteral equivalents, there is substantial inter-patient variation in the relative potency of different opioid drugs and formulations. As such, it is safer to underestimate a patient's 24-hour oral morphine requirement and provide rescue medication (e.g. immediate-release morphine) than to overestimate and manage an adverse reaction. Consider the following general points:

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

Other Oral or Parenteral Opioids to Oral Morphine Sulfate: 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.

The first dose of morphine sulfate extended-release capsules may be taken with the last dose of any immediate-release opioid medication due to the extended-release characteristics of the morphine sulfate extended-release capsules formulation.

2.2 Titration and Maintenance of Therapy

Individually titrate morphine sulfate extended-release capsules to a dose that provides adequate analgesia and minimizes adverse reactions at a frequency of either once or twice daily. Continually reevaluate patients receiving morphine sulfate extended-release capsules to assess the maintenance of pain control and the relative incidence of adverse reactions. During chronic therapy, especially for non-cancer-related pain (or pain associated with other terminal illnesses), periodically reassess the continued need for the use of opioid analgesics.

If the level of pain increases, attempt to identify the source of increased pain, while adjusting the morphine sulfate extended-release capsules dose to decrease the level of pain. Because steady-state plasma concentrations are approximated within 24 to 36 hours, morphine sulfate extended-release capsules dosage adjustments may be done every 1 to 2 days. Patients who experience breakthrough pain may require dosage adjustment or rescue medication with a small dose of an immediate-release medication. In patients experiencing inadequate analgesia with once daily dosing of morphine sulfate extended-release capsules, consider a twice daily regimen.

If signs of excessive opioid-related adverse reactions are observed, the next dose may be reduced. Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

2.3 Discontinuation of Morphine Sulfate Extended-release Capsules, USP 

When a patient no longer requires therapy with morphine sulfate extended-release capsules, use a gradual downward titration, of the dose every two to four days, to prevent signs and symptoms of withdrawal in the physically-dependent patient. Do not abruptly discontinue morphine sulfate extended-release capsules.

2.4 Administration of Morphine Sulfate Extended-release Capsules, USP

Instruct patients to swallow morphine sulfate extended-release capsules intact. The pellets in the capsules are not to be crushed, dissolved, or chewed due to the risk of rapid release and absorption of a potentially fatal dose of morphine [see Warnings and Precautions (5.2)].

Alternatively, the contents of the morphine sulfate extended-release capsules (pellets) may be sprinkled over applesauce and then swallowed. This method is appropriate only for patients able to reliably swallow the applesauce without chewing. Other foods have not been tested and should not be substituted for applesauce. Instruct the patient to:

• •Sprinkle the pellets onto a small amount of applesauce and consume immediately without chewing.
  
• •Rinse the mouth to ensure all pellets have been swallowed.
  
• •Discard any unused portion of the morphine sulfate extended-release capsules after the contents have been sprinkled on applesauce.

The contents of the morphine sulfate extended-release capsules (pellets) may be administered through a 16 French gastrostomy tube.

• 1.Flush the gastrostomy tube with water to ensure that it is wet.
  
• 2.Sprinkle the morphine sulfate extended-release pellets into 10 mL of water.
  
• 3.Use a swirling motion to pour the pellets and water into the gastrostomy tube through a funnel.
  
• 4.Rinse the beaker with a further 10 mL of water and pour this into the funnel.
  
• 5.Repeat rinsing until no pellets remain in the beaker.

Do not administer morphine sulfate extended-release pellets through a nasogastric tube.

3 DOSAGE FORMS AND STRENGTHS

Morphine sulfate extended-release capsules, USP contain white to off-white or tan colored polymer coated extended-release pellets of morphine sulfate and are available in six dose strengths.

20 mg size “4” CS, hard gelatin capsules, yellow opaque cap printed with “KADIAN” and yellow opaque body printed with “20 mg”. Capsules are supplied in a bottle of 100 (NDC 49884-833-01).

30 mg size “4” CS, hard gelatin capsules, blue violet opaque cap printed with “KADIAN” and blue violet body printed with “30mg”. Capsules are supplied in a bottle of 100 (NDC 49884-834-01).

50 mg size “2” CS, hard gelatin capsules, blue opaque cap printed with “KADIAN” and blue opaque body printed with “50 mg”. Capsules are supplied in a bottle of 100 (NDC 49884-835-01).

60 mg size “1” CS, hard gelatin capsules, pink opaque cap printed with “KADIAN” and pink opaque body printed with “60 mg”. Capsules are supplied in a bottle of 100 (NDC 49884-836-01).

80 mg size “0” CS, hard gelatin capsules, light orange opaque cap printed with “KADIAN” and light orange opaque body printed with “80 mg”. Capsules are supplied in a bottle of 100 (NDC 49884-837-01).

100 mg size “0” CS, hard gelatin capsules, green opaque cap printed with “KADIAN” and green opaque body printed with “100mg”. Capsules are supplied in a bottle of 100 (NDC 49884-838-01).

4 CONTRAINDICATIONS

Morphine sulfate extended-release is contraindicated in patients with

• •Significant respiratory depression
  
• •Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
  
• •Known or suspected paralytic ileus
  
• •Hypersensitivity (e.g., anaphylaxis) to morphine [see Adverse Reactions (6.2)]

5 WARNINGS AND PRECAUTIONS

5.1 Abuse Potential

Morphine sulfate extended-release contains morphine, an opioid agonist and a Schedule II controlled substance. Morphine can be abused in a manner similar to other opioid agonists, legal or illicit. Opioid agonists are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing morphine sulfate extended-release in situations where there is concern about increased risks of misuse, abuse, or diversion. Concerns about abuse, addiction, and diversion should not, however, prevent the proper management of pain.

Assess each patient’s risk for opioid abuse or addiction prior to prescribing morphine sulfate extended-release. The risk for opioid abuse is increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Patients at increased risk may still be appropriately treated with modified-release opioid formulations; however these patients will require intensive monitoring for signs of misuse, abuse, or addiction. Routinely monitor all patients receiving opioids for signs of misuse, abuse, and addiction because these drugs carry a risk for addiction even under appropriate medical use.

Misuse or abuse of morphine sulfate extended-release by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the opioid and pose a significant risk that could result in overdose and death [see Overdosage (10)].

Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

5.2 Life Threatening Respiratory Depression

Respiratory depression is the primary risk of morphine sulfate extended-release. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with a “sighing” pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (10)].

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of morphine sulfate extended-release, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with morphine sulfate extended-release and following dose increases. Instruct patients against use by individuals other than the patient for whom morphine sulfate extended-release was prescribed and to keep morphine sulfate extended-release out of the reach of children, as such inappropriate use may result in fatal respiratory depression.

To reduce the risk of respiratory depression, proper dosing and titration of morphine sulfate extended-release are essential [see Dosage and Administration (2.1, 2.2)]. Overestimating the morphine sulfate extended-release dose when converting patients from another opioid product can result in fatal overdose with the first dose. Respiratory depression has also been reported with use of modified-release opioids when used as recommended and not misused or abused.

To further reduce the risk of respiratory depression, consider the following:

• •Proper dosing and titration are essential and morphine sulfate extended-release should only be prescribed by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain. Morphine sulfate extended-release capsules 100 mg are for use in opioid-tolerant patients only. Ingestion of this strength of morphine sulfate extended-release capsules or of the pellets within the capsule may cause fatal respiratory depression when administered to patients not already tolerant to high doses of opioids.
  
• •Instruct patients to swallow morphine sulfate extended-release capsules intact or to sprinkle the capsule contents on applesauce and swallow without chewing. The pellets in the capsules are not to be crushed, dissolved, or chewed. The resulting morphine dose may be fatal, particularly in opioid-naïve individuals.
  
• •Morphine sulfate extended-release is contraindicated in patients with respiratory depression and in patients with conditions that increase the risk of life-threatening respiratory depression [see Contraindications (4)].  

5.3 Accidental Exposure

Accidental consumption of morphine sulfate extended-release, especially in children, can result in a fatal overdose of morphine.

5.4 Elderly, Cachectic, and Debilitated Patients

Respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics due to poor fat stores, muscle wasting, or altered clearance compared to younger, healthier patients. Therefore, monitor such patients closely, particularly when initiating and titrating morphine sulfate extended-release and when morphine sulfate extended-release is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2)].

5.5 Use in Patients with Chronic Pulmonary Disease

Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression for respiratory depression, particularly when initiating therapy and titrating with morphine sulfate extended-release, as in these patients, even usual therapeutic doses of morphine sulfate extended-release may decrease respiratory drive to the point of apnea [see Warnings and Precautions (5.2)]. Consider the use of alternative non-opioid analgesics in these patients if possible.

5.6 Interactions with CNS Depressants and Illicit Drugs

Hypotension, profound sedation, coma, or respiratory depression may result if is used concomitantly with other CNS depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). When considering the use of morphine sulfate extended-release in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, consider the patient’s use, if any, of alcohol or illicit drugs that cause CNS depression. If morphine sulfate extended-release therapy is to be initiated in a patient taking a CNS depressant, start with a lower morphine sulfate extended-release dose than usual and monitor patients for signs of sedation and respiratory depression and consider using a lower dose of the concomitant CNS depressant [see Drug Interactions (7.2)].

5.7 Hypotensive Effect

Morphine sulfate extended-release may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g. phenothiazines or general anesthetics) [see Drug Interactions (7.2)]. Monitor these patients for signs of hypotension after initiating or titrating the dose of morphine sulfate extended-release. In patients with circulatory shock, morphine sulfate extended-release may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of morphine sulfate extended-release in patients with circulatory shock.

5.8 Use in Patients with Head Injury or Increased Intracranial Pressure

Monitor patients taking morphine sulfate extended-release who may be susceptible to the intracranial effects of CO₂ retention (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy with morphine sulfate extended-release. Morphine sulfate extended-release may reduce respiratory drive, and the resultant CO₂ retention can further increase intracranial pressure. Opioids may also obscure the clinical course in a patient with a head injury.

Avoid the use of morphine sulfate extended-release in patients with impaired consciousness or coma.

5.9 Use in Patients with Gastrointestinal Conditions

Morphine sulfate extended-release is contraindicated in patients with paralytic ileus. Avoid the use of morphine sulfate extended-release in patients with other GI obstruction.

The morphine in morphine sulfate extended-release may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Opioids may cause increases in the serum amylase.

5.10 Use in Patients with Convulsive or Seizure Disorders

The morphine in morphine sulfate extended-release may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during morphine sulfate extended-release therapy.

5.11 Avoidance of Withdrawal

Avoid the use of mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including morphine sulfate extended-release,. In these patients, mixed agonists/antagonists analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.

When discontinuing morphine sulfate extended-release, gradually taper the dose [see Dosage and Administration (2.3)]. Do not abruptly discontinue morphine sulfate extended-release.

5.12 Driving and Operating Machinery

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

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed elsewhere in the labeling:

• •Respiratory Depression [see Warnings and Precautions (5.2)]
  
• •Chronic Pulmonary Disease [see Warnings and Precautions (5.5)]
  
• •Head Injuries and Increased Intracranial Pressure [see Warnings and Precautions (5.8)]
  
• •Interactions with Other CNS Depressants [see Warnings and Precautions (5.6)]
  
• •Hypotensive Effect [see Warnings and Precautions (5.7)]
  
• •Gastrointestinal Effects [see Warnings and Precautions (5.9)]
  
• •Seizures [see Warnings and Precautions (5.10)]

In the randomized study, the most common adverse reactions with morphine sulfate extended-release therapy were drowsiness, constipation, nausea, dizziness, and anxiety.  The most common adverse reactions leading to study discontinuation were nausea, constipation (may be severe), vomiting, fatigue, dizziness, pruritus, and somnolence.

6.1 Clinical Studies 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical trials in patients with chronic cancer pain, the most common adverse events reported by patients at least once during therapy were drowsiness (9%), constipation (9%), nausea (7%), dizziness (6%), and anxiety (6%). Other less common side effects expected from morphine sulfate extended-release or seen in less than 2% of patients in the clinical trials were:

• •Body as a Whole: Headache, chills, flu syndrome, back pain, malaise, withdrawal syndrome
  
• •Cardiovascular: Tachycardia, atrial fibrillation, hypotension, hypertension, pallor, facial flushing, palpitations, bradycardia, syncope
  
• •Central Nervous System: Confusion, anxiety, abnormal thinking, abnormal dreams, lethargy, depression, loss of concentration, insomnia, amnesia, paresthesia, agitation, vertigo, foot drop, ataxia, hypesthesia, slurred speech, hallucinations, vasodilation, euphoria, apathy, seizures, myoclonus
  
• •Endocrine: Hyponatremia due to inappropriate ADH secretion, gynecomastia
  
• •Gastrointestinal: Dysphagia, dyspepsia, stomach atony disorder, gastro-esophageal reflux, delayed gastric emptying, biliary colic
  
• •Hemic and Lymphatic: Thrombocytopenia
  
• •Metabolic and Nutritional: Hyponatremia, edema
  
• •Musculoskeletal:  Back pain, bone pain, arthralgia
  
• •Respiratory:  Hiccup, rhinitis, atelectasis, asthma, hypoxia, respiratory insufficiency, voice alteration, depressed cough reflex, non-cardiogenic pulmonary edema
  
• •Skin and Appendages:  Decubitus ulcer, pruritus, skin flush
  
• •Special Senses:  Amblyopia, conjunctivitis, miosis, blurred vision, nystagmus, diplopia
  
• •Urogenital:  Urinary abnormality, amenorrhea, urinary retention, urinary hesitancy, reduced libido, reduced potency, prolonged labor

Four-Week Open-Label Safety Study

In the open-label, 4-week safety study, 1418 patients’ ages 18 to 85 with chronic, non-malignant pain (e.g., back pain, osteoarthritis, neuropathic pain) were enrolled. The most common adverse events reported at least once during therapy were constipation (12%), nausea (9%), and somnolence (3%). Other less common side effects occurring in less than 3% of patients were vomiting, pruritus, dizziness, sedation, dry mouth, headache, fatigue, and rash.

6.2 Post-marketing Experience

Anaphylaxis has been reported with ingredients contained in morphine sulfate extended-release. Advise patients how to recognize such a reaction and when to seek medical attention.

7 DRUG INTERACTIONS

7.1 Alcohol

Concomitant use of alcohol with morphine sulfate extended-release can result in an increase of morphine plasma levels and potentially fatal overdose of morphine. [see Clinical Pharmacology (12.3)].

7.2 CNS Depressants

Concurrent use of morphine sulfate extended-release and other central nervous system (CNS) depressants (e.g. sedatives, hypnotics, general anesthetics, antiemetics, phenothiazines, other tranquilizers, and alcohol) can increase the risk of respiratory depression, hypotension, and profound sedation or coma. Monitor patients receiving CNS depressants and morphine sulfate extended-release for signs of respiratory depression and hypotension. When such combined therapy is contemplated, reduce the initial dose of one or both agents.

7.3 Mixed Agonist/Antagonist Opioid Analgesics

Mixed agonist/antagonist analgesics may reduce the analgesic effect of morphine sulfate extended-release and/or may precipitate withdrawal symptoms in these patients. Avoid the use of agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol) in patients receiving morphine sulfate extended-release.

7.4 Muscle Relaxants

Opioids may enhance the neuromuscular blocking action of skeletal relaxants and produce an increased degree of respiratory depression. Monitor patients receiving muscle relaxants and morphine sulfate extended-release for signs of respiratory depression that may be greater than otherwise expected.

7.5 Monoamine Oxidase Inhibitors (MAOIs)

The effects of morphine may be potentiated by MAOIs. Monitor patients on concurrent therapy with an MAOI and morphine sulfate extended-release for increased respiratory and central nervous system depression. Morphine sulfate extended-release should not be used in patients taking MAOIs or within 14 days of stopping such treatment.

7.6 Cimetidine

Cimetidine can potentiate morphine-induced respiratory depression. There is a report of confusion and severe respiratory depression when a patient undergoing hemodialysis was concurrently administered morphine and cimetidine. Monitor patients for respiratory depression when morphine sulfate extended-release and cimetidine are used concurrently.

7.7 Diuretics

Morphine can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Morphine may also lead to acute retention of urine by causing spasm of the sphincter of the bladder, particularly in men with enlarged prostates.

7.8 Anticholinergics

Anticholinergics or other drugs with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention or reduced gastric motility when morphine sulfate extended-release is used concurrently with anticholinergic drugs.

7.9 P-Glycoprotein (PGP) Inhibitors

PGP inhibitors (e.g. quinidine) may increase the absorption/exposure of morphine by about two-fold. Monitor patients for signs of respiratory and central nervous system depression when PGP inhibitors are used concurrently with morphine sulfate extended-release.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects (Pregnancy Category C)

No formal studies to assess the teratogenic effects of morphine in animals have been conducted. It is also not known whether morphine can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Morphine should be given to a pregnant woman only if clearly needed.

In humans, the frequency of congenital anomalies has been reported to be no greater than expected among the children of 70 women who were treated with morphine during the first four months of pregnancy or in 448 women treated with morphine anytime during pregnancy. Furthermore, no malformations were observed in the infant of a woman who attempted suicide by taking an overdose of morphine and other medication during the first trimester of pregnancy.

Several literature reports indicate that morphine administered subcutaneously during the early gestational period in mice and hamsters produced neurological, soft tissue and skeletal abnormalities. With one exception, the effects that have been reported were following doses that were maternally toxic and the abnormalities noted were characteristic of those observed when maternal toxicity is present. In one study, following subcutaneous infusion of doses greater than or equal to 0.15 mg/kg to mice, exencephaly, hydronephrosis, intestinal hemorrhage, split supraoccipital, malformed sternebrae, and malformed xiphoid were noted in the absence of maternal toxicity. In the hamster, morphine sulfate given subcutaneously on gestation day 8 produced exencephaly and cranioschisis. In rats treated with subcutaneous infusions of morphine during the period of organogenesis, no teratogenicity was observed. No maternal toxicity was observed in this study; however, increased mortality and growth retardation were seen in the offspring. In two studies performed in the rabbit, no evidence of teratogenicity was reported at subcutaneous doses up to 100 mg/kg.

Nonteratogenic Effects

Infants born to mothers who have taken opioids chronically may exhibit neonatal withdrawal syndrome [see Use in Specific Populations (8.6)], reversible reduction in brain volume, small size, decreased ventilatory response to CO₂ and increased risk of sudden infant death syndrome. Morphine sulfate should be used by a pregnant woman only if the need for opioid analgesia clearly outweighs the potential risks to the fetus.

Controlled studies of chronic in utero morphine exposure in pregnant women have not been conducted. Published literature has reported that exposure to morphine during pregnancy in animals is associated with reduction in growth and a host of behavioral abnormalities in the offspring. Morphine treatment during gestational periods of organogenesis in rats, hamsters, guinea pigs and rabbits resulted in the following treatment-related embryotoxicity and neonatal toxicity in one or more studies: decreased litter size, embryo-fetal viability, fetal and neonatal body weights, absolute brain and cerebellar weights, delayed motor and sexual maturation, and increased neonatal mortality, cyanosis and hypothermia. Decreased fertility in female offspring, 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. Decreased litter size and viability were observed in the offspring of male rats administered morphine (25 mg/kg, IP) for 1 day prior to mating. Behavioral abnormalities resulting from chronic morphine exposure of fetal animals included altered reflex and motor skill development, mild withdrawal, and altered responsiveness to morphine persisting into adulthood.

8.2 Labor and Delivery

Morphine sulfate extended-release is not recommended for use in women during and immediately prior to labor, where shorter acting analgesics or other analgesic techniques are more appropriate. Occasionally, opioid analgesics may 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 dilatation which tends to shorten labor.  

Opioids cross the placenta and may produce respiratory depression and psychophysiologic effects in neonates. Closely observe neonates whose mothers received opioid analgesics during labor for signs of respiratory depression. Have a specific opioid antagonist, such as naloxone or nalmefene, available for reversal of opioid-induced respiratory depression in the neonate.

8.3 Nursing Mothers

Morphine is excreted in breast milk, with a milk to plasma morphine AUC ratio of approximately 2.5:1. The amount of morphine received by the infant varies depending on the maternal plasma concentration, the amount of milk ingested by the infant, and the extent of first pass metabolism.

Withdrawal symptoms can occur in breast-feeding infants when maternal administration of morphine is stopped.

Because of the potential for adverse reactions in nursing infants from morphine sulfate extended-release, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

The safety and efficacy of morphine sulfate extended-release in patients less than 18 years have not been established.

8.5 Geriatric Use

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.

8.6 Neonatal Opioid Withdrawal Syndrome

Chronic maternal use of morphine during pregnancy can affect the fetus with subsequent withdrawal signs. Neonatal withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration and severity of neonatal withdrawal syndrome vary based on the drug used, duration of use, the dose of last maternal use, and rate of elimination of the drug by the newborn. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening and should be treated according to protocols developed by neonatology experts.

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Morphine sulfate extended-release contains morphine, a Schedule II controlled substance with a high potential for abuse similar to other opioids including fentanyl, hydromorphone, methadone, oxycodone, and oxymorphone. Morphine sulfate extended-release 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.

9.2 Abuse

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

Drug abuse is the intentional non-therapeutic use of an over-the-counter or prescription drug, even once, for its rewarding psychological or physiological effects. Drug abuse includes, but is not limited to, the following examples: the use of a prescription or over-the counter drug to get “high”, or the use of steroids for performance enhancement and muscle build up.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and include: 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 to addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated claims of loss of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(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. Physicians 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.

Morphine sulfate extended-release, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful recordkeeping of prescribing information, including quantity, frequency, and renewal requests as required by state 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 reduce abuse of opioid drugs.

Risks Specific to Abuse of Morphine Sulfate Extended-release

Morphine sulfate extended-release is for oral use only. Abuse of morphine sulfate extended-release poses a risk of overdose and death. This risk is increased with concurrent abuse of morphine sulfate extended-release with alcohol and other substances. Taking cut, broken, chewed, crushed, or dissolved morphine sulfate extended-release enhances drug release and increases the risk of over dose and death.

Due to the presence of talc as one of the excipients in morphine sulfate extended-release, parenteral abuse 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.

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

Morphine sulfate extended-release should not be abruptly discontinued [see Dosage and Administration (2.3)]. If morphine sulfate extended-release is abruptly discontinued in a physically-dependent patient, an abstinence 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 symptoms [see Use in Specific Populations (8.2, 8.6)].

10 OVERDOSAGE

Clinical Presentation

Acute overdosage with morphine is manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, sometimes, pulmonary edema, bradycardia, hypotension, and death. Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations.

Treatment of Overdose

In cases of overdose, priorities are the reestablishment of a patent airway and institution of assisted or controlled ventilation if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of cardiac and/or pulmonary failure as needed. Cardiac arrest or arrhythmias will require advanced life support techniques.

The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to morphine overdose. Such agents should be administered cautiously to patients who are known, or suspected to be, physically dependent on morphine sulfate extended-release. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute withdrawal syndrome.

Because the duration of reversal would be expected to be less than the duration of action of morphine in morphine sulfate extended-release, carefully monitor the patient until spontaneous respiration is reliably reestablished. Morphine sulfate extended-release will continue to release morphine adding to the morphine load for up to 24 hours after administration, necessitating prolonged monitoring. If the response to opioid antagonists is suboptimal or not sustained, additional antagonist should be given as directed in the product’s prescribing information.

In an individual physically dependent on opioids, administration of the usual dose of the antagonist will precipitate an acute withdrawal. The severity of the withdrawal produced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.

11 DESCRIPTION

Morphine sulfate extended-release capsules are for oral use and contain pellets of morphine sulfate. Morphine sulfate is an agonist at the mu-opioid receptor.

Each morphine sulfate extended-release capsule contains either 20 mg, 30 mg, 50 mg, 60 mg, 80 mg, or 100 mg of Morphine Sulfate USP and the following inactive ingredients common to all strengths: hypromellose, ethylcellulose, methacrylic acid copolymer, polyethylene glycol, diethyl phthalate, talc, corn starch and sucrose.

The capsule shells contain gelatin, silicon dioxide, sodium lauryl sulfate, titanium dioxide, and black ink, D&C yellow #10 (20mg), D&C red #28, FD&C red #40, FD&C blue #1 (50mg), D&C red #28, FD&C red #40, FD&C blue #1 (60mg), FD&C blue #1, FD&C red #40 and FD&C yellow #6 (80mg), D&C yellow #10, FD&C blue #1. The imprint ink contains black iron oxide, potassium hydroxide, propylene glycol, and shellac.

The chemical name of morphine sulfate is 7,8-didehydro-4,5 α- epoxy-17-methyl-morphinan-3,6 α- diol sulfate (2:1) (salt) pentahydrate. The empirical formula is (C₁₇H₁₉NO₃)₂●H₂SO₄●5H₂O and its molecular weight is 758.85.

Morphine sulfate is an odorless, white, crystalline powder with a bitter taste. It has a solubility of 1 in 21 parts of water and 1 in 1000 parts of alcohol, but is practically insoluble in chloroform or ether. The octanol: water partition coefficient of morphine is 1.42 at physiologic pH and the pK_b is 7.9 for the tertiary nitrogen (mostly ionized at pH 7.4). Its structural formula is: