Home – Morphine sulfate

Morphine sulfate

HIGHLIGHTS OF PRESCRIBING INFORMATIONMorphine Sulfate Extended-Release Capsules, USPThese highlights do not include all the information needed to use Morphine sulfate safely and effectively. See full prescribing information for Morphine sulfate. Morphine sulfate (Morphine sulfate) CAPSULE, EXTENDED RELEASE for ORAL use.Initial U.S. Approval: 2010BOXED WARNING WARNING: 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) RECENT MAJOR CHANGES Boxed Warning 07/2012 Indications and Usage (1) 07/2012 Dosage and Administration (2) 07/2012 Contraindications (4) 07/2012 Warnings and Precautions (5) 07/2012INDICATIONS AND USAGE Morphine sulfate extended-release tablets 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 tablets 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 tablets 100 mg and 200 mg tablets 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 intact, or to sprinkle the capsule contents on applesauce and immediately swallow. (2.4) Do not abruptly discontinue morphine sulfate extended-release capsules in a physically dependent patient. (2.3, 5.11) DOSAGE FORMS AND STRENGTHS Capsules: 10 mg, 20 mg, 30 mg, 50 mg, 60 mg, 80 mg, 100 mg, 200 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 capsules in patients with impaired consciousness or coma susceptible to intracranial effects of CO2 retention. (5.8) Side Effects Most common adverse reactions (>10%): constipation, nausea, and somnolence. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact at 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 capsules because they may reduce analgesic effect of morphine sulfate extended-release capsules or precipitate withdrawal symptoms. (5.11, 7.3) Muscle relaxants: Avoid use with morphine sulfate extended-release capsules because of increased risk of respiratory depression. (7.4) Monoamine oxidase inhibitors (MAOIs): Avoid morphine sulfate extended-release capsules in patients taking MAOIs or within 14 days of stopping such treatment. (7.5) USE IN SPECIFIC POPULATIONS Pregnancy: 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 capsules. (8.3)

FULL PRESCRIBING INFORMATION

Abuse Potential

Morphine sulfate extended-release is an opioid agonist and Schedule II controlled substance with an abuse liability similar to other opioid agonists, legal or illicit [see Warnings and Precautions ( 5.1 )] . Assess each patient’s risk for opioid abuse or addiction prior to prescribing morphine sulfate extended-release capsules. 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 depressive disorder). Routinely monitor all patients receiving morphine sulfate extended-release capsules for signs of misuse, abuse, and addiction during treatment [see Drug Abuse and Dependence ( 9 )] .

Life-threatening Respiratory Depression

Respiratory depression, including fatal cases, may occur with use of morphine sulfate extended-release capsules, even when the drug has been used as recommended and not misused or abused [see Warnings and Precautions (5.2 )] . Proper dosing and titration are essential and morphine sulfate extended-release capsules should only be prescribed by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain. Monitor for respiratory depression, especially during initiation of morphine sulfate extended-release capsules or following a dose increase. Instruct patients to swallow morphine sulfate extended-release capsules whole or to sprinkle the contents of the capsule on applesauce and swallow without chewing. Crushing, dissolving, or chewing the pellets within the capsule can cause rapid release and absorption of a potentially fatal dose of morphine.

Accidental Exposure

Accidental consumption of morphine sulfate extended-release capsules, especially in children, can result in a fatal overdose of morphine [see Warnings and Precautions ( 5.3 )] .

Morphine sulfate extended-release capsules 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 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 100 mg and 200 mg capsules 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.

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.

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.

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.

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.

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

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

Morphine sulfate extended-release capsules contain white to off-white or tan colored polymer coated pellets, have an outer opaque capsule with colors as identified below and are available in eight dose strengths:

Each 10 mg capsule has a light blue opaque cap printed with “KADIAN” and a light blue opaque body printed with “10 mg”.

Each 20 mg capsule has a yellow opaque cap printed with “KADIAN” and a yellow opaque body printed with “20 mg”.

Each 30 mg capsule has a blue violet opaque cap printed with “KADIAN” and a blue violet opaque body printed with “30 mg”.

Each 50 mg capsule has a blue opaque cap printed with “KADIAN” and a blue opaque body printed with “50 mg”.

Each 60 mg capsule has a pink opaque cap printed with “KADIAN” and a pink opaque body printed with “60 mg”.

Each 80 mg capsule has a light orange opaque cap printed with “KADIAN” and a light orange opaque body printed with “80 mg”.

Each 100 mg capsule has a green opaque cap printed with “KADIAN” and a green opaque body printed with “100 mg”.

Each 200 mg capsule has a light brown opaque cap printed with “KADIAN” and light brown opaque body printed with “200 mg”.

Morphine sulfate extended-release capsules are 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)]

Morphine sulfate extended-release capsules contain 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 capsules 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 capsules. 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 capsules 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.

Respiratory depression is the primary risk of morphine sulfate extended-release capsules. 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 capsules, 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 capsules and following dose increases. Instruct patients against use by individuals other than the patient for whom morphine sulfate extended-release capsules was prescribed and to keep morphine sulfate extended-release capsules 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 capsules are essential [see Dosage and Administration ( 2.1 , 2.2 )]. Overestimating the morphine sulfate extended-release capsules 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 capsules 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 100 mg and 200 mg capsules 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 capsules are contraindicated in patients with respiratory depression and in patients with conditions that increase the risk of life-threatening respiratory depression [see Contraindications (4)].

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

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 capsules and when morphine sulfate extended-release capsules is given concomitantly with other drugs that depress respiration [see Warnings and Precautions ( 5.2 )].

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 capsules, as in these patients, even usual therapeutic doses of morphine sulfate extended-release capsules 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.

Hypotension, profound sedation, coma, or respiratory depression may result if morphine sulfate extended-release capsules are used concomitantly with other CNS depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). When considering the use of morphine sulfate extended-release capsules 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 capsules therapy is to be initiated in a patient taking a CNS depressant, start with a lower morphine sulfate extended-release capsules 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 )].

Morphine sulfate extended-release capsules 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 capsules. In patients with circulatory shock, morphine sulfate extended-release capsules may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of morphine sulfate extended-release capsules in patients with circulatory shock.

Monitor patients taking morphine sulfate extended-release capsules 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 capsules. Morphine sulfate extended-release capsules 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 capsules in patients with impaired consciousness or coma.

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

The morphine in morphine sulfate extended-release capsules 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.

The morphine in morphine sulfate extended-release capsules 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 capsules therapy.

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 capsules. In these patients, mixed agonists/antagonists analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.

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

Morphine sulfate extended-release capsules 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 capsules and know how they will react to the medication.

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 capsules 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.

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.

Clinical trial patients with chronic cancer pain (n=227) (AE by Body System as seen in 2% or more of patients)	Percentage %
CENTRAL NERVOUS SYSTEM	28
Drowsiness	9
Dizziness	6
Anxiety	5
Confusion	4
Dry Mouth	3
Tremor	2
GASTROINTESTINAL	26
Constipation	9
Nausea	7
Diarrhea	3
Anorexia	3
Abdominal pain	3
Vomiting	2
BODY AS A WHOLE	16
Pain	3
Disease progression	3
Chest pain	2
Diaphoresis	2
Fever	2
Asthenia	2
Accidental Injury	2
RESPIRATORY	3
Dyspnea	3
SKIN & APPENDAGES	3
Rash	3
METABOLIC & NUTRITIONAL	3
Peripheral edema	3
HEMIC & LYMPHATIC	4
Anemia	2
Leukopenia	2

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 capsules 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.

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

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

Concurrent use of morphine sulfate extended-release capsules 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 capsules for signs of respiratory depression and hypotension. When such combined therapy is contemplated, reduce the initial dose of one or both agents.

Mixed agonist/antagonist analgesics may reduce the analgesic effect of morphine sulfate extended-release capsules 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 capsules.

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 capsules for signs of respiratory depression that may be greater than otherwise expected.

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

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 capsules and cimetidine are used concurrently.

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.

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 capsules is used concurrently with anticholinergic drugs.

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 capsules.

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.

Morphine sulfate extended-release capsules are 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.

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 capsules, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

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

Clinical studies of morphine sulfate extended-release capsules did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

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 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.

Morphine sulfate extended-release capsules contain 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 capsules 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, 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 capsules, 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 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 to reduce abuse of opioid drugs.

Risks Specific to Abuse of Morphine Sulfate Extended-Release Capsules

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

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 capsules should not be abruptly discontinued [see Dosage and Administration ( 2.3 )]. If morphine sulfate extended-release capsules are 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 )].

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 re-establishment 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 capsules. 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 capsules, carefully monitor the patient until spontaneous respiration is reliably re-established. Morphine sulfate extended-release capsules 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.

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 10 mg, 20 mg, 30 mg, 50 mg, 60 mg, 80 mg, 100 mg, or 200 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 red #28, FD&C blue #1 (10 mg), D&C yellow #10 (20 mg), FD&C red #3, FD&C blue #1 (30 mg), D&C red #28, FD&C red #40, FD&C blue #1 (50 mg), D&C red #28, FD&C red #40, FD&C blue #1 (60 mg), FD&C blue #1, FD&C red #40, FD&C yellow #6 (80 mg), D&C yellow #10, FD&C blue #1 (100 mg), black iron oxide, yellow iron oxide, red iron oxide (200 mg). 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 (- epoxy-17-methyl-morphinan-3,6 (- 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 pKb is 7.9 for the tertiary nitrogen (mostly ionized at pH 7.4). Its structural formula is:

Morphine sulfate, an opioid agonist, is relatively selective for the mu receptor, although it can interact with other opioid receptors at higher doses. In addition to analgesia, the widely diverse effects of morphine sulfate include analgesia, dysphoria, euphoria, somnolence, respiratory depression, diminished gastrointestinal motility, altered circulatory dynamics, histamine release, physical dependence, and alterations of the endocrine and autonomic nervous systems.

Morphine produces both its therapeutic and its adverse effects by interaction with one or more classes of specific opioid receptors located throughout the body. Morphine acts as a full agonist, binding with and activating opioid receptors at sites in the peri-aqueductal and peri-ventricular grey matter, the ventro-medial medulla and the spinal cord to produce analgesia.

Effects on the Central Nervous System

The principal actions of therapeutic value of morphine are analgesia and sedation. Specific CNS opiate receptors and endogenous compounds with morphine-like activity have been identified throughout the brain and spinal cord and are likely to play a role in the expression of analgesic effects. Morphine produces respiratory depression by direct action on brainstem respiratory centers. The mechanism of respiratory depression involves a reduction in the responsiveness of the brainstem respiratory centers to increases in carbon dioxide tension, and to electrical stimulation. Morphine depresses the cough reflex by direct effect on the cough center in the medulla. Morphine causes miosis, even in total darkness, and little tolerance develops to this effect. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen with worsening hypoxia in the setting of morphine overdose.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Gastric, biliary and pancreatic secretions are decreased by morphine. Morphine causes a reduction in motility associated with an increase in tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone is increased to the point of spasm. The end result is constipation. Morphine can cause a marked increase in biliary tract pressure as a result of spasm of the sphincter of Oddi.

Effects on the Cardiovascular System

Morphine produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Release of histamine may be induced by morphine and can contribute to opioid induced hypotension. Manifestations of histamine release or peripheral vasodilation may include pruritus, flushing, red eyes and sweating.

Effects on the Endocrine System

Opioids inhibit the secretion of ACTH, cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Plasma Level-Analgesia Relationships

While plasma morphine-efficacy relationships can be demonstrated in non-tolerant individuals, they are influenced by a wide variety of factors and are not generally useful as a guide to the clinical use of morphine. The effective dose in opioid-tolerant patients may be 10 to 50 times as great (or greater) than the appropriate dose for opioid-naïve individuals. Dosages of morphine should be chosen and must be titrated on the basis of clinical evaluation of the patient and the balance between therapeutic and adverse effects.

CNS Depressant/Alcohol Interaction

Additive pharmacodynamic effects may be expected when morphine sulfate extended-release capsules are used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.

Absorption

Morphine sulfate extended-release capsules contain polymer coated extended-release pellets of morphine sulfate that release morphine significantly more slowly than oral morphine solution. Following the administration of oral morphine solution, approximately 50% of the morphine absorbed reaches the systemic circulation within 30 minutes compared to 8 hours with an equal amount of morphine sulfate extended-release capsules. Because of pre systemic elimination, only about 20 to 40% of the administered dose reaches the systemic circulation.

Both dose-normalized C_max and dose-normalized AUC_0-48hr values of morphine after a single dose administration of morphine sulfate extended-release capsules in healthy volunteers are less than those for morphine oral solution or an extended-release tablet formulation (Table 1).

When morphine sulfate extended-release capsules were given twice daily to 24 patients with chronic pain due to malignancy, steady state was achieved in about two days. At steady state, morphine sulfate extended-release capsules had a significantly lower C_max and a higher C_min than equivalent doses of oral morphine solution given every 4 hrs and an extended release tablet given twice daily. When given once daily to 24 patients with malignancy, morphine sulfate extended-release capsules had a similar C_max and higher C_min at steady state when compared to an extended release morphine tablets, given twice daily at an equivalent total daily dosage (see Table 1).

The single dose pharmacokinetics of morphine sulfate extended-release capsules are linear over the dosage range of 30 to 100 mg.

Table 1: Mean pharmacokinetic parameters (% coefficient variation) resulting from a fasting single dose study in normal volunteers and a multiple-dose study in patients with cancer pain.
Regimen/Dosage Form	AUC#,+ (ng.h/mL)	C_max+ (ng/mL)	T_max (h)	C_min+ (ng/mL)	Fluctuation^*
# For single dose AUC = AUC_0-48h, for multiple dose AUC = AUC_0-24h at steady state + For single dose parameter normalized to 100 mg, for multiple dose parameter normalized to 100 mg per 24 hours * Steady state fluctuation in plasma concentrations = C_max C_min/C_min ^ Not applicable
Single Dose (n=24)
Morphine Sulfate Extended-Release Capsule	271.0 (19.4)	15.6 (24.4)	8.6 (41.1)	na^	na
Extended Release Tablet	304.3 (19.1)	30.5 (32.1)	2.5 (52.6)	na	na
Morphine Solution	362.4 (42.6)	64.4 (38.2)	0.9 (55.8)	na	na
Multiple Dose (n=24)
Morphine Sulfate Extended-Release Capsule Once Daily	500.9 (38.6)	37.3 (37.7)	10.3 (32.2)	9.9 (52.3)	3.0 (45.5)
Extended Release Tablet Twice Daily	457.3 (40.2)	36.9 (42.0)	4.4 (53.0)	7.6 (60.3)	4.1 (51.5)

Food effect: While concurrent administration of food slows the rate of absorption of morphine sulfate extended-release capsules, the extent of absorption is not affected and morphine sulfate extended-release capsules can be administered without regard to meals.

Distribution

Once absorbed, morphine is distributed to skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen and brain. The volume of distribution of morphine is approximately 3 to 4 L/kg. Morphine is 30 to 35% reversibly bound to plasma proteins. Although the primary site of action of morphine is in the CNS, only small quantities pass the blood brain barrier. Morphine also crosses the placental membranes [see Use in Special Populations ( 8.1 )] and has been found in breast milk [see Use in Special Populations ( 8.3 )].

Metabolism

Major pathways of morphine metabolism include glucuronidation in the liver to produce metabolites including morphine-3-glucuronide, M3G (about 50%) and morphine-6-glucuronide, M6G (about 5 to 15%) and sulfation in the liver to produce morphine-3-etheral sulfate. A small fraction (less than 5%) of morphine is demethylated. M3G has no significant contribution to the analgesic activity. Although M6G does not readily cross the blood-brain barrier, it has been shown to have opioid agonist and analgesic activity in humans.

Studies in healthy subjects and cancer patients have shown that the glucuronide metabolite to morphine mean molar ratios (based on AUC) are similar after both single doses and at steady state for morphine sulfate extended-release capsules, 12 hour extended release morphine sulfate tablets and morphine sulfate solution.

Excretion

Approximately 10% of a morphine dose is excreted unchanged in the urine. Most of the dose is excreted in the urine as M3G and M6G which are then renally excreted. A small amount of the glucuronide metabolites is excreted in the bile and there is some minor enterohepatic cycling. Seven to 10% of administered morphine is excreted in the feces.

The mean adult plasma clearance of morphine is about 20 to 30 mL/minute/kg. The effective terminal half life of morphine after IV administration is reported to be approximately 2 hours. The terminal elimination half-life of morphine following a single dose of morphine sulfate extended-release capsules administration is approximately 11 to 13 hours.

Special Populations

Geriatric Patients: The pharmacokinetics of morphine sulfate extended-release capsules have not been investigated in elderly patients (>65 years) although such patients were included in the clinical studies.

Pediatric Patients: The pharmacokinetics of morphine sulfate extended-release capsules have not been evaluated in a pediatric population.

Gender: No meaningful differences between male and female patients were demonstrated in the analysis of the pharmacokinetic data from clinical studies.

Race: Chinese subjects given intravenous morphine in one study had a higher clearance when compared to Caucasian subjects (1852 ± 116 mL/min versus 1495 ± 80 mL/min).

Hepatic Impairment: The pharmacokinetics of morphine were found to be significantly altered in individuals with alcoholic cirrhosis. The clearance was found to decrease with a corresponding increase in half life. The M3G and M6G to morphine plasma AUC ratios also decreased in these patients indicating a decrease in metabolic activity. Adequate studies of the pharmacokinetics of morphine in patients with severe hepatic impairment have not been conducted.

Renal Impairment: The pharmacokinetics of morphine are altered in patients with renal failure. The AUC is increased and clearance is decreased. Metabolites, M3G and M6G accumulate several fold in patients with renal failure compared to healthy subjects. Adequate studies of the pharmacokinetics of morphine in patients with severe renal impairment have not been conducted.

Carcinogenesis: Studies in animals to evaluate the carcinogenic potential of morphine have not been conducted.

Mutagenesis: No formal studies to assess the mutagenic potential of morphine have been conducted. In the published literature, morphine was found to be mutagenic in vitro increasing DNA fragmentation in human T-cells. Morphine was reported to be mutagenic in the in vivo mouse micronucleus assay and positive for the induction of chromosomal aberrations in mouse spermatids and murine lymphocytes. Mechanistic studies suggest that the in vivo clastogenic effects reported with morphine in mice may be related to increases in glucocorticoid levels produced by morphine in this species. In contrast to the above positive findings, in vitro studies in the literature have also shown that morphine did not induce chromosomal aberrations in human leukocytes or translocations or lethal mutations in Drosophila.

Impairment of Fertility: No formal nonclinical studies to assess the potential of morphine to impair fertility have been conducted. Several nonclinical studies from the literature have demonstrated adverse effects on male fertility in the rat from exposure to morphine. One study in which male rats were administered morphine sulfate subcutaneously prior to mating (up to 30 mg/kg twice daily) and during mating (20 mg/kg twice daily) with untreated females, a number of adverse reproductive effects including reduction in total pregnancies, higher incidence of pseudopregnancies, and reduction in implantation sites were seen. Studies from the literature have also reported changes in hormonal levels (i.e. testosterone, luteinizing hormone, serum corticosterone) following treatment with morphine. These changes may be associated with the reported effects on fertility in the rat.

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

	Morphine Sulfate Extended-Release Capsules, USP 10 mg	Morphine Sulfate Extended-Release Capsules, USP 20 mg	Morphine Sulfate Extended-Release Capsules, USP 30 mg	Morphine Sulfate Extended-Release Capsules, USP 50 mg
Capsule Description	size 4, light blue opaque cap printed with “KADIAN” and light blue opaque body printed with “10 mg”.	size 4, yellow opaque cap printed with “KADIAN” and yellow opaque body printed with “20 mg”.	size 4, blue violet opaque cap printed with “KADIAN” and blue violet opaque body printed with “30 mg”.	size 2, blue opaque cap printed with “KADIAN” and blue opaque body printed with “50 mg”.
Bottle Size	100	100	100	100
NDC #	NDC 0228-3501-11	NDC 0228-3502-11	NDC 0228-3503-11	NDC 0228-3504-11

	Morphine Sulfate Extended-Release Capsules, USP 60 mg	Morphine Sulfate Extended-Release Capsules, USP 80 mg	Morphine Sulfate Extended-Release Capsules, USP 100 mg	Morphine Sulfate Extended-Release Capsules, USP 200 mg
Capsule Description	size 1, pink opaque cap printed with “KADIAN” and pink opaque body printed with “60 mg”.	size 0, light orange opaque cap printed with “KADIAN” and light orange opaque body printed with “80 mg”.	size 0, green opaque cap printed with “KADIAN” and green opaque body printed with “100 mg”.	size 0, light brown opaque cap printed with “KADIAN” and light brown opaque body printed with “200 mg”.
Bottle Size	100	100	100	100
NDC #	NDC 0228-3505-11	NDC 0228-3506-11	NDC 0228-3507-11	NDC 0228-3508-11

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Protect from light and moisture. Dispense in a sealed tamper-evident, childproof, light-resistant container.

See FDA-approved patient labeling (Medication Guide)

Abuse Potential

Inform patients that morphine sulfate extended-release capsules contain morphine, a Schedule II controlled substance that is subject to abuse. Instruct patients not to share morphine sulfate extended-release capsules with others and to take steps to protect morphine sulfate extended-release capsules from theft or misuse.

Life-threatening Respiratory Depression

Discuss the risk of respiratory depression with patients, explaining that the risk is greatest when starting morphine sulfate extended-release capsules or when the dose is increased. Advise patients how to recognize respiratory depression and to seek medical attention if they are experiencing breathing difficulties.

Accidental Exposure

Instruct patients to take steps to store morphine sulfate extended-release capsules securely. Accidental exposure, especially in children, may result in serious harm or death. Advise patients to dispose of unused morphine sulfate extended-release capsules by flushing the capsules down the toilet.

Risks from Concomitant Use of Alcohol and other CNS Depressants

Inform patients that the concomitant use of alcohol with morphine sulfate extended-release capsules can increase the risk of life-threatening respiratory depression.

Inform patients that potentially serious additive effects may occur if morphine sulfate extended-release capsules is used with other CNS depressants, and not to use such drugs unless supervised by a health care provider.

Important Administration Instructions

Instruct patients how to properly take morphine sulfate extended-release capsules, including the following:

●Swallowing morphine sulfate extended-release capsules whole or sprinkling the capsule contents on applesauce and then swallowing without chewing
●Not crushing, chewing, or dissolving the pellets in the capsules
●Using morphine sulfate extended-release capsules exactly as prescribed to reduce the risk of life-threatening adverse reactions (e.g., respiratory depression)
●Not discontinuing morphine sulfate extended-release capsules without first discussing the need for a tapering regimen with the prescriber

Hypotension

Inform patients that morphine sulfate extended-release capsules 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).

Driving or Operating Heavy Machinery

Inform patients that morphine sulfate extended-release capsules 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.

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention.

Anaphylaxis

Inform patients that anaphylaxis has been reported with morphine sulfate extended-release capsules. Advise patients how to recognize such a reaction and when to seek medical attention.

Pregnancy

Advise female patients that morphine sulfate extended-release capsules can cause fetal harm and to inform the prescriber if they are pregnant or plan to become pregnant.

Rx only

Manufactured by:
Actavis Elizabeth LLC
200 Elmora Avenue
Elizabeth, NJ 07207 USA

KADIAN^® is a registered trademark of Actavis Elizabeth LLC.

40-9210

Morphine Sulfate Extended-Release Capsules, USP CII

Morphine sulfate extended-release capsules are:

●A strong prescription pain medicine that contains an opioid (narcotic) that is used to treat moderate to severe around-the-clock pain.
Important information about morphine sulfate extended-release capsules:
●Get emergency help right away if you take too many morphine sulfate extended-release capsules (overdose). Morphine sulfate extended-release capsules overdose can cause life threatening breathing problems that can lead to death.
●Never give anyone else your morphine sulfate extended-release capsules. They could die from taking it. Store morphine sulfate extended-release capsules away from children and in a safe place to prevent stealing or abuse. Selling or giving away morphine sulfate extended-release capsules is against the law.

Do not take morphine sulfate extended-release capsules if you have:

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

Before taking morphine sulfate extended-release capsules, tell your healthcare provider if you have a history of:

•head injury, seizures •liver, kidney, thyroid problems

•problems urinating •pancreas or gallbladder problems

•abuse of street or prescription drugs, alcohol addiction, or mental health problems.

Tell your healthcare provider if you are:

● pregnant or planning to become pregnant. Morphine sulfate extended-release may harm your unborn baby.
● breastfeeding. Morphine sulfate extended-release passes into breast milk and may harm your baby.
●taking prescription or over-the-counter medicines, vitamins, or herbal supplements.

When taking morphine sulfate extended-release capsules:

●Do not change your dose. Take morphine sulfate extended-release capsules exactly as prescribed by your healthcare provider.
●Take your prescribed dose at the same time every day. Do not take more than your prescribed dose in 24 hours. If you miss a dose, take morphine sulfate extended-release capsules as soon as possible and then take your next dose 12 or 24 hours later as directed by your healthcare provider. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule.
●Swallow morphine sulfate extended-release capsules whole. Do not cut, break, chew, crush, dissolve, or inject morphine sulfate extended-release capsules.
●If you cannot swallow morphine sulfate extended-release capsules, see the detailed Instructions for Use.
● Call your healthcare provider if the dose you are taking does not control your pain.
● Do not stop taking morphine sulfate extended-release capsules without talking to your healthcare provider.
●After you stop taking morphine sulfate extended-release capsules, flush any unused capsules down the toilet.

While taking morphine sulfate extended-release capsules Do Not:

●Drive or operate heavy machinery, until you know how morphine sulfate extended-release capsules affects you. Morphine sulfate extended-release capsules can make you sleepy, dizzy, or lightheaded.
●Drink alcohol or use prescription or over-the-counter medicines that contain alcohol.

The possible side effects of morphine sulfate extended-release capsules 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, or you are feeling faint.
These are not all the possible side effects of morphine sulfate extended-release capsules. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or call Actavis at 1-800-432-8534. For more information go to dailymed.nlm.nih.gov

Manufactured by: Actavis Elizabeth LLC, 200 Elmora Avenue, Elizabeth, NJ 07207 USA

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Issue: July 2012

Morphine Sulfate Extended-Release Capsules, USP CII

●If you cannot swallow morphine sulfate extended-release capsules, tell your healthcare provider. There may be another way to take morphine sulfate extended-release capsules that may be right for you. If your doctor tells you that you can take morphine sulfate extended-release capsules using this other way, follow these steps:

Open the morphine sulfate extended-release capsule and sprinkle the pellets over approximately one tablespoon of apple sauce (Figure 1).Swallow all of the apple sauce and pellets right away. Do not save any of the apple sauce and pellets for another dose (Figure 2).Rinse your mouth to make sure you have swallowed all of the pellets. Do not chew the pellets (Figure 3).Flush the empty capsule down the toilet right away (Figure 4).

●
Morphine sulfate extended-release capsules can be opened and the pellets inside the capsule can be sprinkled over apple sauce, as follows:

Figure 1

Figure 2

Figure 3

Figure 4

You should not receive morphine sulfate extended-release capsules through a nasogastric tube.