Graten Li

KADIAN is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Limitations of Use

• Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve KADIAN for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
• KADIAN is not indicated as an as-needed (prn) analgesic.

Graten Li is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Limitations of Use

• Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve Graten Li for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
• Graten Li is not indicated as an as-needed (prn) analgesic.

For the relief of severe pain.

Graten Li tablets are indicated for the relief of severe pain.

For the relief of severe pain in adults, adolescents (aged 13-18 years) and children (aged 1-12 years).

Graten Li injection is indicated for the relief of moderate to severe pain. Graten Li injection is used especially in pain associated with cancer, myocardial infarction and surgery. Morphine also helps to relieve the anxiety and insomnia which may be associated with severe pain.

Initial Dosing

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

KADIAN 100 mg, 130 mg, 150 mg, and 200 mg capsules are only for patients in whom tolerance to an opioid of comparable potency has been established. Patients considered opioid-tolerant are those taking, for one week or longer, 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.

Initiate the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment experience and risk factors for addiction, abuse, and misuse. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with KADIAN.

KADIAN capsules must be taken whole. Crushing, chewing, or dissolving the pellets in KADIAN capsules will result in uncontrolled delivery of morphine and can lead to overdose or death. Patients who are unable to swallow Kadian should be instructed to sprinkle the capsule contents on applesauce and immediately swallow without chewing.

KADIAN is administered at a frequency of either once daily (every 24 hours) or twice daily (every 12 hours).

Use of KADIAN as the First Opioid Analgesic

There has been no evaluation of KADIAN 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 KADIAN as described below.

Use of KADIAN in Patients who are not Opioid Tolerant

The starting dose for patients who are not opioid tolerant is KADIAN 30 mg orally every 24 hours. Patients who are opioid tolerant are those receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, or an equianalgesic dose of another opioid.

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression.

Conversion from Other Opioids to KADIAN

There are no established conversion ratios from other opioids to KADIAN defined by clinical trials. Discontinue all other around-the-clock opioid drugs when KADIAN therapy is initiated and initiate dosing using KADIAN 30 mg orally every 24 hours.

While there are useful tables of opioid equivalents readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products. As such, it is safer to underestimate a patient's 24-hour oral morphine requirements and provide rescue medication (e.g. immediate-release morphine) than to overestimate the 24-hour oral morphine requirements which could result in an adverse reaction.

Conversion from Other Oral Morphine Formulations to KADIAN

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

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

Conversion from Parenteral Morphine, or Other Opioids to KADIAN

When converting from parenteral morphine or other non-morphine opioids (parenteral or oral) to KADIAN, 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.

Conversion from Methadone to KADIAN

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

Titration And Maintenance Of Therapy

Individually titrate KADIAN to a dose that provides adequate analgesia and minimizes adverse reactions at a frequency of either once or twice daily. Continually reevaluate patients receiving KADIAN to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During chronic therapy, periodically reassess the continued need for the use of opioid analgesics.

If the level of pain increases, attempt to identify the source of increased pain, while adjusting the KADIAN dose to decrease the level of pain. Because steady-state plasma concentrations are approximated within 24 to 36 hours, KADIAN dosage adjustments may be done every 1 to 2 days.

Patients who experience breakthrough pain may require a dose increase of KADIAN, or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the KADIAN dose. In patients experiencing inadequate analgesia with once daily dosing of KADIAN, consider a twice daily regimen.

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

Discontinuation Of KADIAN

When a patient no longer requires therapy with KADIAN, 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 KADIAN.

Administration Of KADIAN

KADIAN capsules must be taken whole. Crushing, chewing, or dissolving the pellets in KADIAN capsules will result in uncontrolled delivery of morphine and can lead to overdose or death.

Alternatively, the contents of the KADIAN 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 KADIAN capsules after the contents have been sprinkled on applesauce.

The contents of the KADIAN 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 KADIAN 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 KADIAN pellets through a nasogastric tube.

Initial Dosing

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

Graten Li 100 mg, 130 mg, 150 mg, and 200 mg capsules are only for patients in whom tolerance to an opioid of comparable potency has been established. Patients considered opioid-tolerant are those taking, for one week or longer, 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.

Initiate the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment experience and risk factors for addiction, abuse, and misuse. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with Graten Li.

Graten Li capsules must be taken whole. Crushing, chewing, or dissolving the pellets in Graten Li capsules will result in uncontrolled delivery of morphine and can lead to overdose or death. Patients who are unable to swallow Graten Li should be instructed to sprinkle the capsule contents on applesauce and immediately swallow without chewing.

Graten Li is administered at a frequency of either once daily (every 24 hours) or twice daily (every 12 hours).

Use of Graten Li as the First Opioid Analgesic

There has been no evaluation of Graten Li 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 Graten Li as described below.

Use of Graten Li in Patients who are not Opioid Tolerant

The starting dose for patients who are not opioid tolerant is Graten Li 30 mg orally every 24 hours. Patients who are opioid tolerant are those receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, or an equianalgesic dose of another opioid.

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression.

Conversion from Other Opioids to Graten Li

There are no established conversion ratios from other opioids to Graten Li defined by clinical trials. Discontinue all other around-the-clock opioid drugs when Graten Li therapy is initiated and initiate dosing using Graten Li 30 mg orally every 24 hours.

While there are useful tables of opioid equivalents readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products. As such, it is safer to underestimate a patient's 24-hour oral morphine requirements and provide rescue medication (e.g. immediate-release morphine) than to overestimate the 24-hour oral morphine requirements which could result in an adverse reaction.

Conversion from Other Oral Morphine Formulations to Graten Li

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

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

Conversion from Parenteral Morphine, or Other Opioids to Graten Li

When converting from parenteral morphine or other non-morphine opioids (parenteral or oral) to Graten Li, 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.

Conversion from Methadone to Graten Li

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

Titration And Maintenance Of Therapy

Individually titrate Graten Li to a dose that provides adequate analgesia and minimizes adverse reactions at a frequency of either once or twice daily. Continually reevaluate patients receiving Graten Li to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During chronic therapy, periodically reassess the continued need for the use of opioid analgesics.

If the level of pain increases, attempt to identify the source of increased pain, while adjusting the Graten Li dose to decrease the level of pain. Because steady-state plasma concentrations are approximated within 24 to 36 hours, Graten Li dosage adjustments may be done every 1 to 2 days.

Patients who experience breakthrough pain may require a dose increase of Graten Li, or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the Graten Li dose. In patients experiencing inadequate analgesia with once daily dosing of Graten Li, consider a twice daily regimen.

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

Discontinuation Of Graten Li

When a patient no longer requires therapy with Graten Li, 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 Graten Li.

Administration Of Graten Li

Graten Li capsules must be taken whole. Crushing, chewing, or dissolving the pellets in Graten Li capsules will result in uncontrolled delivery of morphine and can lead to overdose or death.

Alternatively, the contents of the Graten Li 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 Graten Li capsules after the contents have been sprinkled on applesauce.

The contents of the Graten Li 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 Graten Li 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 Graten Li pellets through a nasogastric tube.

Posology

Children under 1 year: Not recommended.

Dosage can be increased under medical supervision according to the severity of the pain and the patient's previous history of analgesic requirements.

Special populations:

Reductions in dosage may be appropriate in the elderly, and in patients with chronic hepatic disease , renal impairment, severe hypothyroidism, adrenocortical insufficiency, prostatic hypertrophy, shock or where sedation is undesirable.

Method of Administration For oral use.

When patients are transferred from other Graten Li preparations to Graten Li Oral Solution dosage titration may be appropriate.

Graten Li Sulfate is readily absorbed from the gastro-intestinal tract following oral administration. However, when Graten Li Oral Solution is used in place of parenteral Graten Li, a 50% to 100% increase in dosage is usually required in order to achieve the same level of analgesia.

Posology

Adults and children over 12 years.

The dosage of Graten Li tablets is dependent on the severity of pain and the patient's previous history of analgesic requirements. One tablet to be taken every four hours or as directed by a physician. Increasing severity of pain or tolerance to morphine will require increased dosage of Graten Li tablets using 10 mg, 20 mg or 50 mg alone or in combination to achieve the desired relief.

Patients receiving Graten Li tablets in place of parenteral morphine should be given a sufficiently increased dosage to compensate for any reduction in analgesic effects associated with oral administration. Usually such increased requirement is of the order of 100%. In such patients individual dose adjustments are required.

Elderly:

A reduction in adult dosage may be advisable.

Paediatric population:

Graten Li tablets 50 mg are not recommended for children below 12 years of age.

Route of administration

Oral.

Posology

Adults: Recommended dose 10-20 mg (0.5 - 1.0 ml) every 4 hours.

Maximum daily dose: 120 mg per day.

Paediatric population:

Dosage can be increased under medical supervision according to the severity of the pain and the patient's previous history of analgesic requirements.

Special populations:

Reductions in dosage may be appropriate in the elderly and in patients with chronic hepatic disease , renal impairment, severe hypothyroidism, adrenocortical insufficiency, prostatic hypertrophy, shock or where sedation is undesirable.

Method of Administration

For oral use

A calibrated oral dosing pipette is supplied with this dosage form for accurate and convenient dose adjustment. The required dose may be added to a soft drink immediately prior to administration.

When patients are transferred from other morphine preparations to Graten Li Oral preparations dosage titration may be appropriate.

Morphine sulfate is readily absorbed from the gastro-intestinal tract following oral administration. However, when oral Graten Li preparations are used in place of parenteral morphine, a 50 % to 100 % increase in dosage is usually required in order to achieve the same level of analgesia.

Posology

Adults and children over 12 years:

Graten Li injection is formulated for use by the intravenous route in Patient Controlled Analgesia (PCA) systems. PCA, which permits adjustment of dosage according to the patient's individual needs, must only be carried out in departments and by staff who are trained and have experience of the system. Patient selection for the use of PCA must ensure that the patient is capable of understanding and following the instructions of the medical/nursing staff. The specific department or unit protocols must be covered to ensure aseptic transfer of the contents of the vial to the PCA system.

There is a considerable variation in analgesic requirements among patients and therefore individualised treatment strategies are required. Dosage should be based on the severity of the pain and the response and opiate tolerance of the patient.

Loading dose

Loading doses of typically between 1 mg and 10 mg (maximum 15 mg) of Graten Li may be given by intravenous infusion over four or five minutes. The loading dose used will depend upon the patient's diagnosis and condition.

PCA demand dose

An initial demand dose of 1 mg Graten Li injection with a lockout period of 5 to 10 minutes is recommended. Dosages may vary depending on the loading dose, the tolerance and condition of the patient, and whether a background infusion of morphine is being given.

The patient should be specifically monitored for pain, sedation and respiratory rate during the first few hours of treatment to ensure that the dosage regimen is suitable.

The duration of treatment should be kept to a minimum, although dependence and tolerance are not generally a problem when morphine is used legitimately in patients with opioid-sensitive pain.

Use in children:

Not recommended for children under 12 years.

Use in the elderly:

Morphine doses need to be reduced in elderly patients.

Method of administration

For intravenous injection.

The product should not be diluted before use.

The medicinal product is to be visually inspected prior to use. Only clear solutions practically free from particles should be used.

KADIAN 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

Graten Li 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

Graten Li Oral Solution is contraindicated in:

- patients known to be hypersensitive to Graten Li sulfate or to any other component of the product

- respiratory depression

- obstructive airways disease

- acute hepatic disease,

- acute alcoholism,

- head injuries

- coma

- convulsive disorders

- increased intracranial pressure

- paralytic ileus

- patients with known Graten Li sensitivity

- concurrent administration with monoamine oxidase inhibitors or within two weeks of discontinuation of their use

- patients with phaeochromocytoma. Graten Li and some other opioids can induce the release of endogenous histamine and thereby stimulate catecholamine release

- )

Respiratory depression, head injury, obstructive airways disease, paralytic ileus, acute abdomen, delayed gastric emptying, known morphine sensitivity, acute hepatic disease, concurrent administration of mono-amine oxidase inhibitors or within two weeks of discontinuation of their use.

Not recommended during pregnancy.

Graten Li 10 mg/20 mg: Not recommended for children below 3 years of age.

Graten Li tablets 50 mg: Not recommended for children below 12 years of age.

Graten Li is contraindicated in:

- patients known to be hypersensitive to morphine sulfate or to any other component of the product

- respiratory depression

- obstructive airways disease

- paralytic ileus

- acute hepatic disease

- acute alcoholism

- head injuries

- coma

- increased intracranial pressure

- convulsive disorders

- patients with known morphine sensitivity

- concurrent administration with monoamine oxidase inhibitors or within two weeks of discontinuation of their use

- patients with phaeochromocytoma. Morphine and some other opioids can induce the release of endogenous histamine and thereby stimulate catecholamine release

- )

- respiratory depression; obstructive airways disease; excessive bronchial secretions; during a bronchial asthma attack or in heart failure secondary to chronic lung disease

- head injury; raised intra-cranial pressure

- coma

- convulsion disorders

- ulcerative colitis

- presence of a risk of paralytic ileus

- biliary and renal tract spasm

- acute alcoholism

- phaeochromocytoma

- moderate to severe renal impairment (glomerular filtration rate <20ml/min)

- severe or acute liver failure

- patients receiving monoamine oxidase inhibitors or within two weeks of discontinuing such treatment

Use of Graten Li injection during pregnancy or lactation is not recommended.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Addiction, Abuse, And Misuse

KADIAN contains morphine, a Schedule II controlled substance. As an opioid, KADIAN exposes users to the risks of addiction, abuse, and misuse. As modified-release products such as KADIAN deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of morphine present.

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed KADIAN and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused.

Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing KADIAN, and monitor all patients receiving KADIAN for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of KADIAN for the proper management of pain in any given patient. Patients at increased risk may be prescribed modified-release opioid formulations such as KADIAN, but use in such patients necessitates intensive counseling about the risks and proper use of KADIAN along with intensive monitoring for signs of addiction, abuse, and misuse.

Abuse or misuse of KADIAN by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of morphine and can result in overdose and death.

Opioid agonists such as KADIAN are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing KADIAN. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug. 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.

Life Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of modified-release opioids, even when used as recommended. Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of KADIAN, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with KADIAN and following dose increases.

To reduce the risk of respiratory depression, proper dosing and titration of KADIAN are essential. Overestimating the KADIAN dose when converting patients from another opioid product can result in fatal overdose with the first dose.

Accidental ingestion of even one dose of KADIAN, especially by children, can result in respiratory depression and death due to an overdose of morphine.

Neonatal Opioid Withdrawal Syndrome

Prolonged use of KADIAN during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn.

Interactions With Central Nervous System Depressants

Patients must not consume alcoholic beverages or prescription or non-prescription products containing alcohol while on KADIAN therapy. The co-ingestion of alcohol with KADIAN may result in increased plasma levels and a potentially fatal overdose of morphine. Hypotension, profound sedation, coma, respiratory depression, and death may result if KADIAN is used concomitantly with alcohol or other central nervous system (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids).

When considering the use of KADIAN in a patient taking a CNS depressant, assess the duration use of the CNS depressant and the patient's response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient's use of alcohol or illicit drugs that cause CNS depression. If the decision to begin KADIAN is made, start with a low dose of KADIAN (30 mg or lower) every 24 hours, monitor patients for signs of sedation and respiratory depression, and consider using a lower dose of the concomitant CNS depressant.

Use In Elderly, Cachectic, And Debilitated Patients

Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Monitor such patients closely, particularly when initiating and titrating KADIAN and when KADIAN is given concomitantly with other drugs that depress respiration.

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 KADIAN, as in these patients, even usual therapeutic doses of KADIAN may decrease respiratory drive to the point of apnea. Consider the use of alternative non-opioid analgesics in these patients if possible.

Hypotensive Effect

KADIAN 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). Monitor these patients for signs of hypotension after initiating or titrating the dose of KADIAN. In patients with circulatory shock, KADIAN may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of KADIAN in patients with circulatory shock.

Use In Patients With Head Injury Or Increased Intracranial Pressure

Monitor patients taking KADIAN 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 KADIAN. KADIAN 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 KADIAN in patients with impaired consciousness or coma.

Use In Patients With Gastrointestinal Conditions

KADIAN is contraindicated in patients with paralytic ileus. Avoid the use of KADIAN in patients with other GI obstruction.

The morphine in KADIAN 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.

Use In Patients With Convulsive Or Seizure Disorders

The morphine in KADIAN 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 KADIAN therapy.

Avoidance Of Withdrawal

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

When discontinuing KADIAN, gradually taper the dose. Do not abruptly discontinue KADIAN.

Driving And Operating Machinery

KADIAN 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 KADIAN and know how they will react to the medication.

Patient Counseling Information

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

Addiction, Abuse, and Misuse

Inform patients that the use of KADIAN, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose or death. Instruct patients not to share KADIAN with others and to take steps to protect KADIAN from theft or misuse.

Life-threatening Respiratory Depression

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting KADIAN or when the dose is increased, and that it can occur even at recommended doses. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

Accidental Ingestion

Inform patients that accidental ingestion, especially in children, may result in respiratory depression or death. Instruct patients to take steps to store KADIAN securely and to dispose of unused KADIAN by flushing the (formulation) down the toilet.

Neonatal Opioid Withdrawal Syndrome

Inform female patients of reproductive potential that prolonged use of KADIAN during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated.

Interactions with Alcohol and other CNS Depressants

Instruct patients not to consume alcoholic beverages, as well as prescription and over-the counter products that contain alcohol, during treatment with KADIAN. The co-ingestion of alcohol with KADIAN may result in increased plasma levels and a potentially fatal overdose of (active opioid).

Inform patients that potentially serious additive effects may occur if KADIAN is used with alcohol or 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 KADIAN, including the following:

• Swallowing KADIAN 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 KADIAN exactly as prescribed to reduce the risk of life-threatening adverse reactions (e.g., respiratory depression)
• Not discontinuing KADIAN without first discussing the need for a tapering regimen with the prescriber

Hypotension

Inform patients that KADIAN 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 KADIAN 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 KADIAN. Advise patients how to recognize such a reaction and when to seek medical attention.

Pregnancy

Advise female patients that KADIAN can cause fetal harm and to inform the prescriber if they are pregnant or plan to become pregnant.

Disposal of Unused KADIAN

Advise patients to flush the unused capsules down the toilet when KADIAN is no longer needed.

For all medical inquiries contact: ACTAVIS Medical Communications Parsippany, NJ 07054 1-800-272-5525

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

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.

Use In Specific Populations

Pregnancy

Clinical Considerations

Fetal/neonatal Adverse Reactions

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Observe newborns for symptoms of neonatal opioid withdrawal syndrome, such as poor feeding, diarrhea, irritability, tremor, rigidity, and seizures, and manage accordingly.

Teratogenic Effects (Pregnancy Category C)

There are no adequate and well-controlled studies in pregnant women. KADIAN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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 , 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.

Labor And Delivery

Opioids cross the placenta and may produce respiratory depression in neonates. KADIAN is not for use in women during and immediately prior to labor, when shorter acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions. However this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor.

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

Pediatric Use

The safety and efficacy of KADIAN in patients less than 18 years have not been established.

Geriatric Use

Clinical studies of KADIAN did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Addiction, Abuse, And Misuse

Graten Li contains morphine, a Schedule II controlled substance. As an opioid, Graten Li exposes users to the risks of addiction, abuse, and misuse. As modified-release products such as Graten Li deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of morphine present.

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Graten Li and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused.

Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing Graten Li, and monitor all patients receiving Graten Li for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of Graten Li for the proper management of pain in any given patient. Patients at increased risk may be prescribed modified-release opioid formulations such as Graten Li, but use in such patients necessitates intensive counseling about the risks and proper use of Graten Li along with intensive monitoring for signs of addiction, abuse, and misuse.

Abuse or misuse of Graten Li by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of morphine and can result in overdose and death.

Opioid agonists such as Graten Li are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Graten Li. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug. 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.

Life Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of modified-release opioids, even when used as recommended. Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Graten Li, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with Graten Li and following dose increases.

To reduce the risk of respiratory depression, proper dosing and titration of Graten Li are essential. Overestimating the Graten Li dose when converting patients from another opioid product can result in fatal overdose with the first dose.

Accidental ingestion of even one dose of Graten Li, especially by children, can result in respiratory depression and death due to an overdose of morphine.

Neonatal Opioid Withdrawal Syndrome

Prolonged use of Graten Li during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn.

Interactions With Central Nervous System Depressants

Patients must not consume alcoholic beverages or prescription or non-prescription products containing alcohol while on Graten Li therapy. The co-ingestion of alcohol with Graten Li may result in increased plasma levels and a potentially fatal overdose of morphine. Hypotension, profound sedation, coma, respiratory depression, and death may result if Graten Li is used concomitantly with alcohol or other central nervous system (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids).

When considering the use of Graten Li in a patient taking a CNS depressant, assess the duration use of the CNS depressant and the patient's response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient's use of alcohol or illicit drugs that cause CNS depression. If the decision to begin Graten Li is made, start with a low dose of Graten Li (30 mg or lower) every 24 hours, monitor patients for signs of sedation and respiratory depression, and consider using a lower dose of the concomitant CNS depressant.

Use In Elderly, Cachectic, And Debilitated Patients

Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Monitor such patients closely, particularly when initiating and titrating Graten Li and when Graten Li is given concomitantly with other drugs that depress respiration.

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 Graten Li, as in these patients, even usual therapeutic doses of Graten Li may decrease respiratory drive to the point of apnea. Consider the use of alternative non-opioid analgesics in these patients if possible.

Hypotensive Effect

Graten Li 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). Monitor these patients for signs of hypotension after initiating or titrating the dose of Graten Li. In patients with circulatory shock, Graten Li may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Graten Li in patients with circulatory shock.

Use In Patients With Head Injury Or Increased Intracranial Pressure

Monitor patients taking Graten Li 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 Graten Li. Graten Li 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 Graten Li in patients with impaired consciousness or coma.

Use In Patients With Gastrointestinal Conditions

Graten Li is contraindicated in patients with paralytic ileus. Avoid the use of Graten Li in patients with other GI obstruction.

The morphine in Graten Li 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.

Use In Patients With Convulsive Or Seizure Disorders

The morphine in Graten Li 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 Graten Li therapy.

Avoidance Of Withdrawal

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

When discontinuing Graten Li, gradually taper the dose. Do not abruptly discontinue Graten Li.

Driving And Operating Machinery

Graten Li 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 Graten Li and know how they will react to the medication.

Patient Counseling Information

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

Addiction, Abuse, and Misuse

Inform patients that the use of Graten Li, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose or death. Instruct patients not to share Graten Li with others and to take steps to protect Graten Li from theft or misuse.

Life-threatening Respiratory Depression

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Graten Li or when the dose is increased, and that it can occur even at recommended doses. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

Accidental Ingestion

Inform patients that accidental ingestion, especially in children, may result in respiratory depression or death. Instruct patients to take steps to store Graten Li securely and to dispose of unused Graten Li by flushing the (formulation) down the toilet.

Neonatal Opioid Withdrawal Syndrome

Inform female patients of reproductive potential that prolonged use of Graten Li during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated.

Interactions with Alcohol and other CNS Depressants

Instruct patients not to consume alcoholic beverages, as well as prescription and over-the counter products that contain alcohol, during treatment with Graten Li. The co-ingestion of alcohol with Graten Li may result in increased plasma levels and a potentially fatal overdose of (active opioid).

Inform patients that potentially serious additive effects may occur if Graten Li is used with alcohol or 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 Graten Li, including the following:

• Swallowing Graten Li 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 Graten Li exactly as prescribed to reduce the risk of life-threatening adverse reactions (e.g., respiratory depression)
• Not discontinuing Graten Li without first discussing the need for a tapering regimen with the prescriber

Hypotension

Inform patients that Graten Li 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 Graten Li 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 Graten Li. Advise patients how to recognize such a reaction and when to seek medical attention.

Pregnancy

Advise female patients that Graten Li can cause fetal harm and to inform the prescriber if they are pregnant or plan to become pregnant.

Disposal of Unused Graten Li

Advise patients to flush the unused capsules down the toilet when Graten Li is no longer needed.

For all medical inquiries contact: ACTAVIS Medical Communications Parsippany, NJ 07054 1-800-272-5525

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

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.

Use In Specific Populations

Pregnancy

Clinical Considerations

Fetal/neonatal Adverse Reactions

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Observe newborns for symptoms of neonatal opioid withdrawal syndrome, such as poor feeding, diarrhea, irritability, tremor, rigidity, and seizures, and manage accordingly.

Teratogenic Effects (Pregnancy Category C)

There are no adequate and well-controlled studies in pregnant women. Graten Li should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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 , 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.

Labor And Delivery

Opioids cross the placenta and may produce respiratory depression in neonates. Graten Li is not for use in women during and immediately prior to labor, when shorter acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions. However this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor.

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

Pediatric Use

The safety and efficacy of Graten Li in patients less than 18 years have not been established.

Geriatric Use

Clinical studies of Graten Li did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Care should be exercised if Graten Li sulfate is given

- in the first 24 hours post-operatively,

- in hypothyroidism ,and where there is reduced respiratory function such as kyphoscoliosis, emphysema, cor pulmonale and severe obesity.

Asthma

It has been suggested that opioids can be used with caution in controlled asthma. However, opioids are contraindicated in acute asthma exacerbations.

Head injury and increased intracranial pressure

Graten Li Oral Solution is contraindicated in patients with increased intracranial pressure; head injuries and coma. The capacity of Graten Li to elevate cerebrospinal fluid pressure may be greatly increased in the presence of already elevated intracranial pressure produced by trauma. Also, Graten Li may produce confusion, miosis, vomiting and other adverse reactions which may obscure the clinical course of patients with head injury.

Abdominal conditions

Graten Li sulfate must not be given if paralytic ileus is likely to occur or if the patient has bowel or obstructive biliary disease. Should paralytic ileus be suspected or occur during use, Oral Graten Li Solution should be discontinued immediately.

Caution should be exercised where there is an obstructive bowel disorder, biliary colic, operations on the biliary tract, acute pancreatitis or prostatic hyperplasia.

If constipation occurs, this may be treated with the appropriate laxatives. Care should be exercised in patients with inflammatory bowel disease.

Graten Li may obscure the diagnosis or clinical course of patients with acute abdominal conditions and complications following abdominal surgery.

Hypotensive effect

The administration of Graten Li may result in severe hypotension in individuals whose ability to maintain homeostatic blood pressure has already been compromised by depleted blood volume or the concurrent administration of drugs such as phenothiazine or certain anaesthetics.

Drug dependence and abuse

Tolerance and dependence may occur. Withdrawal symptoms may occur on abrupt discontinuation or on the administration of a narcotic antagonist e.g. naloxone.

Graten Li sulfate is an opioid agonist and controlled drug. Such drugs are sought by drug abusers and people with addiction disorders. Graten Li sulfate can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing Graten Li in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion. Graten Li should be used with particular care in patients with a history of alcohol and drug abuse.

Graten Li sulfate may be abused by inhaling or injecting the product. These practices pose a significant risk to the abuser that could result in overdose and death.

Hypersensitivity

Hypersensitivity and anaphylactic reactions have both occurred with the use of Graten Li Oral Solution. Care should be taken to elicit any history of allergic reactions to opiates. Graten Li Oral Solution is contraindicated in patients known to be hypersensitive to Graten Li sulfate.

Risk in special populations

Graten Li is metabolised by the liver and should be used with caution in patients with hepatic disease as oral bioavailability may be increased. It is wise to reduce dosage in chronic hepatic and renal disease, severe hypothyroidism, adrenocortical insufficiency, prostatic hypertrophy or shock.

The active metabolite Graten Li-6-glucoranide may accumulate in patients with renal failure, leading to CNS and respiratory depression.

Excipient related warnings

Contains the excipients Sodium propyl hydroxybenzoate (E217) and sodium methyl hydroxybenzoate (E219) which are preservatives, and may cause an allergic reaction (possibly delayed).

Graten Li Oral solution contains alcohol, which is harmful for those suffering from alcoholism. To be taken into account in pregnant or breast-feeding women, children and high-risk groups such as patients with liver disease, or epilepsy.

The major risk of opioid excess is respiratory depression.

As with all narcotics a reduction in dosage may be advisable in the elderly, in hypothyroidism, in renal and chronic hepatic disease. Use with caution in patients with impaired respiratory function, severe bronchial asthma, convulsive disorders, acute alcoholism, delirium tremens, raised intracranial pressure, hypotension with hypovolaemia, severe cor pulmonale, opioid dependent patients, patients with a history of substance abuse, diseases of the biliary tract, pancreatitis, inflammatory bowel disorders, prostatic hypertrophy, adrenocortical insufficiency.

Graten Li tablets should not be used where there is a possibility of paralytic ileus occurring. Should paralytic ileus be suspected or occur during use, Graten Li tablets should be discontinued immediately.

Morphine may lower the seizure threshold in patients with a history of epilepsy.

Concomitant use of benzodiazepines and opioids may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing of sedative medicines such as benzodiazepines or related drugs with opioids should be reserved for patients for whom alternative treatment options are not possible.

The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their environment to be aware of these symptoms.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Patients about to undergo additional pain relieving procedures (e.g. surgery, plexus blockade) should not receive Graten Li tablets for 4 hours prior to the intervention. If further treatment with Graten Li tablets is indicated then the dosage should be adjusted to new post-operative requirements. Graten Li tablets should be used with caution pre-operatively and within the first 24 hours post-operatively. Graten Li tablets should also be used with caution following abdominal surgery as morphine impairs intestinal motility and should not be used until the physician is assured of normal bowel function.

The patient may develop tolerance to the drug with chronic use and require progressively higher doses to maintain pain control. Prolonged use of this product may lead to physical dependence and a withdrawal syndrome may occur upon abrupt cessation of therapy. When a patient no longer requires therapy with morphine, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal

Hyperalgesia that will not respond to a further dose increase of morphine sulphate may occur in particular in high doses. A morphine sulphate dose reduction or change in opioid may be required.

Morphine has an abuse profile similar to other strong agonist opioids. Morphine may be sought and abused by people with latent or manifest addiction disorders. There is potential for development of psychological dependence (addiction) to opioid analgesics, including morphine. The product should be used with particular care in patients with a history of alcohol and drug abuse.

Abuse of oral dosage forms by parenteral administration can be expected to result in serious adverse events, which may be fatal.

Opioids, such as morphine sulfate, may influence the hypothalamic-pituitary-adrenal or -gonadal axes. Some changes that can be seen include an increase in serum prolactin, and decreases in plasma cortisol and testosterone in association with inappropriately low or normal ACTH, LH or FSH levels. Clinical symptoms may be manifest from these hormonal changes.

Care should be exercised if morphine sulfate is given

- in the first 24 hours post-operatively,

- in hypothyroidism ,

- and where there is reduced respiratory function, such as kyphoscoliosis, emphysema, cor pulmonale and severe obesity.

Asthma

It has been suggested that opioids can be used with caution in controlled asthma. However, opioids are contraindicated in acute asthma exacerbations.

Head injury and increased intracranial pressure

Graten Li is contraindicated in patients with increased intracranial pressure, head injuries and coma. The capacity of morphine to elevate cerebrospinal fluid pressure may be greatly increased in the presence of already elevated intracranial pressure produced by trauma. Also, morphine may produce confusion, miosis, vomiting and other adverse reactions which may obscure the clinical course of patients with head injury.

Abdominal conditions

Morphine sulfate must not be given if paralytic ileus is likely to occur , or if the patient has bowel or obstructive biliary disease. Should paralytic ileus be suspected or occur during use, Graten Li should be discontinued immediately.

Caution should be exercised where there is an obstructive bowel disorder, biliary colic, operations on the biliary tract, acute pancreatitis or prostatic hyperplasia.

If constipation occurs this may be treated with the appropriate laxatives.

Care should be exercised in patients with inflammatory bowel disease.

Morphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions and complications following abdominal surgery.

Hypotensive effect

The administration of morphine may result in severe hypotension in individuals whose ability to maintain homeostatic blood pressure has already been compromised by depleted blood volume or the concurrent administration of drugs such as phenothiazine or certain anaesthetics.

Drug dependence and abuse

Tolerance and dependence may occur. Withdrawal symptoms may occur on abrupt discontinuation or on the administration of a narcotic antagonist e.g. naloxone.

Morphine sulfate is an opioid agonist and controlled drug. Such drugs are sought by drug abusers and people with addiction disorders. Morphine sulfate can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing morphine in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion. Morphine should be used with particular care in patients with a history of alcohol and drug abuse.

Morphine sulfate may be abused by inhaling or injecting the product. These practices pose a significant risk to the abuser that could result in overdose and death.

Hypersensitivity

Hypersensitivity and anaphylactic reactions have both occurred with the use of Graten Li. Care should be taken to elicit any history of allergic reactions to opiates. Graten Li is contraindicated in patients known to be hypersensitive to morphine sulfate.

Risk in special populations

Morphine is metabolised by the liver and should be used with caution in patients with hepatic disease as oral bioavailability may be increased. It is wise to reduce dosage in chronic hepatic and renal disease, severe hypothyroidism, adrenocortical insufficiency, prostatic hypertrophy or shock.

The active metabolite Morphine-6-glucuronide may accumulate in patients with renal failure, leading to CNS and respiratory depression.

Excipient related warnings

Graten Li Concentrated Oral Solution contains the excipient Amaranth (E123), which may cause allergic reactions.

As with other narcotics, a dose reduction may be appropriate in elderly patients, in patients with hypothyroidism, renal and chronic hepatic disease.

Graten Li injection should be used with caution in debilitated patients and those with adrenocortical insufficiency; hypopituitarism; prostatic hypertrophy; shock; diabetes mellitus; diseases of the biliary tract; myasthenia gravis; cardiac arrhythmias; excessive obesity; hypotension and severe cardiac failure.- Interaction with other medicinal products and other forms of interaction).

Drug dependence and tolerance

Morphine can produce drug dependence and therefore has the potential for being abused or misused. Upon repeated administration of morphine, psychological and physical dependence may occur and tolerance may develop, particularly in individuals with a history of alcohol or drug abuse and dependence. However, when doses of morphine are carefully titrated against pain, clinically significant respiratory depression, addiction, rapid tolerance and euphoria rarely develop. With regular administration of morphine at doses optimised for the individual patient drug dependence does not develop, and psychological dependence does not occur. A certain degree of physical dependence is possible, however. If patients no longer require morphine for relief of pain, doses should be gradually reduced in order to prevent withdrawal symptoms. Clinically significant tolerance to morphine is unusual in cancer patients with severe pain.

Graten Li injection contains 0.15 mmol (or 3.54 mg) sodium per millilitre solution. By application of large volumes of the solution (e.g. more than 6.5 ml corresponding to more than 1 mmol sodium) this has to be taken into consideration by patients on a controlled sodium diet.

Graten Li sulfate is likely to impair ability to drive and to use machinery. This effect is even more enhanced, when used in combination with alcohol or CNS depressants. Patients should be warned not to drive or operate dangerous machinery after taking Graten Li Oral Solution.

This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

- The medicine is likely to affect your ability to drive

- Do not drive until you know how the medicine affects you

- It is an offence to drive while under the influence of this medicine

- However, you would not be committing an offence (called 'statutory defence') if:

o The medicine has been prescribed to treat a medical or dental problem and

o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

o It was not affecting your ability to drive safely

Treatment with Graten Li tablets may cause sedation and it is not recommended that patients drive or use machines if they experience drowsiness.

This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

- The medicine is likely to affect your ability to drive.

- Do not drive until you know how the medicine affects you.

- It is an offence to drive while you have this medicine in your body over a specified limit unless you have a defence (called the 'statutory defence').

- This defence applies when:

- Please note that it is still an offence to drive if you are unfit because of the medicine (i.e. your ability to drive is being affected).”

Details regarding a new driving offence concerning driving after drugs have been taken in the UK may be found here: https://www.gov.uk/drug-driving-law

Morphine sulfate is likely to impair ability to drive or use machinery. This effect is even more enhanced, when used in combination with alcohol or CNS depressants.

Patients should be warned not to drive or operate dangerous machinery after taking Graten Li.

This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

- The medicine is likely to affect your ability to drive

- Do not drive until you know how the medicine affects you

- It is an offence to drive while under the influence of this medicine

- However, you would not be committing an offence (called 'statutory defence') if:

o The medicine has been prescribed to treat a medical or dental problem and

o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

o It was not affecting your ability to drive safely

Morphine has major influence on the ability to drive and use machines. It may modify the patient's reactions to a varying extent depending on the dosage and individual susceptibility. Ambulatory patients should be warned not to use machines.

This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

- The medicine is likely to affect your ability to drive

- Do not drive until you know how the medicine affects you

- It is an offence to drive while under the influence of this medicine

- However, you would not be committing an offence (called 'statutory defence') if:

o The medicine has been prescribed to treat a medical or dental problem and

o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

o It was not affecting your ability to drive safely

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

• Addiction, Abuse, and Misuse
• Life Threatening Respiratory Depression
• Neonatal Opioid Withdrawal Syndrome
• Interactions with Other CNS Depressants
• Hypotensive Effect
• Gastrointestinal Effects
• Seizures

In the randomized study, the most common adverse reactions with KADIAN 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.

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared 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 KADIAN 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.

Post-Marketing Experience

Anaphylaxis has been reported with ingredients contained in KADIAN. Advise patients how to recognize such a reaction and when to seek medical attention.

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

• Addiction, Abuse, and Misuse
• Life Threatening Respiratory Depression
• Neonatal Opioid Withdrawal Syndrome
• Interactions with Other CNS Depressants
• Hypotensive Effect
• Gastrointestinal Effects
• Seizures

In the randomized study, the most common adverse reactions with Graten Li 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.

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared 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 Graten Li 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.

Post-Marketing Experience

Anaphylaxis has been reported with ingredients contained in Graten Li. Advise patients how to recognize such a reaction and when to seek medical attention.

In normal doses the commonest side effects of Graten Li sulfate are respiratory depression, nausea, vomiting, constipation, drowsiness and confusion. If constipation occurs, this may be treated with appropriate laxatives. The effects of Graten Li have led to its abuse and misuse. Dependence and addiction may develop with regular, inappropriate use.

Adverse effects can be listed in terms of their frequency of occurrence:

- Very common (>1/10)

- Common (>1/100 to <1/100)

- Uncommon (>1/1,000 to <1/100)

- Not known (cannot be estimated from available data)

Data from clinical trials are not available. Therefore it is not possible to provide information on the frequencies of undesirable effects. A full list of currently known adverse reactions is presented below.

These effects are more common in ambulant patients than in those who are bedridden.

Reporting of suspected adverse reactions

Reporting suspected adverse reaction after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

In normal doses, the commonest side effects of morphine are nausea, vomiting, constipation and drowsiness. With chronic therapy, nausea and vomiting are unusual with Graten Li tablets but should they occur the tablets can be readily combined with an anti-emetic if required. Constipation may be treated with appropriate laxatives.

The following frequencies are the basis for assessing undesirable effects:

Very common (>1/10);

Common (> 1/100 to < 1/10);

Uncommon (> 1/1,000 to < 1/100);

Rare (> 1/10,000 to < 1/1,000);

Very rare (< 1/10,000);

Not known (cannot be estimated from the available data).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

In normal doses, the commonest side effects of morphine sulfate are nausea, vomiting, constipation, drowsiness and confusion. If constipation occurs, this may be treated with appropriate laxatives. The effects of morphine have led to its abuse and misuse. Dependence and addiction may develop with regular, inappropriate use.

Data from clinical trials are not available. Therefore it is not possible to provide information on the frequencies of undesirable effects. A full list of currently known adverse reactions is presented below:

Reporting of suspected adverse reactions

Reporting suspected adverse reaction after authorisation of the medicinal product is important. It allows continued monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

The side-effects most commonly seen with morphine and other opioids are respiratory depression, nausea, vomiting, constipation, drowsiness and confusion. With long term use these symptoms generally lessen, although constipation frequently persists.

The following adverse events are from published literature and frequencies are not known.

Immune system disorders

Anaphylactic reactions to morphine have been reported rarely.

Endocrine disorders

Long term use of opioid analgesics can cause adrenal insufficiency. Exacerbation of pancreatitis.

Psychiatric disorders

Restlessness, mood changes, hallucinations, delirium, disorientation, excitation, agitation, sleep disturbance.

Nervous system disorders

Headache, vertigo, euphoria, dysphoria, dizziness, taste disturbances, seizures, paraesthesia, raised intracranial pressure.

Eye disorders

Visual disturbances, nystagmus, miosis.

Ear and labyrinth disorders

Vertigo.

Cardiac disorders

Bradycardia, tachycardia, palpitations, syncope.

Vascular disorders

Orthostatic hypotension, hypotension, hypertension, facial flushing, oedema.

Respiratory, thoracic and mediastinal disorders

Bronchospasm (in association with anaphylaxis), inhibition of cough reflex.

Gastrointestinal disorders

Dyspepsia, paralytic ileus, abdominal pain, anorexia.

Hepatobiliary disorders

Biliary spasm.

Skin and subcutaneous tissue disorders

Rashes, urticaria, pruritus.

Musculoskeletal and connective tissue disorders

Muscle fasciculation, myoclonus, rhabdomyolysis, muscle rigidity.

Renal and urinary disorders

Difficult micturition, ureteric spasm, urinary retention.

Reproductive system and breast disorders

Long term use of opioid analgesics can cause hypogonadism in both men and women.

This can lead to amenorrhoea, reduced libido, infertility, depression and erectile dysfunction.

General disorders and administration site conditions

Dry mouth, sweating, hypothermia, malaise, asthenia, pain and irritation at the injection site.

Long Term Use

Long term use of opioid analgesics has been associated with a state of abnormal pain sensitivity (hyperalgesia).

Tolerance and psychological and physical dependence may occur. Decreased potency may be experienced.

High doses may produce respiratory depression and hypotension, with deepening coma. Convulsions may occur particularly in infants.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

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 KADIAN. 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 KADIAN, carefully monitor the patient until spontaneous respiration is reliably re-established. KADIAN 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.

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 Graten Li. 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 Graten Li, carefully monitor the patient until spontaneous respiration is reliably re-established. Graten Li 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.

Symptoms:

Signs of Graten Li toxicity and overdosage are likely to consist of pin-point pupils, respiratory depression and hypotension. Circulatory failure and deepening coma may occur in more severe cases. Convulsions may occur in infants and children. Death may occur from respiratory failure.

Treatment:

Adults: Administer 0.4-2 mg of naloxone intravenously. Repeat at 2-3 minute intervals as necessary to a maximum of 10 mg, or by an infusion of 2 mg in 500 ml of normal saline or 5 % dextrose (4 micrograms/ml).

Children: 5-10 micrograms per kilogram body weight of naloxone intravenously. If this does not result in the desired degree of clinical improvement, a subsequent dose of 100 mcg/kg body weight may be administered.

Care should always be taken to ensure that the airway is maintained. Assist respiration if necessary. Maintain fluid and electrolyte levels Oxygen, i.v. fluids, vasopressors and other supportive measures should be employed as indicated. Peak plasma concentrations of Graten Li are expected to occur within 15 minutes of oral ingestion. Therefore gastric lavage and activated charcoal are unlikely to be beneficial.

Caution: the duration of the effect of naloxone (2-3 hours) may be shorter than the duration of the effect of the Graten Li overdose. It is recommended that a patient who has regained consciousness after naloxone treatment should be observed for at least 6 hours after the last dose of naloxone.

Signs of morphine toxicity and overdose are pin-point pupils, skeletal muscle flaccidity, bradycardia, hypotension, respiratory depression, pneumonia aspiration, somnolence and central nervous system depression which can progress to stupor or coma. Circulatory failure and deepening coma may occur in more severe cases. Overdose can result in death. Rhabdomyolysis progressing to renal failure has been reported in opioid overdose.

Treatment of morphine overdose

Primary attention should be given to the establishment of a patent airway and institution of assisted or controlled ventilation.

Oral activated charcoal (50g) for adults, 1g/kg for children) may be considered if a substantial amount has been ingested within one hour, provided the airway can be protected.

The pure opioid antagonists are specific antidotes against the effects of opioid overdose. Other supportive measures should be employed as needed.

In the case of massive overdose, administer naloxone 0.8 mg intravenously. Repeat at 2-3 minute intervals as necessary, or by an infusion of 2 mg in 500 ml of normal saline or 5% dextrose (0.004 mg/ml).

The infusion should be run at a rate related to the previous bolus doses administered and should be in accordance with the patient's response. However, because the duration of action of naloxone is relatively short, the patient must be carefully monitored until spontaneous respiration is reliably re-established.

For less severe overdose, administer naloxone 0.2 mg intravenously followed by increments of 0.1 mg every 2 minutes if required.

Naloxone should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to morphine overdose. Naloxone should be administered cautiously to persons who are known, or suspected, to be physically dependent on morphine. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute withdrawal syndrome.

Symptoms

Signs of morphine toxicity and overdosage are likely to consist of pin-point pupils, respiratory depression and hypotension. Circulatory failure and deepening coma may occur in more severe cases. Convulsions may occur in infants and children. Death may occur from respiratory failure.

Treatment

Adults: Administer 0.4-2 mg of naloxone intravenously. Repeat at 2-3 minute intervals as necessary to a maximum of 10 mg, or by 2 mg in 500 ml of normal saline or 5 % dextrose (4 micrograms/ml). Children: 5-10 micrograms per kilogram body weight intravenously. If this does not result in the desired degree of clinical improvement, a subsequent dose of 100 mcg/kg body weight may be administered.

Care should always be taken to ensure that the airway is maintained. Assist respiration if necessary. Maintain fluid and electrolyte levels. Oxygen, i.v. fluids, vasopressors and other supportive measures should be employed as indicated. Peak plasma concentrations of morphine are expected to occur within 15 minutes of oral ingestion. Therefore gastric lavage and activated charcoal are unlikely to be beneficial.

Caution: the duration of the effect of naloxone (2-3 hours) may be shorter than the duration of the effect of the morphine overdose. It is recommended that a patient who has regained consciousness after naloxone treatment should be observed for at least 6 hours after the last dose of naloxone.

Signs:

The signs of morphine overdosage consist of pin-point pupils, respiratory depression, and hypotension. Circulatory failure and deepening coma may develop in severe cases and death may ensue. Less severe cases may be manifest by nausea, vomiting, tremor, dysphoria, hypothermia, hypotension, confusion and sedation. Rhabdomyolysis progressing to renal failure can also be a consequence of overdosage.

Treatment:

It is vital to maintain and support respiration and circulation. The specific opioid antagonist naloxone should be employed for the reversal of coma and restoration of spontaneous respiration. 400 micrograms of naloxone should be administered intravenously, repeated at 2-3 minute intervals as necessary up to a maximum dose of 10 mg.

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 KADIAN is used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.

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 Graten Li is used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.

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.

Pharmacotherapeutic Group: Natural opium alkaloids

ATC Code: N02A A01

Graten Li binds to specific receptors, which are located at various levels of the central nervous system and also in various peripheral organs. The pain sensation and the affective reaction to pain is relieved by interaction with the receptors in the central nervous system.

Pharmacotherapeutic group: natural opium alkaloid

ATC code: N02A A01

Morphine acts as an agonist at opiate receptors in the CNS particularly mu and to a lesser extent kappa receptors. Mu receptors are thought to mediate supraspinal analgesia, respiratory depression and euphoria and kappa receptors, spinal analgesia, miosis and sedation.

Central Nervous System

The principal actions of therapeutic value of morphine are analgesia and sedation (i.e., sleepiness and anxiolysis). Morphine produces respiratory depression by direct action on brain stem respiratory centers.

Morphine depresses the cough reflex by direct effect on the cough center in the medulla. Antitussive effects may occur with doses lower than those usually required for analgesia.

Morphine causes miosis, even in total darkness. Pinpoint pupils are a sign of narcotic overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in the setting of morphine overdose.

Gastrointestinal Tract and Other Smooth Muscle

Morphine causes a reduction in motility associated with an increase in smooth muscle 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 resulting in constipation.

Morphine generally increases smooth muscle tone, especially the sphincters of the gastrointestinal and biliary tracts. Morphine may produce spasm of the sphincter of Oddi, thus raising intrabiliary pressure.

Cardiovascular System

Morphine may produce release of histamine with or without associated peripheral vasodilation. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Endocrine System

Opioids may affect the hypothalamic pituitary adrenal and hypothalamic pituitary gonadal system resulting in adrenal insufficiency or hypogonadism respectively.

Other Pharmacologic Effects

In vitro and animal studies indicate various effects of natural opioids, such as morphine, on components of the immune system; the clinical significance of these findings is unknown.

Pharmacotherapeutic group: Natural opium alkaloids. ATC code: NO2AA01

Morphine binds to specific receptors which are located at various levels of the central nervous system and also in various peripheral organs. The pain sensation and the affective reaction to pain is relieved by interaction with the receptors in the central nervous system.

Pharmacotherapeutic group: Opioids, natural opium alkaloids, ATC code: N02AA01

Morphine acts as a competitive agonist at opiate receptors in the CNS, particularly mu and to a lesser extent kappa receptors. Activity at the mu-1 subtype receptor is thought to mediate analgesia, euphoria and dependence whilst activity at the mu-2 receptor is thought to be responsible for respiratory depression and inhibition of gut motility. Action at the kappa receptor may mediate spinal analgesia. The analgesic action of morphine is effective at several spinal and supraspinal sites.

Absorption

KADIAN 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 KADIAN. Because of pre-systemic elimination, only about 20 to 40% of the administered dose reaches the systemic circulation.

Both dose-normalized Cmax and dose-normalized AUC0-48hr values of morphine after a single dose administration of KADIAN in healthy volunteers are less than those for morphine oral solution or an extended-release tablet formulation (Table 1).

When KADIAN was given twice daily to 24 patients with chronic pain due to malignancy, steady-state was achieved in about two days. At steady-state, KADIAN has a significantly lower Cmax and a higher Cmin 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, KADIAN had a similar Cmax and higher Cmin 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 KADIAN 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.

Food effect: While concurrent administration of food slows the rate of absorption of KADIAN, the extent of absorption is not affected and KADIAN 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 and has been found in breast milk.

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 KADIAN, 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 KADIAN administration is approximately 11 to 13 hours.

Absorption

Graten Li 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 Graten Li. Because of pre-systemic elimination, only about 20 to 40% of the administered dose reaches the systemic circulation.

Both dose-normalized Cmax and dose-normalized AUC0-48hr values of morphine after a single dose administration of Graten Li in healthy volunteers are less than those for morphine oral solution or an extended-release tablet formulation (Table 1).

When Graten Li was given twice daily to 24 patients with chronic pain due to malignancy, steady-state was achieved in about two days. At steady-state, Graten Li has a significantly lower Cmax and a higher Cmin 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, Graten Li had a similar Cmax and higher Cmin 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 Graten Li 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.

Food effect: While concurrent administration of food slows the rate of absorption of Graten Li, the extent of absorption is not affected and Graten Li 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 and has been found in breast milk.

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 Graten Li, 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 Graten Li administration is approximately 11 to 13 hours.

Absorption

Graten Li is modestly absorbed from the gastrointestinal tract following oral administration. Following oral administration of radiolabelled Graten Li to humans, peak plasma levels were reached after approximately 15 minutes. Graten Li undergoes significant first pass metabolism in the liver resulting in a systemic bioavailability of approximately 25%.

Distribution

Approximately one third of Graten Li in the plasma is protein bound after a therapeutic dose.

Biotransformation

Metabolism of Graten Li principally involves conjugation to Graten Li 3- and 6- glucuronides. Small amounts are also metabolised by N-demethylation and N-dealkylation. Graten Li-6-glucuronide has pharmacological effects indistinguishable from those of Graten Li. The half-life of Graten Li is approximately 2 hours. The t1/2 of Graten Li-6- glucuronide is somewhat longer.

Elimination

A small amount of a dose of Graten Li is excreted through the bowel into the faeces. The remainder is excreted in the urine, mainly in the form of conjugates. Approximately 90 % of a single dose of Graten Li is excreted in the first 24 hours. Enterohepatic circulation of Graten Li and its metabolites can occur, and may result in small quantities of Graten Li to be present in the urine or faeces for several days after the last dose.

Morphine is well absorbed from Graten Li tablets, however first pass metabolism does occur. Apart from the liver, metabolism also occurs in the kidney and intestinal mucosa. The major urinary metabolite is morphine-3-glucuronide but morphine-6-glucuronide is also formed. The half life for morphine in the plasma is approximately 2.5 - 3.0 hours.

Absorption

Morphine is modestly absorbed from the gastrointestinal tract following oral administration. Following oral administration of radiolabelled morphine to humans, peak plasma levels were reached after approximately 15 minutes. Morphine undergoes significant first pass metabolism in the liver resulting in a systemic bioavailability of approximately 25%.

Distribution

Approximately one third of morphine in the plasma is protein bound after a therapeutic dose.

Biotransformation

Metabolism of morphine principally involves conjugation to morphine 3- and 6- glucuronides. Small amounts are also metabolised by N-demethylation and N-dealkylation. Morphine-6-glucuronide has pharmacological effects indistinguishable from those of morphine. The half-life of morphine is approximately 2 hours. The t1/2 of morphine-6-glucuronide is somewhat longer.

Elimination

A small amount of a dose of morphine is excreted through the bowel into the faeces. The remainder is excreted in the urine, mainly in the form of conjugates. Approximately 90 % of a single dose of morphine is excreted in the first 24 hours. Enterohepatic circulation of morphine and its metabolites can occur, and may result in small quantities of morphine to be present in the urine or faeces for several days after the last dose.

Absorption

Onset of action is rapid following parenteral administration of morphine with peak analgesic effect occurring within 20 minutes via the intravenous route.

Distribution

Morphine is widely distributed in the body, with an apparent volume of distribution of 2-3 lkg^-1. Due to its relatively hydrophilic nature, morphine does not readily cross the blood-brain barrier although it is detectable in the cerebrospinal fluid.

Biotransformation

Morphine is extensively metabolised by the liver. Renal glucuronidation also takes place. The major metabolite, quantitatively, is morphine-3-glucuronide although morphine-6-glucuronide is significant in terms of potency. The metabolites are excreted mainly via the renal route.

There are no additional pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SmPC.

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

No further relevant preclinical data are available.

Non-clinical data based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development reveal no special hazard additional to the known safety profile of morphine in humans.