KADIAN- morphine sulfate capsule, extended release
Bryant Ranch Prepack
HIGHLIGHTS OF PRESCRIBING INFORMATION
KADIAN® (morphine sulfate) Extended-Release Capsules, for oral use, CII
These highlights do not include all the information needed to use KADIAN safely and effectively. See full prescribing information for KADIAN.
KADIAN® (morphine sulfate) extended-release capsules, for oral use, CII
Initial U.S. Approval: 1941
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and INTERACTION WITH ALCOHOL
See full prescribing information for complete boxed warning.
RECENT MAJOR CHANGES
INDICATIONS AND USAGE
KADIAN is an opioid agonist 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. (1)
Limitations of Use (1)
DOSAGE AND ADMINISTRATION
DOSAGE FORMS AND STRENGTHS
Extended-release capsules: 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 100 mg, 130 mg, 150 mg, 200 mg (3)
WARNINGS AND PRECAUTIONS
USE IN SPECIFIC POPULATIONS
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
FULL PRESCRIBING INFORMATION: CONTENTS*
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.
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.
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.
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:
The contents of the KADIAN capsules (pellets) may be administered through a 16 French gastrostomy tube.
Do not administer KADIAN pellets through a nasogastric tube.
KADIAN contains white to off-white or tan colored polymer coated pellets, have an outer opaque capsule with colors as identified below and are available in twelve dose strengths:
Each 10 mg extended-release capsule has a light blue opaque cap printed with “KADIAN” and a light blue opaque body printed with “10 mg”.
Each 20 mg extended-release capsule has a yellow opaque cap printed with “KADIAN” and a yellow opaque body printed with “20 mg”.
Each 30 mg extended-release capsule has a blue violet opaque cap printed with “KADIAN” and a blue violet opaque body printed with “30 mg”.
Each 40 mg extended-release capsule has a yellow opaque cap printed with “KADIAN” and a blue violet opaque body printed with “40 mg”.
Each 50 mg extended-release capsule has a blue opaque cap printed with “KADIAN” and a blue opaque body printed with “50 mg”.
Each 60 mg extended-release capsule has a pink opaque cap printed with “KADIAN” and a pink opaque body printed with “60 mg”.
Each 70 mg extended-release capsule has a light blue opaque cap printed with “KADIAN” and a blue violet opaque body printed with “70 mg”.
Each 80 mg extended-release capsule has a light orange opaque cap printed with “KADIAN” and a light orange opaque body printed with “80 mg”.
Each 100 mg extended-release capsule has a green opaque cap printed with “KADIAN” and a green opaque body printed with “100 mg”.
Each 130 mg extended-release capsule has a light orange opaque cap printed with “KADIAN” and a light brown opaque body printed with “130 mg”.
Each 150 mg extended-release capsule has a green opaque cap printed with “KADIAN” and a light brown opaque body printed with “150 mg”.
Each 200 mg extended-release capsule has a light brown opaque cap printed with “KADIAN” and light brown opaque body printed with “200 mg”.
KADIAN is contraindicated in patients with
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 [see Dosage and Administration (2)]. Overestimating the KADIAN dose when converting patients from another opioid product can result in fatal overdose with the first dose.
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 [see Warnings and Precautions (5.2)]. Consider the use of alternative non-opioid analgesics in these patients if possible.
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) [see Drug Interactions (7.2)]. 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.
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.
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.
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.
When discontinuing KADIAN, gradually taper the dose [see Dosage and Administration (2.3)]. Do not abruptly discontinue KADIAN.
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.
The following serious adverse reactions are discussed elsewhere in the labeling:
Life Threatening Respiratory Depression [see Warnings and Precautions (5.2)]
Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.3)]
Interactions with Other CNS Depressants [see Warnings and Precautions (5.4)]
Hypotensive Effect [see Warnings and Precautions (5.7)]
Gastrointestinal Effects [see Warnings and Precautions (5.9)]
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 somn
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Clinical trial patients with chronic cancer pain (n = 227)(AE by Body System as seen in 2% or more of patients)
|CENTRAL NERVOUS SYSTEM||28|
|BODY AS A WHOLE||16|
|SKIN & APPENDAGES||3|
|METABOLIC & NUTRITIONAL||3|
|HEMIC & LYMPHATIC||4|
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:
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.
Concomitant use of alcohol with KADIAN can result in an increase of morphine plasma levels and potentially fatal overdose of morphine. Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on KADIAN therapy [See Clinical Pharmacology (12.3)].
The concomitant use of KADIAN with other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, and alcohol can increase the risk of respiratory depression, profound sedation, coma and death. Monitor patients receiving CNS depressants and KADIAN for signs of respiratory depression, sedation and hypotension.
Mixed agonist/antagonist (i.e., pentazocine, nalbuphine, butorphanol) and partial agonist (buprenorphine) analgesics may reduce the analgesic effect of KADIAN or precipitate withdrawal symptoms. Avoid the use of mixed agonist/antagonist and partial agonist analgesics in patients receiving KADIAN.
Morphine may enhance the neuromuscular blocking action of skeletal relaxants and produce an increased degree of respiratory depression. Monitor patients receiving muscle relaxants and KADIAN for signs of respiratory depression that may be greater than otherwise expected.
The effects of morphine may be potentiated by MAOIs. Monitor patients on concurrent therapy with an MAOI and KADIAN for increased respiratory and central nervous system depression. KADIAN should not be used in patients taking MAOIs or within 14 days of stopping such treatment.
Cimetidine can potentiate morphine-induced respiratory depression. There is a report of confusion and severe respiratory depression when a patient undergoing hemodialysis was concurrently administered morphine and cimetidine. Monitor patients for respiratory depression when KADIAN and cimetidine are used concurrently.
Morphine can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Morphine may also lead to acute retention of urine by causing spasm of the sphincter of the bladder, particularly in men with enlarged prostates.
Anticholinergics or other drugs with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention or reduced gastric motility when KADIAN is used concurrently with anticholinergic drugs.
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 [see Warnings and Precautions (5.3)].
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.
Infants born to mothers who have taken opioids chronically may exhibit neonatal withdrawal syndrome [see Warnings and Precautions (5.3)], 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.
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.
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.
The safety and efficacy of KADIAN in patients less than 18 years have not been established.
KADIAN contains morphine, a Schedule II controlled substance with a high potential for abuse similar to other opioids including fentanyl, hydromorphone, methadone, oxycodone, and oxymorphone. KADIAN can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1)].
The high drug content in extended-release formulations adds to the risk of adverse outcomes from abuse and misuse.
All patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use.
Drug abuse is the intentional non-therapeutic use of an over-the-counter or prescription drug, even once, for its rewarding psychological or physiological effects. Drug abuse includes, but is not limited to, the following examples: the use of a prescription or over-the counter drug to get “high”, or the use of steroids for performance enhancement and muscle build up.
Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and include: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.
“Drug seeking” behavior is very common to addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated claims of loss of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.
KADIAN, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests as required by state law, is strongly advised.
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to reduce abuse of opioid drugs.
Risks Specific to Abuse of KADIAN
KADIAN is for oral use only. Abuse of KADIAN poses a risk of overdose and death. This risk is increased with concurrent abuse of KADIAN with alcohol and other substances. Taking cut, broken, chewed, crushed, or dissolved KADIAN enhances drug release and increases the risk of over dose and death.
Due to the presence of talc as one of the excipients in KADIAN, parenteral abuse can be expected to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.
Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.
Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone, nalmefene, mixed agonist/antagonist analgesics (pentazocine, butorphanol, nalbuphine) or partial agonists (buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.
KADIAN should not be abruptly discontinued [see Dosage and Administration (2.3)]. If KADIAN is abruptly discontinued in a physically-dependent patient, an abstinence syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.
Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations (8.2), and Warnings and Precautions (5.3)].
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.
KADIAN (morphine sulfate) extended-release capsules are for oral use and contain pellets of morphine sulfate. Morphine sulfate is an agonist at the mu-opioid receptor.
Each KADIAN extended-release capsule contains either 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 100 mg, 130 mg, 150 mg, or 200 mg of Morphine Sulfate USP and the following inactive ingredients common to all strengths: hypromellose, ethylcellulose, methacrylic acid copolymer, polyethylene glycol, diethyl phthalate, talc, corn starch, and sucrose.
The capsule shells contain gelatin, silicon dioxide, sodium lauryl sulfate, titanium dioxide, and black ink, D&C red #28, FD&C blue #1 (10 mg), D&C yellow #10 (20 mg), FD&C red #3, FD&C blue #1 (30 mg), D&C yellow #10, FD&C blue #1, FD&C red #3 (40 mg), D&C red #28, FD&C red #40, FD&C blue #1 (50 mg), D&C red #28, FD&C red #40, FD&C blue #1 (60 mg), D&C red #28, FD&C blue #1, FD&C red #3 (70 mg), FD&C blue #1, FD&C red #40, FD&C yellow #6 (80 mg), D&C yellow #10, FD&C blue #1 (100 mg), FD&C red #40, FD&C blue #1, FD&C yellow #6, black iron oxide, red iron oxide, yellow iron oxide (130 mg), FD&C blue #1, D&C yellow #10, black iron oxide, red iron oxide, yellow iron oxide (150 mg), black iron oxide, yellow iron oxide, red iron oxide (200 mg). The imprint ink contains black iron oxide, potassium hydroxide, propylene glycol, and shellac.
The chemical name of morphine sulfate is 7,8-didehydro-4,5 α-epoxy-17-methyl-morphinan-3,6 α- diol sulfate (2:1) (salt) pentahydrate. The empirical formula is (C17H19NO3)2●H2SO4●5H2O and its molecular weight is 758.85.
Morphine sulfate is an odorless, white, crystalline powder with a bitter taste. It has a solubility of 1 in 21 parts of water and 1 in 1000 parts of alcohol, but is practically insoluble in chloroform or ether. The octanol: water partition coefficient of morphine is 1.42 at physiologic pH and the pKb is 7.9 for the tertiary nitrogen (mostly ionized at pH 7.4). Its structural formula is:
Morphine sulfate, an opioid agonist, is relatively selective for the mu receptor, although it can interact with other opioid receptors at higher doses. In addition to analgesia, the widely diverse effects of morphine sulfate include analgesia, dysphoria, euphoria, somnolence, respiratory depression, diminished gastrointestinal motility, altered circulatory dynamics, histamine release, physical dependence, and alterations of the endocrine and autonomic nervous systems.
Morphine produces both its therapeutic and its adverse effects by interaction with one or more classes of specific opioid receptors located throughout the body. Morphine acts as a full agonist, binding with and activating opioid receptors at sites in the peri-aqueductal and peri-ventricular grey matter, the ventro-medial medulla and the spinal cord to produce analgesia.
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.
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.
| AUC* †
|Single Dose (n = 24)|
|Extended-Release Tablet|| 304.3
|Morphine Solution|| 362.4
|Multiple Dose (n = 24)|
|KADIAN Capsule Once Daily|| 500.9
|Extended-Release Tablet Twice Daily|| 457.3
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.
Once absorbed, morphine is distributed to skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen and brain. The volume of distribution of morphine is approximately 3 to 4 L/kg. Morphine is 30 to 35% reversibly bound to plasma proteins. Although the primary site of action of morphine is in the CNS, only small quantities pass the blood-brain barrier. Morphine also crosses the placental membranes [see Use in Specific Populations (8.1)] and has been found in breast milk [see Use in Specific Populations (8.3)].
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.
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.
Geriatric Patients: The pharmacokinetics of KADIAN have not been investigated in elderly patients (> 65 years) although such patients were included in the clinical studies.
Pediatric Patients: The pharmacokinetics of KADIAN have not been evaluated in a pediatric population.
Gender: No meaningful differences between male and female patients were demonstrated in the analysis of the pharmacokinetic data from clinical studies.
Race: Chinese subjects given intravenous morphine in one study had a higher clearance when compared to Caucasian subjects (1852 ± 116 mL/min versus 1495 ± 80 mL/min).
Hepatic Impairment: The pharmacokinetics of morphine were found to be significantly altered in individuals with alcoholic cirrhosis. The clearance was found to decrease with a corresponding increase in half-life. The M3G and M6G to morphine plasma AUC ratios also decreased in these patients indicating a decrease in metabolic activity. Adequate studies of the pharmacokinetics of morphine in patients with severe hepatic impairment have not been conducted.
Renal Impairment: The pharmacokinetics of morphine are altered in patients with renal failure. The AUC is increased and clearance is decreased. Metabolites, M3G and M6G accumulate several fold in patients with renal failure compared to healthy subjects. Adequate studies of the pharmacokinetics of morphine in
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.
NDC: 63629-4191-1 60 CAPSULE, EXTENDED RELEASE in a BOTTLE
NDC: 63629-4191-2 30 CAPSULE, EXTENDED RELEASE in a BOTTLE
NDC: 63629-4191-3 90 CAPSULE, EXTENDED RELEASE in a BOTTLE
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 [see Warnings and Precautions (5.1)]. 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 [see Warnings and Precautions (5.2)]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.
Inform patients that accidental ingestion, especially in children, may result in respiratory depression or death [see Warnings and Precautions (5.2)]. Instruct patients to take steps to store KADIAN securely and to dispose of unused KADIAN by flushing the capsules 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 [see Warnings and Precautions (5.3)].
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 morphine [see Warnings and Precautions (5.4)].
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:
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.
Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention.
Inform patients that anaphylaxis has been reported with KADIAN. Advise patients how to recognize such a reaction and when to seek medical attention.
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:
Parsippany, NJ 07054
Distributed by: Actavis Pharma, Inc.
Parsippany, NJ 07054 USA
Content Updated: April 2014
(morphine sulfate) extended-release capsules, CII
Important information about KADIAN:
Do not take KADIAN if you have:
Before taking KADIAN, tell your healthcare provider if you have a history of:
Tell your healthcare provider if you are:
When taking KADIAN:
While taking KADIAN Do Not:
The possible side effects of KADIAN are:
Get emergency medical help if you have:
These are not all the possible side effects of KADIAN. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov
Actavis Pharma, Inc.
Parsippany, NJ 07054 USA
www.KADIAN.com or call 1-800-272-5525
This Medication Guide has been approved by the U.S. Food and Drug Administration.
(morphine sulfate) extended-release capsules, CII
If you cannot swallow KADIAN capsules, tell your healthcare provider. There may be another way to take KADIAN that may be right for you. If your healthcare provider tells you that you can take KADIAN using this other way, follow these steps:
KADIAN can be opened and the pellets inside the capsule can be sprinkled over applesauce, as follows:
You should not receive KADIAN through a nasogastric tube.
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Distributed By: Actavis Pharma, Inc.
Parsippany, NJ 07054 USA
morphine sulfate capsule, extended release
|Labeler - Bryant Ranch Prepack (171714327)|
|Bryant Ranch Prepack||171714327||REPACK(63629-4191) , RELABEL(63629-4191)|