Risk Evaluation and Mitigation Strategy (REMS)
What is it? A Risk Evaluation and Mitigation Strategy program is required by the Food and Drug Administration (FDA) when there are important information and safety considerations that must be communicated to healthcare professionals and patients for some classes of medications. FDA recently (July 2012) required a REMS program for all Extended-Release (ER) and Long-Acting (LA) and opioid analgesics, including KADIAN® CII (morphine sulfate extended-release) Capsules.
The goal of the ER and LA Opioid Analgesics REMS program is “to reduce serious adverse outcomes resulting from inappropriate prescribing, misuse, and abuse of extended-release or long-acting (ER/LA) opioid analgesics while maintaining patient access to pain medications. Adverse outcomes of concern include addiction, unintentional overdose, and death.”*
There are several elements of the program including:
*Source: http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafety InformationforPatientsandProviders/UCM311290.pdf, "EXTENDED-RELEASE (ER) AND LONG-ACTING (LA) OPIOID ANALGESICS RISK EVALUATION AND MITIGATION STRATEGY (REMS)"; Initial REMS Approval: 07/2012; Most Recent Modification: 08/2012. Reference ID: 3181514. Accessed November 27, 2012.
Risk and safety information about KADIAN®
The BOXED WARNING in the prescribing information for Healthcare Providers states:
WARNING: ABUSE POTENTIAL, LIFE-THREATENING RESPIRATORY DEPRESSION, and ACCIDENTAL EXPOSURE
KADIAN® contains morphine, an opioid agonist and Schedule II controlled substance with an abuse liability similar to other opioid agonists, legal or illicit. Assess each patient’s risk for opioid abuse or addiction prior to prescribing KADIAN®. The risk for opioid abuse is increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depressive disorder). Routinely monitor all patients receiving KADIAN® for signs of misuse, abuse, and addiction during treatment.
Life-threatening Respiratory Depression
Respiratory depression, including fatal cases, may occur with use of KADIAN®, even when the drug has been used as recommended and not misused or abused. Proper dosing and titration are essential and KADIAN® should only be prescribed by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain. Monitor for respiratory depression, especially during initiation of KADIAN® or following a dose increase. Instruct patients to swallow KADIAN® capsules whole or to sprinkle the contents of the capsule on applesauce and swallow without chewing. Crushing, dissolving, or chewing the pellets within the capsule can cause rapid release and absorption of a potentially fatal dose of morphine.
Accidental consumption of KADIAN®, especially in children, can result in a fatal overdose of morphine.
IMPORTANT INFORMATION ABOUT KADIAN®
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, and hypersensitivity to morphine.
KADIAN® 100 mg, 130 mg, 150 mg, and 200 mg capsule strengths ARE FOR USE IN OPIOID TOLERANT PATIENTS ONLY. Ingestion of these capsules or the contents within the capsules may cause fatal respiratory depression when administered to patients not already tolerant to high doses of opioids.
Warnings and Precautions
KADIAN® contains morphine, an opioid agonist and a Schedule II controlled substance. Morphine can be abused in a manner similar to other opioid agonists, legal or illicit. Opioid agonists are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing KADIAN® in situations where there is concern about increased risks of misuse, abuse, or diversion. Concerns about abuse, addiction, and diversion should not, however, prevent the proper management of pain.
Misuse or abuse of KADIAN® by crushing, chewing, snorting or injecting the dissolved product poses a significant risk that could result in overdose and death. Assess each patient’s risk for opioid abuse or addiction prior to prescribing KADIAN®. The risk for opioid abuse is increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Routinely monitor all patients receiving opioids for signs of misuse, abuse, and addiction because these drugs carry a risk for addiction even under appropriate medical use. Patients at increased risk may still be appropriately treated with modified-release opioid formulations; however these patients will require intensive monitoring for signs of misuse, abuse, or addiction.
Respiratory depression is the primary risk of KADIAN® and if not immediately recognized and treated, may lead to respiratory arrest and death. Serious, life-threatening, or fatal respiratory depression can occur at any time during the use of KADIAN®. Closely monitor patients for respiratory depression when initiating therapy with KADIAN® and following dose increases. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists.
Instruct patients that KADIAN® should only be used by the patient to whom KADIAN® is prescribed. Inappropriate use may result in fatal respiratory depression. KADIAN® must be kept in a secure place, and out of reach of children. Accidental consumption of KADIAN®, especially in children, can result in a fatal overdose of morphine.
To reduce the risk of respiratory depression, proper dosing and titration of KADIAN® is essential. Overestimating the KADIAN® dose when converting patients from another opioid product can result in fatal overdose with the first dose.
Respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance as compared to younger, healthier patients. Monitor patients closely particularly when initiating and titrating KADIAN® and when KADIAN® is given concomitantly with other drugs that depress respiration.
Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression, particularly when initiating therapy and titrating with KADIAN®. 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.
Hypotension, profound sedation, coma, or respiratory depression may result if KADIAN® is used concomitantly with 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 of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression, and the patient’s use, if any, of alcohol or illicit drugs that cause CNS depression.
Start with a lower KADIAN® dose than usual and monitor patients for signs of sedation and respiratory depression. Also consider using a lower dose of the concomitant CNS depressant.
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 KADIAN®. In patients with circulatory shock, KADIAN® should be avoided as it may cause vasodilation that can further reduce cardiac output and blood 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.
KADIAN® is contraindicated in patients with paralytic ileus, and its use should be avoided in patients with other gastrointestinal obstructions.
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.
Morphine may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures. Monitor patients with a history of seizure disorders for worsening/worsened seizure control during KADIAN® therapy.
Avoid the use of mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including KADIAN®. Mixed agonists/antagonists analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.
When discontinuing KADIAN®, gradually taper the dose. 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.
Concomitant use of alcohol with KADIAN® can result in increased plasma levels of morphine and result in a potentially fatal overdose of morphine.
KADIAN® should be used with great caution and in reduced dosage in patients who are concurrently receiving other CNS depressants including sedatives, hypnotics, general anesthetics, antiemetics, phenothiazines, other tranquilizers and alcohol because of the risk of respiratory depression, hypotension and profound sedation or coma. Additive effects may be expected when KADIAN® is used concurrently with CNS depressant drugs, and reduced doses of KADIAN® or the other drug(s) should be considered.
Mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) may reduce the analgesic effect of KADIAN® or may precipitate withdrawal symptoms. Avoid the use of agonist/antagonist analgesics in patients receiving KADIAN®.
Opioids may enhance the neuromuscular blocking action of skeletal relaxants and produce an increased degree of respiratory depression. Monitor patients receiving KADIAN® concomitantly with muscle relaxants for increased respiratory depression.
Monoamine Oxidase Inhibitors (MAOIs) may potentiate the effects of morphine. KADIAN® should not be used in patients taking MAOIs or within 14 days of stopping such treatment.
There is an isolated report of confusion and severe respiratory depression in a hemodialysis patient who was concurrently administered morphine and cimetidine. Monitor patients receiving KADIAN® concomitantly with cimetidine for increased respiratory and CNS depression.
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 prostatism.
Anticholinergics used concurrently with opioid analgesics may result in urinary retention and/or severe constipation. Monitor patients receiving KADIAN® concomitantly with anticholinergic drugs for signs of urinary retention or reduced gastric motility.
P-Glycoprotein (PGP) inhibitors may increase the absorption/exposure of morphine by two fold. Monitor patients receiving KADIAN® concurrently with a PGP inhibitor for respiratory and CNS depression.
The most serious adverse events associated with KADIAN® and other opioid analgesics are respiratory depression, chronic pulmonary disease, increased intracranial pressure, interactions with other CNS depressants, hypotensive effect, gastrointestinal effects and seizures.
The most frequent (³ 5% of patients) adverse reactions with KADIAN® therapy are constipation, nausea, somnolence, dizziness and anxiety.
KADIAN® is in Pregnancy Category C. It is not known if morphine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Chronic maternal use of morphine during pregnancy can affect the fetus with subsequent withdrawal signs. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening and should be treated according to protocols developed by neonatology experts. KADIAN® should be given to a pregnant woman ONLY if clearly needed.
KADIAN® is not recommended for use in women during and immediately prior to labor. Closely observe neonates whose mothers received opioid analgesics during labor for signs of respiratory depression.
Caution should be used when KADIAN® is administered to a nursing mother due to the potential for serious adverse reactions in nursing infants. Take into account the importance of KADIAN® to the mother.
The safety and effectiveness of KADIAN® in patients less than 18 years of age has not been established.
Use caution when selecting a dose of KADIAN® in elderly patients aged 65 years or older. Dosing should be initiated at the low end of the dosing range. Monitor patients closely for respiratory and central nervous system depression.