"Nov. 2, 2012 -- Safety steps taken in the wake of the fungal meningitis outbreak have worsened drug shortages, raising questions about whether the U.S. must choose between the safety and the availability of crucial medicines.
The following serious adverse reactions are discussed elsewhere in the labeling:
- Addiction, Abuse, and Misuse [see WARNINGS AND PRECAUTIONS]
- Life Threatening Respiratory Depression [see WARNINGS AND PRECAUTIONS]
- Neonatal Opioid Withdrawal Syndrome [see WARNINGS AND PRECAUTIONS]
- Interactions with Other CNS Depressants [see WARNINGS AND PRECAUTIONS]
- Hypotensive Effect [see WARNINGS AND PRECAUTIONS]
- Gastrointestinal Effects [see WARNINGS AND PRECAUTIONS]
- Seizures [see WARNINGS AND PRECAUTIONS]
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.
|Clinical trial patients with chronic cancer pain (n=227) (AE by Body System as seen in 2% or more of patients)||Percentage %|
|CENTRAL NERVOUS SYSTEM||28|
|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:
- Body as a Whole: Headache, chills, flu syndrome, back pain, malaise, withdrawal syndrome
- Cardiovascular: Tachycardia, atrial fibrillation, hypotension, hypertension, pallor, facial flushing, palpitations, bradycardia, syncope
- Central Nervous System: Confusion, anxiety, abnormal thinking, abnormal dreams, lethargy, depression, loss of concentration, insomnia, amnesia, paresthesia, agitation, vertigo, foot drop, ataxia, hypesthesia, slurred speech, hallucinations, vasodilation, euphoria, apathy, seizures, myoclonus
- Endocrine: Hyponatremia due to inappropriate ADH secretion, gynecomastia
- Gastrointestinal: Dysphagia, dyspepsia, stomach atony disorder, gastro-esophageal reflux, delayed gastric emptying, biliary colic
- Hemic and Lymphatic: Thrombocytopenia
- Metabolic and Nutritional: Hyponatremia, edema
- Musculoskeletal: Back pain, bone pain, arthralgia
- Respiratory: Hiccup, rhinitis, atelectasis, asthma, hypoxia, respiratory insufficiency, voice alteration, depressed cough reflex, non-cardiogenic pulmonary edema
- Skin and Appendages: Decubitus ulcer, pruritus, skin flush
- Special Senses: Amblyopia, conjunctivitis, miosis, blurred vision, nystagmus, diplopia
- Urogenital: Urinary abnormality, amenorrhea, urinary retention, urinary hesitancy, reduced libido, reduced potency, prolonged labor
Four-Week Open-Label Safety Study
In the open-label, 4-week safety study, 1418 patients ages 18 to 85 with chronic, non-malignant pain (e.g., back pain, osteoarthritis, neuropathic pain) were enrolled. The most common adverse events reported at least once during therapy were constipation (12%), nausea (9%), and somnolence (3%). Other less common side effects occurring in less than 3% of patients were vomiting, pruritus, dizziness, sedation, dry mouth, headache, fatigue, and rash.
Anaphylaxis has been reported with ingredients contained in KADIAN. Advise patients how to recognize such a reaction and when to seek medical attention.
Read the Kadian (morphine sulfate extended-release) Side Effects Center for a complete guide to possible side effects
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].
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.
Interactions With Mixed Agonist/Antagonist And Partial Agonist Opioid Analgesics
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.
Monoamine Oxidase Inhibitors (MAOIs)
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.
P-Glycoprotein (PGP) Inhibitors
PGP inhibitors (e.g. quinidine) may increase the absorption/exposure of morphine by about two-fold. Monitor patients for signs of respiratory and central nervous system depression when PGP inhibitors are used concurrently with KADIAN.
Drug Abuse And Dependence
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].
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]. 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].
Read the Kadian Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 4/30/2014
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