Concomitant use of alcohol with AVINZA 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 AVINZA therapy [see Clinical Pharmacology].
Concurrent use of AVINZA and other central nervous system (CNS) depressants including sedatives, hypnotics, general anesthetics, antiemetics, phenothiazines, other tranquilizers, and alcohol, can increase the risk of respiratory depression, hypotension, profound sedation, or coma. Monitor patients receiving CNS depressants and AVINZA for signs of respiratory depression and hypotension. When such combined therapy is contemplated, reduce the initial dose of one or both agents.
Mixed Agonist/Antagonist Opioid Analgesics
Mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine and butorphanol) may reduce the analgesic effect of AVINZA or may precipitate withdrawal symptoms in these patients. Avoid the use of agonist/antagonist analgesics in patients receiving AVINZA.
Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Monitor patients receiving muscle relaxants and AVINZA 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 AVINZA for increased respiratory and central nervous system depression. MAOIs have been reported to potentiate the effects of morphine anxiety, confusion, and significant depression of respiration or coma. AVINZA 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 AVINZA 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 medications 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 AVINZA is used concurrently with anticholinergic drugs.
P-Glycoprotein (PGP) Inhibitors
PGP inhibitors (e.g. quinidine) may increase the absorption/exposure of morphine sulfate by about two-fold. Therefore, monitor patients for signs of respiratory and central nervous system depression when AVINZA is used concurrently with PGP inhibitors.
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, in some cases, 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 case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. 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 persons who are known, or suspected to be physically dependent on AVINZA. 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 AVINZA, carefully monitor the patient until spontaneous respiration is reliably re-established. AVINZA will continue to release morphine and add to the morphine load for 36 to 48 hours or longer following ingestion necessitating prolonged monitoring. If the response to opioid antagonists is suboptimal or not sustained, additional antagonist should be administered 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 syndrome. The severity of the withdrawal symptoms experienced 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.
DRUG ABUSE AND DEPENDENCE
AVINZA contains morphine, a Schedule II controlled substance with a high potential for abuse similar to other opioids including fentanyl, hydromorphone, methadone, oxycodone, and oxymorphone. AVINZA 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.
AVINZA, 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 AVINZA
AVINZA is for oral use only. Abuse of AVINZA poses a risk of overdose and death. This risk is increased with concurrent abuse of AVINZA with alcohol and other substances. Taking cut, broken, chewed, crushed, or dissolved AVINZA enhances drug release and increases the risk of overdose and death.
Due to the presence of talc as one of the excipients in AVINZA, parenteral abuse can be expected to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.
Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.
Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone, nalmefene, or mixed agonist/antagonist analgesics (pentazocine, butorphanol, buprenorphine, nalbuphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.
AVINZA should not be abruptly discontinued [see Dosage and Administration]. If AVINZA 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, 8.6)