Drug: Avinza

AVINZA extended-release capsules are for oral use and contain pellets of morphine sulfate. Morphine sulfate is an agonist at the mu-opioid receptor. Each AVINZA extended-release capsule contains either 30, 45, 60, 75, 90, or 120 mg of morphine sulfate, USP and the following inactive ingredients: ammoniomethacrylate copolymers, NF, fumaric acid, NF, povidone, USP, sodium lauryl sulfate, NF, sugar starch spheres, NF, and talc, USP. The capsule shell contains black ink, gelatin, titanium dioxide, D&C yellow No. 10 (30 mg), FD&C blue No. 2 (45 mg), FD&C green No. 3 (60 mg), FDA iron oxide and FDA yellow iron oxide (75 mg), FD&C red No. 40 (90 mg), FD&C red No. 3 (120 mg), and FD&C blue No. 1 (120 mg). The chemical name of morphine sulfate is 7,8-didehydro-4,5 alpha-epoxy-17-methylmorphinan-3,6 alpha-diol sulfate (2:1) (salt) pentahydrate with a molecular weight of 758. The empirical formula is (C17H19NO3)2•H2SO4•5H2O. Morphine sulfate is an odorless, white, crystalline powder. It is soluble in water and slightly soluble in alcohol, but is practically insoluble in chloroform or ether. The octanol:water partition coefficient of morphine is 1.42 at physiologic pH and the pKa is 7.9 for the tertiary nitrogen (the majority is ionized at pH 7.4). Its structural formula is:

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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]
The most common adverse reactions with AVINZA include constipation, nausea 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 controlled and open-label clinical studies, 560 patients with chronic malignant or non-malignant pain were treated with AVINZA. The most common serious adverse events reported with administration of AVINZA were vomiting, nausea, death, dehydration, dyspnea, and sepsis. (Deaths occurred in patients treated for pain due to underlying malignancy.) Serious adverse events caused by morphine include respiratory depression, apnea, and to a lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest. The most common adverse events (seen in greater than 10%) reported by patients treated with AVINZA during the clinical trials at least once during therapy were constipation, nausea, somnolence, vomiting, and headache. Adverse events occurring in 5-10% of study patients were peripheral edema, diarrhea, abdominal pain, infection, urinary tract infection, accidental injury, flu syndrome, back pain, rash, sweating, fever, insomnia, depression, paresthesia, anorexia, dry mouth, asthenia and dyspnea. Other less common side effects expected from opioid analgesics, including morphine, or seen in fewer than 5% of patients taking AVINZA in the clinical trials were: Body as a Whole: malaise, withdrawal syndrome. Cardiovascular System: bradycardia, hypertension, hypotension, palpitations, syncope, tachycardia. Digestive System: biliary pain, dyspepsia, dysphagia, gastroenteritis, abnormal liver function tests, rectal disorder, thirst. Hemic and Lymphatic System: anemia, thrombocytopenia. Metabolic and Nutritional Disorders: edema, weight loss. Musculoskeletal: skeletal muscle rigidity. Nervous System: abnormal dreams, abnormal gait, agitation, amnesia, anxiety, ataxia, confusion, convulsions, coma, delirium, euphoria, hallucinations, lethargy, nervousness, abnormal thinking, tremor, vasodilation, vertigo. Respiratory System: hiccup, hypoventilation, voice alteration. Skin and Appendages: dry skin, urticaria. Special Senses: amblyopia, eye pain, taste perversion. Urogenital System: abnormal ejaculation, dysuria, impotence, decreased libido, oliguria, urinary retention. Anaphylaxis has been reported with ingredients contained in AVINZA. Advise patients how to recognize such a reaction and when to seek medical attention. Read the Avinza (morphine sulfate) Side Effects Center for a complete guide to possible side effectsLearn More »

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Initial Dosing AVINZA should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain. AVINZA 90 mg and 120 mg capsules are for use only in patients in whom tolerance to an opioid of comparable potency has been established. 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. 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 [see WARNINGS AND PRECAUTIONS]. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with AVINZA [see WARNINGS AND PRECAUTIONS]. AVINZA capsules must be taken whole. Crushing, chewing, or dissolving the pellets in AVINZA capsules will result in uncontrolled delivery of morphine and can lead to overdose or death [see WARNINGS AND PRECAUTIONS]. Patients who are unable to swallow AVINZA should be instructed to sprinkle the capsule contents on applesauce and immediately swallow without chewing [see Administration of AVINZA]. AVINZA is administered at a frequency of once daily (every 24 hours). Use of AVINZA as the First Opioid Analgesic Initiate treatment with AVINZA with 30 mg capsule orally every 24 hours. Adjust the dose of AVINZA in increments not greater than 30 mg every 3 to 4 days. Use of AVINZA in Patients who are not Opioid Tolerant The starting dose for patients who are not opioid tolerant is AVINZA 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 AVINZA There are no established conversion ratios from other opioids to AVINZA defined by clinical trials. Discontinue all other around-the-clock opioid drugs when AVINZA therapy is initiated and initiate dosing using AVINZA 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 adverse reactions. Conversion from Other Oral Morphine Formulations to AVINZA Patients receiving other oral morphine formulations may be converted to AVINZA by administering the patient's total daily oral morphine dose as AVINZA once-daily. AVINZA should not be given more frequently than every 24 hours. Conversion from Parenteral Morphine or Other Non-Morphine Opioids (Parenteral or Oral) to AVINZA When converting from parenteral morphine or other non-morphine opioids (parenteral or oral) to AVINZA, consider the following general points: Parenteral to oral morphine ratio: Between 2 to 6 mg of oral morphine may be required to provide analgesia equivalent to 1 mg of parenteral morphine. Typically, a dose of morphine that is approximately three times the previous daily parenteral morphine requirement is sufficient. Other parenteral or oral non-morphine 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 AVINZA 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. The first dose of AVINZA may be taken with the last dose of any immediate-release opioid medication due to the extended-release characteristics of the AVINZA formulation. Titration And Maintenance Of Therapy Individually titrate AVINZA to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving AVINZA 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 opioid analgesics. If the level of pain increases, attempt to identify the source of increased pain, while adjusting the AVINZA dose to decrease the level of pain. Because steady-state plasma concentrations are approximated within 2 to 3 days, AVINZA dosage adjustments may be done every 3 to 4 days. Patients who experience breakthrough pain may require a dose increase of AVINZA, 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 AVINZA dose. The daily dose of AVINZA must be limited to a maximum of 1600 mg/day. AVINZA doses of over 1600 mg/day contain a quantity of fumaric acid that has not been demonstrated to be safe, and which may result in serious renal toxicity. 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 AVINZA When a patient no longer requires therapy with AVINZA, use a gradual downward titration of the dose every 2 to 4 days, to prevent signs and symptoms of withdrawal in the physically-dependent patient. Do not abruptly discontinue AVINZA. Administration Of AVINZA AVINZA capsules must be taken whole. Crushing, chewing, or dissolving the pellets in AVINZA will result in uncontrolled delivery of morphine and can lead to overdose or death [see WARNINGS AND PRECAUTIONS]. Alternatively, the contents of the AVINZA 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 AVINZA capsules after the contents have been sprinkled on applesauce.
Do not administer AVINZA pellets through a nasogastric or gastric tubes.

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Alcohol 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]. CNS Depressants The concomitant use of AVINZA 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 AVINZA for signs of respiratory depression, sedation and hypotension. When combined therapy with any of the above medications is considered, the dose of one or both agents should be reduced [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS]. Mixed Agonist/Antagonist And Partial Agonist Opioid Analgesics Mixed agonist/antagonist (i.e., pentazocine, nalbuphine, and butorphanol) and partial agonist (buprenorphine) analgesics may reduce the analgesic effect of AVINZA or may precipitate withdrawal symptoms. Avoid the use of agonist/antagonist and partial agonist analgesics in patients receiving AVINZA. Muscle Relaxants 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 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. Diuretics 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 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. Drug Abuse And Dependence Controlled Substance 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. Abuse 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. Dependence 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. 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]. Read the Avinza Drug Interactions Center for a complete guide to possible interactions Learn More »

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AVINZA 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 AVINZA 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.
  • AVINZA is not indicated as an as-needed (prn) analgesic.

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AVINZA 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 [see ADVERSE REACTIONS]
Last reviewed on RxList: 5/1/2014
This monograph has been modified to include the generic and brand name in many instances.

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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, 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.

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Dosage Forms And Strengths AVINZA contains white to off-white color pellets, have an outer opaque capsule with colors as identified below and are available in six dose strengths: Each 30 mg extended-release capsule has a yellow opaque cap with “AVINZA” printed on it and a white opaque body printed with “30” and “505”. Each 45 mg extended-release capsule has a light blue opaque cap with “AVINZA” printed on it and a white opaque body printed with “45” and “509”. Each 60 mg extended-release capsule has a bluish-green opaque cap with “AVINZA” printed on it and a white opaque body printed with “60” and “506”. Each 75 mg extended-release capsule has an orange opaque cap with “AVINZA” printed on it and a white opaque body printed with “75” and “510”. Each 90 mg extended-release capsule has a red opaque cap with “AVINZA” printed on it and a white opaque body printed with “90” and “507”. Each 120 mg extended-release capsule has a blue-violet opaque cap with “AVINZA” printed on it and a white opaque body printed with “120” and “508”. Storage And Handling 30 mg extended-release capsule: size 3 capsule, yellow cap and white, opaque body imprinted AVINZA 30 mg and 505. NDC 60793-605-01: Bottles of 100 capsules. 45 mg extended-release capsule: size 3 capsule, light blue cap and white, opaque body imprinted AVINZA 45 mg and 509. NDC 60793-603-01: Bottles of 100 capsules. 60 mg extended-release capsule: size 3 capsule, bluish-green cap and white, opaque body imprinted AVINZA 60 mg and 506. NDC 60793-606-01: Bottles of 100 capsules. 75 mg extended-release capsule: size 1 capsule, orange cap and white, opaque body imprinted AVINZA 75 mg and 510. NDC 60793-604-01: Bottles of 100 capsules. 90 mg extended-release capsule: size 1 capsule, red cap and white, opaque body imprinted AVINZA 90 mg and 507. NDC 60793-607-01: Bottles of 100 capsules. 120 mg extended-release capsule: size 1 capsule, blue-violet cap and white, opaque body imprinted AVINZA 120 mg and 508. NDC 60793-608-01: Bottles of 100 capsules. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). [see USP Controlled Room Temperature] Protect from light and moisture. Dispense in a tight, light-resistant container as defined in USP. CAUTION: DEA Order Form Required. Manufactured for: Pfizer Inc, New York, NY 10017 by: Alkermes Gainesville LLC, Gainesville, GA. Issued: April 2014 Last reviewed on RxList: 5/1/2014
This monograph has been modified to include the generic and brand name in many instances.

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Addiction, Abuse, And Misuse AVINZA contains morphine, a Schedule II controlled substance. As an opioid, AVINZA exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence]. As modified-release products such as AVINZA 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 AVINZA 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 AVINZA, and monitor all patients receiving AVINZA 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 AVINZA for the proper management of pain in any given patient. Patients at increased risk may be prescribed modified-release opioid formulations such as AVINZA, but use in such patients necessitates intensive counseling about the risks and proper use of AVINZA along with intensive monitoring for signs of addiction, abuse, and misuse. Abuse or misuse of AVINZA by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the morphine and can result in overdose and death [see OVERDOSAGE]. Opioid agonists such as AVINZA are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing AVINZA. 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 [see PATIENT INFORMATION]. 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 [see OVERDOSAGE]. 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 AVINZA, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with AVINZA and following dose increases. To reduce the risk of respiratory depression, proper dosing and titration of AVINZA are essential [see DOSAGE AND ADMINISTRATION]. Overestimating the AVINZA dose when converting patients from another opioid product can result in fatal overdose with the first dose. Accidental ingestion of even one dose of AVINZA, especially by children, can result in respiratory depression and death due to an overdose of morphine. Neonatal Opioid Withdrawal Syndrome Prolonged use of AVINZA 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 AVINZA therapy. The co-ingestion of alcohol with AVINZA may result in increased plasma levels and a potentially fatal overdose of morphine [see CLINICAL PHARMACOLOGY]. Hypotension, profound sedation, coma, respiratory depression, and death may result if AVINZA 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 AVINZA 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. Additionally, evaluate the patient's use of alcohol or illicit drugs that cause CNS depression. If the decision to begin AVINZA is made, start with AVINZA 30 mg every 24 hours, monitor patients for signs of sedation and respiratory depression, and consider using a lower dose of the concomitant CNS depressant [see DRUG INTERACTIONS]. 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 AVINZA and when AVINZA is given concomitantly with other drugs that depress respiration [see Life-Threatening Respiratory Depression]. 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 AVINZA, as in these patients, even usual therapeutic doses of AVINZA may decrease respiratory drive to the point of apnea [see Life-Threatening Respiratory Depression]. Consider the use of alternative non-opioid analgesics in these patients if possible. Hypotensive Effect AVINZA 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]. Monitor these patients for signs of hypotension after initiating or titrating the dose of AVINZA. In patients with circulatory shock, AVINZA may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of AVINZA in patients with circulatory shock. Use In Patients With Head Injury Or Increased Intracranial Pressure Monitor patients taking AVINZA 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 AVINZA. AVINZA 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 AVINZA in patients with impaired consciousness or coma. Use In Patients With Gastrointestinal Conditions AVINZA is contraindicated in patients with paralytic ileus. Avoid the use of AVINZA in patients with other GI obstruction. The morphine in AVINZA 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 AVINZA 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 AVINZA therapy. Avoidance Of Withdrawal Avoid the use of mixed agonist/antagonist (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 opioid agonist analgesic, including AVINZA. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms. When discontinuing AVINZA, gradually taper the dose [see DOSAGE AND ADMINISTRATION]. Do not abruptly discontinue AVINZA. Driving And Operating Machinery AVINZA 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 AVINZA and know how they will react to the medication. Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Addiction, Abuse, and Misuse Inform patients that the use of AVINZA, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose or death [see WARNINGS AND PRECAUTIONS]. Instruct patients not to share AVINZA with others and to take steps to protect AVINZA 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 AVINZA or when the dose is increased, and that it can occur even at recommended doses [see WARNINGS AND PRECAUTIONS]. 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 [see WARNINGS AND PRECAUTIONS]. Instruct patients to take steps to store AVINZA securely and to dispose of unused AVINZA by flushing the capsules down the toilet. Neonatal Opioid Withdrawal Syndrome Inform female patients of reproductive potential that prolonged use of AVINZA during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see WARNINGS AND PRECAUTIONS]. 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 AVINZA. The co-ingestion of alcohol with AVINZA may result in increased plasma levels and a potentially fatal overdose of morphine [see WARNINGS AND PRECAUTIONS]. Inform patients that potentially serious additive effects may occur if AVINZA is used with alcohol or other CNS depressants, and not to use such drugs unless supervised by a healthcare provider. Important Administration Instructions Instruct patients how to properly take AVINZA, including the following:
  • Swallowing AVINZA capsules whole or sprinkling the capsule contents on applesauce and then swallowing immediately without chewing
  • Not crushing, chewing, or dissolving the pellets in the capsules
  • Using AVINZA exactly as prescribed to reduce the risk of life-threatening adverse reactions (e.g., respiratory depression)
  • Not discontinuing AVINZA without first discussing the need for a tapering regimen with the prescriber
Hypotension Inform patients that AVINZA 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 AVINZA 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 ingredients contained in AVINZA. Advise patients how to recognize such a reaction and when to seek medical attention. Pregnancy Advise female patients that AVINZA can cause fetal harm and to inform the prescriber if they are pregnant or plan to become pregnant. Disposal of Unused AVINZA Advise patients to flush the unused capsules down the toilet when AVINZA is no longer needed. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenesis Studies in animals to evaluate the carcinogenic potential of morphine sulfate 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 [see WARNINGS AND PRECAUTIONS]. Teratogenic Effects - Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. AVINZA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 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 [see WARNINGS AND PRECAUTIONS], 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. AVINZA 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. Closely monitor infants of nursing women receiving AVINZA. 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 AVINZA, 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 effectiveness of AVINZA in pediatric patients below the age of 18 have not been established. Geriatric Use The pharmacokinetics of AVINZA have not been studied in elderly patients. In clinical studies of AVINZA, 100 patients who received AVINZA were age 65 and over, including 37 patients over the age of 74. No overall differences in safety were observed between these subjects and younger subjects. [see CLINICAL PHARMACOLOGY]. Last reviewed on RxList: 5/1/2014
This monograph has been modified to include the generic and brand name in many instances.

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