AVINZA must be swallowed whole (not chewed, crushed, or dissolved) or AVINZA may be opened and the entire bead contents sprinkled on a small amount of applesauce immediately prior to ingestion. THE CAPSULES MUST NOT BE CHEWED, CRUSHED, OR DISSOLVED DUE TO THE RISK OF RAPID RELEASE AND ABSORPTION OF A POTENTIALLY FATAL DOSE OF MORPHINE. (see BOX WARNING, CLINICAL PHARMACOLOGY)
Patients must not consume alcoholic beverages while on AVINZA therapy. Additionally, patients must not use prescription or non-prescription medications containing alcohol while on AVINZA therapy. Consumption of alcohol while taking AVINZA may result in the rapid release and absorption of a potentially fatal dose of morphine.
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.
Misuse, Abuse and Diversion of Opioids
Morphine is an opioid agonist and a Schedule II controlled substance. Such drugs are sought by drug abusers and people with addiction disorders. Diversion of Schedule II products is an act subject to criminal penalty.
Morphine can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing AVINZA in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.
Abuse of AVINZA by crushing, chewing, snorting, or injecting the dissolved product will result in the immediate release of the entire daily dose of the opioid and pose a significant risk to the abuser that could result in overdose and death. Intravenous abuse of a water extract of AVINZA may lead to serious pulmonary complications due to the extraction of talc along with morphine sulfate. (see DRUG ABUSE AND ADDICTION)
Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. Healthcare professionals should contact their State Professional Licensing Board, or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.
Interactions with Alcohol and Drugs of Abuse
Morphine may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression. In vitro studies performed by the FDA demonstrated that when AVINZA 30 mg was mixed with 900 mL of buffer solutions containing ethanol (20% and 40%), the dose of morphine that was released was alcohol concentration-dependent, leading to a more rapid release of morphine. While the relevance of in vitro lab tests regarding AVINZA to the clinical setting remains to be determined, this acceleration of release may correlate with in vivo rapid release of the total morphine dose, which could result in the absorption of a potentially fatal dose of morphine.
Respiratory depression is the chief hazard of all morphine preparations. Respiratory depression occurs more frequently in elderly or debilitated patients and in those suffering from conditions accompanied by hypoxia, hypercapnia, or upper airway obstruction, in whom even moderate therapeutic doses may significantly decrease pulmonary ventilation.
Morphine should be used with extreme caution in patients with chronic obstructive pulmonary disease or cor pulmonale and in patients having a substantially decreased respiratory reserve (e.g., severe kyphoscoliosis), hypoxia, hypercapnia, or pre-existing respiratory depression. In such patients, even usual therapeutic doses of morphine may increase airway resistance and decrease respiratory drive to the point of apnea.
Head Injury and Increased Intracranial Pressure
The respiratory depressant effects of morphine with carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions, or a pre-existing increase in intracranial pressure. Morphine produces effects which may obscure neurologic signs of further increases in intracranial pressure in patients with head injuries. Morphine should only be administered under such circumstances when considered essential and then with extreme care.
AVINZA, like all morphine products, may cause severe hypotension in an individual whose ability to maintain blood pressure has already been compromised by a depleted blood volume or concurrent administration of drugs such as phenothiazines or general anesthetics. (see also PRECAUTIONS, Drug Interactions) AVINZA may produce orthostatic hypotension and syncope in ambulatory patients.
AVINZA is an opioid analgesic which should be administered with caution to patients in circulatory shock, as vasodilation produced by the drug may further reduce cardiac output and blood pressure.
AVINZA should not be administered to patients with gastrointestinal obstruction, especially paralytic ileus because AVINZA, like all morphine preparations, diminishes propulsive peristaltic waves in the gastrointestinal tract and may prolong the obstruction.
AVINZA is intended for use in patients requiring continuous around-the-clock treatment with an opioid analgesic. It is not appropriate as a prn treatment for pain. As with any opioid, it is critical to adjust the dose of AVINZA for each individual patient, taking into account the patient’s prior experience with analgesics. (see DOSAGE AND ADMINISTRATION)
Use in Pancreatic/Biliary Tract Disease
AVINZA should be used with caution in patients with biliary tract disease, including acute pancreatitis, as morphine may cause spasm of the sphincter of Oddi and diminish biliary and pancreatic secretions.
Special Risk Groups
AVINZA should be administered cautiously and in reduced dosages in patients with severe renal or hepatic insufficiency, Addison's disease, hypothyroidism, prostatic hypertrophy, or urethral stricture, and in elderly or debilitated patients. (see Geriatric Use and CLINICAL PHARMACOLOGY, Special Populations)
Caution should be exercised in the administration of morphine to patients with CNS depression, toxic psychosis, acute alcoholism and delirium tremens, and seizure disorders.
Driving and Operating Machinery
Patients should be cautioned that AVINZA could impair the mental and/or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery.
Patients should also be cautioned about the potential combined effects of AVINZA with other CNS depressants, including other opioids, phenothiazines, sedative/hypnotics and alcohol. (see PRECAUTIONS, Drug Interactions)
Tolerance and Physical Dependence
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). Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist. Physical dependence and tolerance are not unusual during chronic opioid therapy.
The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other 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.
In general, opioids should not be abruptly discontinued. (see DOSAGE AND ADMINISTRATION, Cessation of Therapy)
Information for Patients
Patients receiving AVINZA (morphine sulfate extended-release capsules) should be given the following instructions by the physician:
- Patients should be advised that AVINZA capsules contain morphine and should be taken once daily.
- AVINZA must be swallowed whole (not chewed, crushed, or dissolved) or AVINZA may be opened and the entire bead contents sprinkled on a small amount of applesauce immediately prior to ingestion. The beads must NOT be chewed, crushed, or dissolved due to the risk of exposure to a potentially toxic dose of morphine.
- Patients should be informed that they must not consume alcoholic beverages while on AVINZA therapy. Additionally, patients should be informed that they must not use prescription or non-prescription medication containing alcohol while on AVINZA therapy. Consumption of alcohol while taking AVINZA may result in the rapid release and absorption of a potentially fatal dose of morphine.
- The dose of AVINZA should not be adjusted without consulting with a physician or other healthcare professional.
- Patients should be advised that AVINZA may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating machinery). Patients started on AVINZA or patients whose dose has been adjusted should refrain from any potentially dangerous activity until it is established that they are not adversely affected.
- Patients should be advised that AVINZA should not be combined with alcohol or other CNS depressants (e.g., sleep medications, tranquilizers). A physician should be consulted if other medications are currently being used or are added in the future.
- Women of childbearing potential who become or are planning to become pregnant should consult a physician prior to initiating or continuing therapy with AVINZA.
- If patients have been receiving treatment with AVINZA for more than a few weeks and cessation of therapy is indicated, they should be counseled on the importance of safely tapering the dose and that abruptly discontinuing the medication could precipitate withdrawal symptoms. The physician should provide a dose schedule to accomplish a gradual discontinuation of the medication
- Patients should be advised that AVINZA is a potential drug of abuse. They should protect it from theft. It should never be given to anyone other than the individual for whom it was prescribed.
- Patients should be instructed to keep AVINZA in a secure place out of the reach of children. When AVINZA is no longer needed, the unused capsules should be destroyed by flushing down the toilet.
As with other opioids, patients taking AVINZA should be advised of the potential for severe constipation; appropriate laxatives, and/or stool softeners as well as other appropriate treatments should be initiated from the onset of opioid therapy.
CNS Depressants: The concurrent use of other central nervous system (CNS) depressants including sedatives, hypnotics, general anesthetics, antiemetics, phenothiazines, or other tranquilizers or alcohol increases the risk of respiratory depression, hypotension, profound sedation, or coma. Use with caution and in reduced dosages in patients taking these agents.
Muscle Relaxants: Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Mixed Agonist/Antagonist Opioid Analgesics: Mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine and butorphanol) should NOT be administered to patients who have received or are receiving a course of therapy with a pure opioid agonist analgesic. In these patients, mixed agonist/antagonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.
Monoamine Oxidase Inhibitors (MAOIs): MAOIs markedly potentiate the action of morphine. AVINZA should not be used in patients taking MAOIs or within 14 days of stopping such treatment.
Cimetidine: Concomitant administration of morphine and cimetidine has been reported to precipitate apnea, confusion and muscle twitching in an isolated report. Patients should be monitored for increased respiratory and CNS depression when receiving cimetidine concomitantly with AVINZA.
Food: AVINZA can be administered without regard to food. (see CLINICAL PHARMACOLOGY, Food Effects)
Carcinogenicity/Mutagenicity/Impairment of Fertility
Studies in animals to evaluate the carcinogenic potential of morphine sulfate have not been conducted. No formal studies to assess the mutagenic potential of morphine have been conducted. In the published literature, the results of in vitro studies showed that morphine is non‑mutagenic in the Drosophila melanogaster lethal mutation assay and produced no evidence of chromosomal aberrations when incubated with murine splenocytes. Contrary to these results, morphine was found to increase DNA fragmentation when incubated in vitro with a human lymphoma cell line. In vivo, morphine has been reported to produce an increase in the frequency of micronuclei in bone marrow cells and immature red blood cells in the mouse micronucleus test and to induce chromosomal aberrations in murine lymphocytes and spermatids. Some of the in vivo clastogenic effects reported with morphine in mice may be directly related to increases in glucocorticoid levels produced by morphine in this species.
Teratogenic Effects (Pregnancy Category C)
No formal studies to assess the teratogenic effects of morphine in animals have been performed. 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. Morphine was not a significant teratogen in the rat at exposure levels significantly beyond that normally encountered in clinical practice. In one study however, decreased litter size and viability were observed in the offspring of male rats administered morphine at doses approximately 3-fold the maximum recommended human daily dose (MRHDD) for 10 days prior to mating. In two studies performed in the rabbit, no evidence of teratogenicity was reported at subcutaneous doses up to 100 mg/kg.
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 this drug 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.
Published literature has reported that exposure to morphine during pregnancy is associated with reduction in growth and a host of behavioral abnormalities in the offspring of animals. 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, lengths or widths at birth and during the neonatal period, 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. 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.
Controlled studies of chronic in utero morphine exposure in pregnant women have not been conducted. Infants born to mothers who have taken opioids chronically may exhibit withdrawal symptoms, 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.
Labor and Delivery
Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. AVINZA is not recommended for use in women during and immediately prior to labor, when use of shorter acting analgesics or other analgesic techniques are more appropriate. Occasionally, opioid analgesics may prolong labor through actions which 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. Neonates whose mothers received opioid analgesics during labor should be observed closely for signs of respiratory depression. A specific opioid antagonist, such as naloxone or nalmefene, should be available for reversal of opioid-induced respiratory depression in the neonate.
Neonatal Withdrawal Syndrome
Chronic maternal use of opioids during pregnancy may cause newborns to suffer from neonatal withdrawal syndrome (NWS) following birth. Manifestations of this syndrome include irritability, hyperactivity, abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, weight loss, and failure to gain weight. The time and amount of the mother’s last dose, and the rate of elimination of the drug from the newborn may affect the onset, duration, and severity of the disorder. When severe symptoms occur, pharmacologic intervention may be required.
Low levels of morphine sulfate have been detected in human milk. Breast-feeding infants might experience withdrawal symptoms upon cessation of AVINZA administration to the mother. Because of the potential for nursing infants to experience adverse reactions, a decision should be made whether to discontinue nursing or discontinue AVINZA, taking into account the benefit of the drug to the mother.
Safety and effectiveness of AVINZA in pediatric patients below the age of 18 have not been established. The range of dose strengths available may not be appropriate for treatment of very young pediatric patients. Sprinkling on applesauce is NOT a suitable alternative for these patients.
Of the total number of subjects in clinical studies of AVINZA, there were 168 patients age 65 and over, including 64 patients over the age of 74, 100 of whom were treated with AVINZA. Subgroup analyses comparing efficacy were not possible given the small number of subjects in each treatment group. No overall differences in safety were observed between these subjects and younger subjects. In general, caution should be exercised in the selection of the starting dose of AVINZA for an elderly patient, usually starting at the low end of the dosing range. As with all opioids, the starting dose should be reduced in debilitated and non-tolerant patients. (see CLINICAL PHARMACOLOGY, Special Populations, Geriatric and PRECAUTIONS, Special Risk Groups)