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AVINZA (morphine sulfate) must be swallowed whole (not chewed, crushed, or dissolved) or AVINZA (morphine sulfate) 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 (morphine sulfate) therapy. Additionally, patients must not use prescription or non-prescription medications containing alcohol while on AVINZA (morphine sulfate) therapy. Consumption of alcohol while taking AVINZA (morphine sulfate) may result in the rapid release and absorption of a potentially fatal dose of morphine.

THE DAILY DOSE OF AVINZA (morphine sulfate) MUST BE LIMITED TO A MAXIMUM OF 1600 MG/DAY. AVINZA (morphine sulfate) 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 (morphine sulfate) in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.

Abuse of AVINZA (morphine sulfate) 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 (morphine sulfate) 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 (morphine sulfate) 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 (morphine sulfate) 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.

Impaired Respiration

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 preexisting 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.

Hypotensive Effect

AVINZA (morphine sulfate) , 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 (morphine sulfate) may produce orthostatic hypotension and syncope in ambulatory patients.

AVINZA (morphine sulfate) 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.

Gastrointestinal Obstruction

AVINZA (morphine sulfate) should not be administered to patients with gastrointestinal obstruction, especially paralytic ileus because AVINZA (morphine sulfate) , like all morphine preparations, diminishes propulsive peristaltic waves in the gastrointestinal tract and may prolong the obstruction.

General

AVINZA (morphine sulfate) 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 (morphine sulfate) 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 (morphine sulfate) 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 (morphine sulfate) should be administered cautiously and in reduced dosages in patients with severe renal or hepatic insufficiency, Addison'sphy, 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 (morphine sulfate) 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 (morphine sulfate) 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)

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 melanogasterlethal mutation assay and produced no evidence of chromosomal aberrations when incubated with murine spleno-cytes. 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.

Pregnancy

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, exenceph-aly, 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.

Nonteratogenic Effects

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 embryo-toxicity 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 ven- and increased risk of sudden infant death syndrome. Morphine tilatory response to CO₂ 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 (morphine sulfate) 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 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.

Nursing Mothers

Low levels of morphine sulfate have been detected in human milk. Breast-feeding infants might experience withdrawal symptoms upon cessation of AVINZA (morphine sulfate) 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 (morphine sulfate) , taking into account the benefit of the drug to the mother.

Pediatric Use

Safety and effectiveness of AVINZA (morphine sulfate) 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.

Geriatric Use

Of the total number of subjects in clinical studies of AVINZA (morphine sulfate) , there were 168 patients age 65 and over, including 64 patients over the age of 74, 100 of whom were treated with AVINZA (morphine sulfate) . 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 (morphine sulfate) 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 nontolerant patients. (see CLINICAL PHARMACOLOGY, Special Populations, Geriatric and PRECAUTIONS, Special Risk Groups)

Last reviewed on RxList: 2/26/2009
This monograph has been modified to include the generic and brand name in many instances.