Included as part of the PRECAUTIONS section.
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
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
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.
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
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
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
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
Instruct patients not to share AVINZA with others and to take steps to protect
AVINZA from theft or misuse.
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
Inform patients that accidental ingestion, especially in
children, may result in respiratory depression or death [see WARNINGS
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
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
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
- 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
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
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.
Advise patients of the potential for severe constipation,
including management instructions and when to seek medical attention.
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.
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.
Carcinogenesis, Mutagenesis, 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, 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
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
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.
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.
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
The safety and effectiveness of AVINZA in pediatric
patients below the age of 18 have not been established.
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].