A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Avinza Side Effects, and Drug Interactions - Morphine Sulfate
Avinza Side Effects, and Drug Interactions - Morphine Sulfate
SIDE EFFECTS
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.
Adverse Events
The common adverse events seen on initiation of therapy with
morphine are dose-dependent and are typical opioid related side effects. The
most frequent of these include constipation, nausea and somnolence. The frequency
of these events depends upon several factors including the clinical setting,
the patient’s level of opioid tolerance, and host factors specific to the individual.
These events should be anticipated and managed as part of opioid analgesia therapy.
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 from 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.
DRUG ABUSE AND ADDICTION
AVINZA is a mu-agonist opioid and is a Schedule II controlled
substance. Morphine, like other opioids used in analgesia, can be abused and
is subject to criminal diversion.
Drug addiction is characterized by compulsive use, use for
non-medical purposes, and continued use despite harm or risk of harm. Drug addiction
is a treatable disease, utilizing a multi-disciplinary approach, but relapse
is common.
"Drug seeking" behavior is very common in 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 "loss" of prescriptions, tampering with prescriptions
and reluctance to provide prior medical records or contact information for other
treating physician(s). "Doctor shopping" to obtain additional prescriptions
is common among drug abusers and people suffering from untreated addiction.
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.
The converse is also true. In addition, abuse of opioids can occur in the absence
of true addiction and is characterized by misuse for non-medical purposes, often
in combination with other psychoactive substances. Careful record-keeping of
prescribing information, including quantity, frequency, and renewal requests
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 limit abuse of opioid drugs.
AVINZA is intended for oral use only. Abuse of the crushed
capsule poses a hazard of overdose and death. This risk is increased with concurrent
abuse of alcohol and other substances. With parenteral abuse, the capsule excipients,
especially talc, 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.
DRUG INTERACTIONS
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 Pharmacokinetics, 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 have 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.
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, 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 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 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.
Nursing Mothers
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.
Pediatric Use
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.
Geriatric Use
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).
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