Included as part of the PRECAUTIONS section.
Death Related To Ultra-Rapid Metabolism Of Codeine To Morphine
Respiratory depression and death have occurred in
children who received codeine in the post-operative period following
tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid
metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450
isoenzyme 2D6 [CYP2D6] or high morphine concentrations). Deaths have also
occurred in nursing infants who were exposed to high levels of morphine in
breast milk because their mothers were ultra-rapid metabolizers of codeine [see
Use in Specific Populations].
Some individuals may be ultra-rapid metabolizers because
of a specific CYP2D6 genotype (gene duplications denoted as *1/*1xN or
*1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been
estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1 to
10% in Caucasians, 3% in African Americans, and 16 to 28% in North Africans,
Ethiopians, and Arabs. Data are not available for other ethnic groups. These
individuals convert codeine into its active metabolite, morphine, more rapidly
and completely than other people. This rapid conversion results in higher than
expected serum morphine levels. Even at labeled dosage regimens, individuals
who are ultra-rapid metabolizers may have life-threatening or fatal respiratory
depression or experience signs of overdose (such as extreme sleepiness,
confusion, or shallow breathing) [see OVERDOSAGE].
Children with obstructive sleep apnea who are treated
with codeine for post-tonsillectomy and/or adenoidectomy pain may be
particularly sensitive to the respiratory depressant effects of codeine that
has been rapidly metabolized to morphine. Codeine is contraindicated for
post-operative pain management in all pediatric patients undergoing tonsillectomy
and/or adenoidectomy [see CONTRAINDICATIONS].
When prescribing codeine, healthcare providers should
choose the lowest effective dose for the shortest period of time and inform
patients and caregivers about these risks and the signs of morphine overdose [see
Use in Specific Populations, OVERDOSAGE].
Respiratory depression is the primary risk of codeine
sulfate. 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. Codeine
produces dose-related respiratory depression.
Caution should be exercised when codeine sulfate is used
postoperatively, in patients with pulmonary disease or shortness of breath, or
whenever ventilatory function is depressed. Opioid related 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. Opioids, including codeine sulfate, 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 codeine sulfate may increase airway resistance and decrease
respiratory drive to the point of apnea. Alternative non-opioid analgesics
should be considered, and codeine sulfate should be employed only under careful
medical supervision at the lowest effective dose in such patients [see
Misuse And Abuse of Opioids
Codeine sulfate is an opioid agonist of the morphine-type
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.
Codeine can be abused in a manner similar to other opioid
agonists, legal or illicit. This should be considered when prescribing or
dispensing codeine sulfate in situations where the physician or pharmacist is
concerned about an increased risk of misuse, abuse, or diversion.
Misuse and abuse of codeine sulfate poses a significant
risk to the abuser that could result in overdose and death. Codeine may be
abused by crushing, chewing, snorting or injecting the product [see Drug
Abuse and Dependence].
Concerns about abuse and addiction 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.
Interaction With Alcohol And Drugs Of Abuse
Codeine sulfate may be expected to have additive effects
when used in conjunction with alcohol, other opioids, or illicit drugs that
cause central nervous system depression, because respiratory depression,
hypotension, profound sedation, coma or death may result.
Head Injury And Increased Intracranial Pressure
Respiratory depressant effects of opioids and their
capacity to elevate cerebrospinal fluid pressure resulting from vasodilation
following CO2 retention may be markedly exaggerated in the presence of head
injury, other intracranial lesions or a pre-existing increase in intracranial
pressure. Furthermore, opioids including codeine sulfate, produce adverse
reactions which may obscure the clinical course of patients with head injuries.
Codeine sulfate 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. Codeine sulfate may produce
orthostatic hypotension and syncope in ambulatory patients.
Codeine sulfate should be administered with caution to
patients in circulatory shock, as vasodilation produced by the drug may further
reduce cardiac output and blood pressure.
Codeine sulfate should not be administered to patients
with gastrointestinal obstruction, especially paralytic ileus because codeine
sulfate diminishes propulsive peristaltic waves in the gastrointestinal tract
and may prolong the obstruction.
Chronic use of opioids, including codeine sulfate, may
result in obstructive bowel disease especially in patients with underlying
intestinal motility disorder. Codeine sulfate may cause or aggravate
Administration of codeine sulfate may obscure the
diagnosis or clinical course of patients with acute abdominal conditions.
Use In Pancreatic/Biliary Tract Disease
Codeine sulfate should be used in caution in patients
with biliary tract disease, including acute pancreatitis, as codeine sulfate
may cause spasm of the sphincter of Oddi and diminish biliary and pancreatic
Special Risk Patients
As with other opioids, codeine sulfate should be used
with caution in elderly or debilitated patients and those with severe
impairment of hepatic or renal function, hypothyrodism, Addison's disease,
prostatic hypertrophy or urethral stricture [see Use in Specific Populations].
The usual precautions should be observed and the possibility of respiratory
depression should be kept in mind.
Caution should be exercised in the administration of
codeine sulfate to patients with CNS depression, acute alcoholism, and delirium
All opioids may aggravate convulsions in patients with
convulsive disorders, and all opioids may induce or aggravate seizures in some
Driving And Operating Machinery
Patients should be cautioned that codeine 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 codeine sulfate with other CNS depressants, including
opioids, phenothiazines, sedative/hypnotics, and alcohol [see DRUG
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Two year carcinogenicity studies have been conducted in
F344/N rats and B6C3F1 mice. There was no evidence of carcinogenicity in male
and female rats, respectively, at dietary doses up to 70 and 80 mg/kg/day of
codeine (approximately 2 times the maximum recommended daily dose of 360 mg/day
for adults on a mg/m² basis) for two years. Similiarly there was no
evidence of carcinogenicity activity in male and female mice at dietary doses
up to 400 mg/kg/day of codeine (approximately 5 times the maximum recommended
daily dose of 360 mg/day for adults on a mg/m² basis) for two years.
Codeine was not mutatgenic in the in vitro bacterial
reverse mutation assay or clastogenic in the in vitro Chinese hamster ovary
cell chromosome aberration assay.
Impairment Of fertility
No animal studies were conducted
to evaluate the effect of codeine on male or female fertility.
Reproduction And Developmental Toxicology
Studies on the reproductive and developmental effects of
codeine have been reported in the published literature in hamsters, rats, mice
A study in hamsters administered 150 mg/kg bid of codeine
(PO; approximately 7 times the maximum recommended daily dose of 360 mg/day for
adults on a mg/m² basis) reported the development of cranial
malformations (i.e., meningoencephalocele) in several fetuses examined; as well
as the observation of increases in the percentage of resorptions per litter
examined. Doses of 50 and 150 mg/kg, bid resulted in fetotoxicity as
demonstrated by decreased fetal body weight. In an earlier study in hamsters,
doses of 73-360 mg/kg level (PO; approximately 2-8 times the maximum
recommended daily dose of 360 mg/day for adults on a mg/m² basis),
reportedly produced cranioschisis in all of the fetuses examined.
In studies in rats, doses at the 120 mg/kg level (PO;
approximately 3 times the maximum recommended daily dose of 360 mg/day for
adults on a mg/m² basis), in the toxic range for the adult animal,
were associated with an increase in embryo resorption at the time of
In pregnant mice, a single 100 mg/kg dose (SC;
approximately 1.4 times the recommended daily dose of 360 mg/day for adults on
a mg/mg2 basis) reportedly resulted in delayed ossification in the
No teratogenic effects were observed in rabbits administered
up to 30 mg/kg (approximately 2 times the maximum recommended daily dose of 360
mg/day for adults on a mg/m² basis) of codeine during organogenesis.
Use In Specific Populations
Pregnancy Category C
There are no adequate and well-controlled studies in
pregnant women. Codeine should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
Codeine has been shown to have embryolethal and fetotoxic
effects (reduced fetal body weights and delayed or incomplete ossification) in
the hamster, rat and mouse models at approximately 2-4 times the maximum
recommended human dose of 360 mg/day based on a body surface area comparison.
Maternally toxic doses that were approximately 7 times the maximum recommended
human dose of 360 mg/day, were associated with evidence of resorptions and
incomplete ossification, including meningioencephalocele and cranioschisis. In
contrast, codeine did not demonstrate evidence of embrytoxicity or fetotoxicity
in the rabbit model at doses up to 2 times the maximum recommended human dose
of 360 mg/day based on a body surface area comparison [see Nonclinical
Neonatal codeine withdrawal has occurred in infants born
to addicted and non-addicted mothers who had been taking codeine-containing
medications in the days prior to delivery. Typical symptoms of narcotic
withdrawal include irritability, excessive crying, tremors, hyperreflexia,
seizures, fever, vomiting, diarrhea, and poor feeding. These signs occur
shortly after birth and may require specific treatment.
Codeine (30 mg/kg) administered subcutaneously to
pregnant rats during pregnancy and for 25 days after delivery increased
neonatal mortality at birth. This dose is 0.8 times the maximum recommended
human dose of 360 mg/day on a body surface area comparison.
Labor And Delivery
Opioid analgesics cross the placental barrier and may
produce respiratory depression and psycho-physiologic effects in neonates.
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. The closer
to delivery and the larger the dose used, the greater the possibility of
respiratory depression in the newborn. Opioid analgesics should be avoided
during labor if delivery of a premature infant is anticipated. If the mother
has received narcotic analgesics during labor, newborn infants should be
observed closely for signs of respiratory depression. Resuscitation may be
required [see OVERDOSAGE]. A specific opioid antagonist, such as
naloxone or nalmefene, should be available for reversal of opioid-induced
respiratory depression in the neonate.
Codeine is secreted into human milk. In women with normal
codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted
into human milk is low and dose-dependent. However, some women are ultra-rapid
metabolizers of codeine. These women achieve higher-than-expected serum levels
of codeine's active metabolite, morphine, leading to higher-than-expected
levels of morphine in breast milk and potentially dangerously high serum
morphine levels in their breastfed infants. Therefore, maternal use of codeine
can potentially lead to serious adverse reactions, including death, in nursing
The risk of infant exposure to codeine and morphine
through breast milk should be weighed against the benefits of breastfeeding for
both the mother and the baby. Caution should be exercised when codeine is
administered to a nursing woman. If a codeine containing product is selected,
the lowest dose should be prescribed for the shortest period of time to achieve
the desired clinical effect. Mothers using codeine should be informed about
when to seek immediate medical care and how to identify the signs and symptoms
of neonatal toxicity, such as drowsiness or sedation, difficulty breastfeeding,
breathing difficulties, and decreased tone, in their baby. Nursing mothers who
are ultra-rapid metabolizers may also experience overdose symptoms such as
extreme sleepiness, confusion, or shallow breathing. Prescribers should closely
monitor mother-infant pairs and notify treating pediatricians about the use of
codeine during breastfeeding [see WARNINGS AND PRECAUTIONS].
The safety and effectiveness and the pharmacokinetics of
codeine sulfate in pediatric patients below the age of 18 have not been
established. FDA has not required pediatric studies in ages birth to one month
because there is evidence strongly suggesting that codeine would be ineffective
in this pediatric group since the metabolic pathways to metabolize codeine are
Respiratory depression and death have occurred in
children with obstructive sleep apnea who received codeine in the postoperative
period following tonsillectomy and/or adenoidectomy and had evidence of being
ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for
cytochrome P450 isoenzyme 2D6 or high morphine concentrations). These children
may be particularly sensitive to the respiratory depressant effects of codeine
that has been rapidly metabolized to morphine. Codeine is contraindicated for
post-operative pain management in all pediatric patients undergoing
tonsillectomy and/or adenoidectomy [see CONTRAINDICATIONS].
Codeine may cause confusion and over-sedation in the
elderly. In general, dose selection for an elderly patient should be
cautious, usually starting at the low end of the dosing range, reflecting the
greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant
disease or other drug therapy.
Codeine pharmacokinetics may be altered in patients with
renal failure. Clearance may be decreased and the metabolites may accumulate to
much higher plasma levels in patients with renal failure as compared to
patients with normal renal function. Start these patients cautiously with lower
doses of codeine sulfate or with longer dosing intervals and titrate slowly
while carefully monitoring for side effects.
No formal studies have been conducted in patients with
hepatic impairment so the pharmacokinetics of codeine in this patient
population are unknown. Start these patients cautiously with lower doses of
codeine sulfate or with longer dosing intervals and titrate slowly while
carefully monitoring for side effects.