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 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
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. TUXARIN ER is contraindicated for
post-operative pain management in all pediatric patients undergoing
tonsillectomy and/or adenoidectomy [see CONTRAINDICATIONS].
When prescribing codeine-containing drugs, healthcare
professionals 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]
Risks From Concomitant Use With Benzodiazepines Or Other CNS
Concomitant use of opioids, including TUXARIN ER, with
benzodiazepines, or other CNS depressants, including alcohol, may result in
profound sedation, respiratory depression, coma, and death. Because of these
risks, avoid use of opioid cough medications in patients taking
Benzodiazepines, other CNS depressants, or alcohol [see DRUG INTERACTIONS].
Observational studies have demonstrated that concomitant
use of opioid analgesics and benzodiazepines increases the risk of drug-related
mortality compared to use of opioids alone. Because of similar pharmacologic
properties, it is reasonable to expect similar risk with concomitant use of
opioid cough medications and benzodiazepines, other CNS depressants, or
Advise both patients and caregivers about the risks of
respiratory depression and sedation if TUXARIN ER is used with benzodiazepines,
alcohol, or other CNS depressants. [see PATIENT INFORMATION]
Codeine, one of the active ingredients in TUXARIN ER,
produces dose-related respiratory depression by directly acting on brain stem
Overdose of codeine in adults has been associated with
fatal respiratory depression, and the use of codeine in children has been
associated with fatal respiratory depression. Exercise caution when
administering TUXARIN ER because of the potential for respiratory depression.
If respiratory depression occurs, discontinue TUXARIN ER and use naloxone
hydrochloride when indicated to antagonize the effect and other supportive
measures as necessary. [see OVERDOSAGE].
Codeine can produce drug dependence of the morphine type
and, therefore, has the potential for being abused. Psychological dependence,
physical dependence, and tolerance may develop upon repeated administration of
TUXARIN ER. Prescribe and administer TUXARIN ER with the same degree of caution
appropriate to the use of other opioid drugs. [see Drug Abuse and Dependence]
Head Injury And Increased Intracranial Pressure
The respiratory depression effects of opioids and their
capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in
the presence of head injury, other intracranial lesions, or a pre-existing
increase in intracranial pressure. Furthermore, opioids produce adverse
reactions that may obscure the clinical course of patients with head injuries.
The use of TUXARIN ER should be avoided in these patients.
Activities Requiring Mental Alertness
Codeine and chlorpheniramine, the active ingredients in
TUXARIN ER, may produce marked drowsiness and impair the mental and/or physical
abilities required for the performance of potentially hazardous tasks such as
driving a car or operating machinery. Advise patients to avoid engaging in
hazardous tasks requiring mental alertness and motor coordination after
ingestion of TUXARIN ER. Concurrent use of TUXARIN ER with alcohol or other
central nervous system depressants should be avoided because additional
impairment of central nervous system performance may occur.
Obstructive Bowel Disease
Chronic use of opioids, including codeine, may result in
obstructive bowel disease especially in patients with underlying intestinal
motility disorders. Codeine may cause or aggravate constipation. Use with
caution in patients with underlying intestinal motility disorders.
Acute Abdominal Conditions
TUXARIN ER should be used with caution in patients with
acute abdominal conditions since the administration of codeine may obscure the
diagnosis or clinical course of patients with acute abdominal conditions. The
concurrent use of other anticholinergics with codeine may produce paralytic
ileus. [see DRUG INTERACTIONS]
Special Risk Patients
As with other opioids, TUXARIN ER should be used with
caution in elderly or debilitated patients and those with asthma, persistent or
chronic cough, hypothyroidism, Addison's disease, prostatic hypertrophy or
urethral stricture. The usual precautions should be observed and the
possibility of respiratory depression should be kept in mind.
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (Medication Guide).
Advise patients not to increase the dose or dosing
frequency of TUXARIN ER because serious adverse events such as respiratory
depression may occur with overdosage. [see WARNINGS AND PRECAUTIONS; OVERDOSAGE]
Interactions With Benzodiazepines And Other Central
Nervous System Depressants
Inform patients and caregivers that potentially fatal
additive effects may occur if TUXARIN ER is used with benzodiazepines or other
CNS depressants, including alcohol. Because of this risk, patients should avoid
concomitant use of TUXARIN ER with benzodiazepines or other CNS depressants,
including alcohol [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS].
Activities Requiring Mental Alertness
Caution patients that TUXARIN ER may produce marked
drowsiness and impair the mental and/or physical abilities required for the
performance of potentially hazardous tasks such as driving a car or operating
machinery. [see WARNINGS AND PRECAUTIONS]
Controlled Substance Status/Potential For Abuse And Dependence
Caution patients that TUXARIN ER contains codeine and can
produce drug dependence. [see Abuse and Dependence].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenicity, mutagenicity, and reproductive studies
have not been conducted with TUXARIN ER however, published information is
available for the active ingredients
In 2-year studies in F344/N rats and B6C3F1 mice, codeine
showed no evidence of tumorigenicity at dietary doses up to 70 and 400
mg/kg/day, respectively (approximately 9 and 25 times, respectively, the MRHDD
dose for adults and children on a mg/m² basis).
Codeine was not mutagenic in the in vitro bacterial
reverse mutation assay or clastogenic in the in vitro Chinese hamster ovary
(CHO) cell chromosomal aberration assay.
Fertility studies with codeine have not been conducted.
In 2-year studies in F344/N rats and B6C3F1 mice,
chlorpheniramine maleate showed no evidence of tumorigenicity when administered
5 days/week at oral doses up to 30 and 50 mg/kg/day, respectively
(approximately 25 and 20 times, respectively, the MRHDD on a mg/m² basis).
Chlorpheniramine maleate was not mutagenic in the in
vitro bacterial reverse mutation assay or the in vitro mouse lymphoma forward
mutation assay. Chlorpheniramine maleate was clastogenic in the in vitro CHO
cell chromosomal aberration assay.
Chlorphenirimaleate had no effects on fertility in rats
and rabbits at oral doses approximately 25 and 30 times, respectively, the
MRHDD on a mg/m² basis.
Use In Specific Populations
Pregnancy Category C
There are no adequate and well-controlled studies of
TUXARIN ER in pregnant women.
Reproductive toxicity studies have not been conducted
with TUXARIN ER; however, studies are available with individual active
ingredients or related active ingredients. Because animal reproduction studies
are not always predictive of human response, TUXARIN ER should be used during
pregnancy only if the benefit justifies the potential risk to the fetus.
Codeine has embryolethal and fetotoxic effects in rats.
In a study in which pregnant rats were dosed throughout organogenesis, a dose
approximately 15 times the maximum recommended human daily dose (MRHDD; on a
mg/m² basis at an oral maternal dose of 120 mg/kg/day) increased resorptions
and decreased fetal weight; however, these effects occurred in the presence of
In studies in which rabbits and mice were dosed
throughout organogenesis, codeine at doses approximately 7 and 35 times the
MRHDD (on a mg/m² basis at 30 and 600 mg/kg/day, respectively) produced no
adverse developmental effects.
A retrospective study found a small, but statistically
significant, association between maternal use of chlorpheniramine and inguinal
hernia and eye or ear anomalies in children. Other retrospective studies have
found that the frequency of congenital anomalies, in general, was not increased
among offspring of women who took chlorpheniramine during pregnancy. The
significance of these findings to the therapeutic use of chlorpheniramine in
human pregnancy is not known.
In studies with chlorpheniramine in which pregnant rats
and rabbits were dosed throughout organogenesis, oral doses up to approximately
25 and 30times the MRHDD on a mg/m² basis, respectively, produced no adverse
developmental effects. However, when mice were dosed throughout pregnancy, a
dose approximately 9times the MRHDD (on a mg/m² basis at an oral maternal dose
of 20 mg/kg/day) was embryolethal, and postnatal survival was decreased when
dosing was continued after parturition. Embryolethality was also observed when
male and female rats were dosed with approximately 9times the MRHDD (on a mg/m²
basis at an oral parental dose of 10 mg/kg/day) prior to mating.
Babies born to mothers who have been taking opioids
regularly prior to delivery will be physically dependent. The withdrawal signs
include irritability and excessive crying, tremors, hyperactive reflexes,
increased respiratory rate, increased stools, sneezing, yawning, vomiting, and
fever. The intensity of the syndrome does not always correlate with the
duration of maternal opioid use or dose.
Labor And Delivery
As with all opioids, administration of TUXARIN ER to the
mother shortly before delivery may result in some degree of respiratory
depression in the newborn, especially if higher doses are used.
Caution should be exercised when TUXARIN ER is
administered to nursing mothers. 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 infants.
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 breast-feeding [see WARNINGS AND PRECAUTIONS].
Chlorpheniramine is excreted in human milk. The clinical
significance is unknown; however, the anticholinergic action of
chlorpheniramine may suppress lactation if taken prior to nursing.
Safety and effectiveness of TUXARIN ER in patients under
18 years of age have not been established. The use of codeine in children has
been associated with fatal respiratory depression. [see WARNINGS AND
Clinical efficacy and safety studies have not been
conducted with TUXARIN ER. Other reported clinical experience with the
individual active ingredients of TUXARIN ER did not include sufficient numbers
of subjects aged 65 and over to determine whether they respond differently from
younger subjects. In general, dose selection for an elderly patient should be
made with caution, 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.
Pharmacokinetics of TUXARIN ER has not been characterized
in renal impairment subjects.
Both codeine phosphate and chlorpheniramine maleate are
cleared substantially by the kidney. As such, impaired renal function could
potentially lead to the risk of decreased clearance and thereby increased
retention or systemic levels of both these drugs. TUXARIN ER should be used
with caution in patients with severe renal impairment.
Pharmacokinetics of TUXARIN ER has not been characterized
in hepatic impairment subjects. Both codeine and chlorpheniramine maleate are
extensively metabolized by liver before elimination from the body. As such,
impaired hepatic function could potentially lead to the risk of decreased
metabolism and thereby increased systemic levels of both these drugs. TUXARIN
ER should be used with caution in patients with severe hepatic impairment.