Narcotic analgesics, including codeine, should be
administered with caution and the initial dose reduced in patients with acute
abdominal conditions, convulsive disorders, significant hepatic or renal
impairment, fever, hypothyroidism, Addison's disease, ulcerative colitis,
prostatic hypertrophy, in patients with recent gastrointestinal or urinary
tract surgery, and in the very young or elderly or debilitated patients.
Drugs having anticholinergic properties should be used
with caution in patients with narrow-angle glaucoma, prostatic hypertrophy,
stenosing peptic ulcer, pyloroduodenal obstruction, and bladder-neck
Promethazine should be used cautiously in persons with
cardiovascular disease or with impairment of liver function.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term animal studies have not been performed to
assess the carcinogenic potential of codeine or of promethazine, nor are there
other animal or human data concerning carginogenicity, mutagenicity, or
impairment of fertility with these agents. Codeine has been reported to show no
evidence of carcinogenicity or mutagenicity in a variety of test systems,
including the micronucleus and sperm abnormality assays and the Salmonella assay.
Promethazine was nonmutagenic in the Salmonella test system of Ames.
Pregnancy Category C
A study in rats and rabbits reported no teratogenic
effect of codeine administered during the period of organogenesis in doses ranging
from 5 to 120 mg/kg. In the rat, doses at the 120-mg/kg level, in the toxic
range for the adult animal were associated with an increase in embryo
resorption at the time of implantation. In another study a single 100-mg/kg
dose of codeine administered to pregnant mice reportedly resulted in delayed
ossification in the offspring.
There are no studies in humans, and the significance of
these findings to humans, if any, is not known.
Teratogenic effects have not been demonstrated in
rat-feeding studies at doses of 6.25 and 12.5 mg/kg of promethazine HCl. These
doses are from approximately 2.1 to 4.2 times the maximum recommended total
daily dose of promethazine for a 50-kg subject depending upon the indication
for which the drug is prescribed. Daily doses of 25 mg/kg intraperitoneally
have been found to produce fetal mortality in rats.
Specific studies to test the action of the drug on
parturition, lactation, and development of the animal neonate were not done,
but a general preliminary study in rats indicated no effect on these
parameters. Although antihistamines have been found to produce fetal mortality
in rodents, the pharmacological effects of histamine in the rodent do not
parallel those in man. There are no adequate and well-controlled studies of
promethazine in pregnant women.
Animal reproduction studies have not been conducted with
the drug combination – promethazine and codeine. It is not known whether this
drug combination can cause fetal harm when administered to a pregnant woman or
can affect reproduction capacity. Promethazine HCl and Codeine Phosphate Oral
Solution should be given to a pregnant woman only if clearly needed.
Promethazine HCl and Codeine Phosphate Oral Solution
should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
Dependence has been reported in newborns whose mothers
took opiates regularly during pregnancy. Withdrawal signs include irritability,
excessive crying, tremors, hyperreflexia, fever, vomiting, and diarrhea. Signs
usually appear during the first few days of life.
Promethazine administered to a pregnant woman within two
weeks of delivery may inhibit platelet aggregation in the newborn.
Labor And Delivery
Narcotic analgesics cross the placental barrier. The
closer to the delivery and the larger the dose used, the greater the
possibility of respiratory depression in the newborn. Narcotic 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). Limited data suggests
that use of promethazine hydrochloride during labor and delivery does not have
an appreciable effect on the duration of labor or delivery and does not
increase the risk of need for intervention in the newborn.
The effect of promethazine and/or codeine on later growth
and development of the newborn is unknown.
Codeine is secreted into human milk. In women with normal
codeine metabolism (normal CYP2D6 activity), the amount of codeine excreted
into human milk is low and dose-dependent. Despite the common use of codeine
products to manage postpartum pain, reports of adverse events in infants are
rare. 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 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 -Death Related to
Ultra-Rapid Metabolism of Codeine to Morphine.)
The combination of promethazine hydrochloride and
codeine phosphate is contraindicated in pediatric patients less than 6 years of
age, because the combination may cause fatal respiratory depression in this age
population (see WARNINGS – Boxed Warning and Use in Pediatric Patients).
Respiratory depression and death have occurred in
children with obstructive sleep apnea 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 CYP2D6 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 WARNINGS - Death Related to
Ultra-Rapid Metabolism of Codeine to Morphine and CONTRAINDICATIONS).
Clinical studies of Promethazine HCl and Codeine
Phosphate Oral Solution did not include sufficient numbers of subjects aged 65
and over to determine whether they respond differently from younger subjects.
Other reported clinical experience has not identified differences in responses
between the elderly and younger patients. 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.
Sedating drugs may cause confusion and over-sedation in
the elderly; elderly patients generally should be started on low doses of
Promethazine Hydrochloride and Codeine Phosphate Oral Solution and observed