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 subcutaneous dose of codeine administered to pregnant mice reportedly resulted in delayed ossification in the offspring.
There are no adequate and well-controlled studies in pregnant women. Acetaminophen and codeine phosphate tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
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.
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. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly (see WARNINGS).
Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Acetaminophen and codeine phosphate tablets are not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including acetaminophen and codeine phosphate tablets, and can 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 dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.
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). The effect of codeine, if any, on the later growth, development, and functional maturation of the child is unknown.
Codeine and its active metabolite, morphine, are present in human milk. There are published studies and cases that have reported excessive sedation, respiratory depression, and death in infants exposed to codeine via breast milk. Women who are ultra-rapid metabolizers of codeine achieve higher than expected serum levels of morphine, potentially leading to higher levels of morphine in breast milk that can be dangerous in their breastfed infants. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent.
There is no information on the effects of codeine on milk production. Because of the potential for serious adverse reactions, including excess sedation, respiratory depression, and death in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with acetaminophen and codeine phosphate tablets (see WARNINGS).
Limited published studies report that acetaminophen passes rapidly into human milk with similar levels in the milk and plasma. Average and maximum neonatal doses of 1% and 2%, respectively, of the weight-adjusted maternal dose are reported after a single oral administration of 1gram APAP. There is one well documented report of rash in a breast-fed infant that resolved when the mother stopped acetaminophen use and recurred when she resumed acetaminophen use.
If infants are exposed to acetaminophen and codeine phosphate tablets through breast milk, they should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breastfeeding is stopped.
The safety and effectiveness of acetaminophen and codeine phosphate tablets with Codeine in pediatric patients below the age of 18 have not been established.
Life-threatening respiratory depression and death have occurred in children who received codeine (see WARNINGS). In most of the reported cases, these events followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for CYP2D6 or high morphine concentrations). Children with sleep apnea may be particularly sensitive to the respiratory depressant effects of codeine.
Because of the risk of life-threatening respiratory depression and death:
· Acetaminophen and codeine phosphate tablets are contraindicated for all children younger than 12 years of age (see CONTRAINDICATIONS).
· Acetaminophen and codeine phosphate tablets are contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy (see CONTRAINDICATIONS).
· Avoid the use of acetaminophen and codeine phosphate tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation, such as post-operative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression (see WARNINGS).
Elderly patients (aged 65 years or older) may have increased sensitivity to acetaminophen and codeine phosphate tablets. In general, use caution when selecting a dosage for an elderly patient, 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.
Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of acetaminophen and codeine phosphate tablets slowly in geriatric patients and monitor closely for signs of central nervous system depression (see WARNINGS).
These drugs are known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
The following serious adverse reactions are described, or described in greater detail, in other sections:
· Addiction, Abuse, and Misuse (see WARNINGS)
· Life-Threatening Respiratory Depression (see WARNINGS)
· Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children (see WARNINGS)
· Neonatal Opioid Withdrawal Syndrome (see WARNINGS)
· Interactions with CNS Depressants (see WARNINGS)
· Severe Hypotension (see WARNINGS)
· Gastrointestinal Adverse Reactions (see WARNINGS)
· Seizures (see WARNINGS)
· Withdrawal (see WARNINGS)
The following adverse reactions have been identified during post-approval use of acetaminophen and codeine phosphate tablets. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Serious adverse reactions associated with codeine are respiratory depression and, to a lesser degree, circulatory depression, respiratory arrest, shock, and cardiac arrest.
The most frequently observed adverse reactions with codeine administration include drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, sweating, and constipation.
Other adverse reactions include allergic reactions, euphoria, dysphoria, abdominal pain, pruritus, rash, thrombocytopenia, and agranulocytosis.
Other less frequently observed adverse reactions expected from opioid analgesics, including acetaminophen and codeine phosphate tablets:
Cardiovascular system: faintness, flushing, hypotension, palpitations, syncope.
Digestive System: abdominal cramps, anorexia, diarrhea, dry mouth, gastrointestinal distress, pancreatitis.
Nervous system: anxiety, drowsiness, fatigue, headache, insomnia, nervousness, shakiness, somnolence, vertigo, visual disturbances, weakness.
Skin and Appendages: fixed eruption, rash, sweating, urticarial.
· Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.
· Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.
· Anaphylaxis: Anaphylaxis has been reported with ingredients contained in acetaminophen and codeine phosphate tablets.
· Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids (see CLINICAL PHARMACOLOGY).
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