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Drug overview for ALKA-SELTZER PLUS COLD+FLU (dextromethorphan/pseudoephrine hcl/acetaminophen/doxylamine):
Generic name: DEXTROMETHORPHAN/PSEUDOEPHRINE HCL/ACETAMINOPHEN/DOXYLAMINE
Drug class: Amphetamines/Anorexiants/Stimulants
Therapeutic class:
Dextromethorphan, a derivative of levorphanol, is an antitussive agent. Doxylamine is an ethanolamine-derivative, first generation antihistamine. Pseudoephedrine is a sympathomimetic agent that occurs naturally in plants of the genus Ephedra; the drug acts directly on both alpha- and, to a lesser degree, beta-adrenergic receptors. Acetaminophen is a synthetic nonopiate derivative of p-aminophenol that produces analgesia and antipyresis.
Dextromethorphan is used for the temporary relief of coughs caused by minor Doxylamine succinate shares the actions and uses of other antihistamines. Pseudoephedrine is used as a nasal decongestant for self-medication for the temporary relief of nasal congestion associated with upper respiratory throat and bronchial irritation such as may occur with common colds or with allergy and to provide temporary relief of sinus congestion and pressure. inhaled irritants.
Dextromethorphan is most effective in the treatment of chronic, nonproductive cough. The drug is a common ingredient in commercial The drug also has been used for self-medication in the symptomatic cough mixtures available without prescription. prevention of otitic barotrauma+ (aerotitis ( barotitis) media).
Pseudoephedrine also has been misused for clandestine synthesis of Although cough and cold preparations that contain cough suppressants methamphetamine and methcathinone for illicit use. (including dextromethorphan), nasal decongestants, antihistamines, and/or expectorants commonly are used in pediatric patients younger than 2 years of age, systematic reviews of controlled trials have concluded that nonprescription (over-the-counter, OTC) cough and cold preparations are not more effective than placebo in reducing acute cough and other symptoms of upper respiratory tract infection in these patients. Furthermore, adverse events, including deaths, have been (and continue to be) reported in pediatric patients younger than 2 years of age receiving these preparations.
(See Cautions: Pediatric Precautions and see Acute Toxicity: Manifestations.) For information on abuse of dextromethorphan, see Cautions. For use of dextromethorphan hydrobromide in fixed combination with quinidine sulfate in the treatment of pseudobulbar affect (PBA), see Dextromethorphan Hydrobromide and Quinidine Sulfate 28:92. Acetaminophen is used extensively in the treatment of mild to moderate pain and fever.
Generic name: DEXTROMETHORPHAN/PSEUDOEPHRINE HCL/ACETAMINOPHEN/DOXYLAMINE
Drug class: Amphetamines/Anorexiants/Stimulants
Therapeutic class:
Dextromethorphan, a derivative of levorphanol, is an antitussive agent. Doxylamine is an ethanolamine-derivative, first generation antihistamine. Pseudoephedrine is a sympathomimetic agent that occurs naturally in plants of the genus Ephedra; the drug acts directly on both alpha- and, to a lesser degree, beta-adrenergic receptors. Acetaminophen is a synthetic nonopiate derivative of p-aminophenol that produces analgesia and antipyresis.
Dextromethorphan is used for the temporary relief of coughs caused by minor Doxylamine succinate shares the actions and uses of other antihistamines. Pseudoephedrine is used as a nasal decongestant for self-medication for the temporary relief of nasal congestion associated with upper respiratory throat and bronchial irritation such as may occur with common colds or with allergy and to provide temporary relief of sinus congestion and pressure. inhaled irritants.
Dextromethorphan is most effective in the treatment of chronic, nonproductive cough. The drug is a common ingredient in commercial The drug also has been used for self-medication in the symptomatic cough mixtures available without prescription. prevention of otitic barotrauma+ (aerotitis ( barotitis) media).
Pseudoephedrine also has been misused for clandestine synthesis of Although cough and cold preparations that contain cough suppressants methamphetamine and methcathinone for illicit use. (including dextromethorphan), nasal decongestants, antihistamines, and/or expectorants commonly are used in pediatric patients younger than 2 years of age, systematic reviews of controlled trials have concluded that nonprescription (over-the-counter, OTC) cough and cold preparations are not more effective than placebo in reducing acute cough and other symptoms of upper respiratory tract infection in these patients. Furthermore, adverse events, including deaths, have been (and continue to be) reported in pediatric patients younger than 2 years of age receiving these preparations.
(See Cautions: Pediatric Precautions and see Acute Toxicity: Manifestations.) For information on abuse of dextromethorphan, see Cautions. For use of dextromethorphan hydrobromide in fixed combination with quinidine sulfate in the treatment of pseudobulbar affect (PBA), see Dextromethorphan Hydrobromide and Quinidine Sulfate 28:92. Acetaminophen is used extensively in the treatment of mild to moderate pain and fever.
DRUG IMAGES
No Image Available
The following indications for ALKA-SELTZER PLUS COLD+FLU (dextromethorphan/pseudoephrine hcl/acetaminophen/doxylamine) have been approved by the FDA:
Indications:
None.
Professional Synonyms:
None.
Indications:
None.
Professional Synonyms:
None.
The following dosing information is available for ALKA-SELTZER PLUS COLD+FLU (dextromethorphan/pseudoephrine hcl/acetaminophen/doxylamine):
Dosages of dextromethorphan hydrobromide and dextromethorphan polistirex are expressed in terms of dextromethorphan hydrobromide.
The usual dosage of dextromethorphan hydrobromide for adults and children 12 years of age or older is 10-20 mg every 4 hours or 30 mg every 6-8 hours, not to exceed 120 mg daily, or as directed by a clinician. The usual dosage for children 6 to younger than 12 years of age is 5-10 mg every 4 hours or 15 mg every 6-8 hours, not to exceed 60 mg daily, or as directed by a clinician. Children 2 to younger than 6 years of age may receive 2.5-5
mg every 4 hours or 7.5 mg every 6-8 hours, not to exceed 30 mg daily, or as directed by a clinician. Dosage in children younger than 2 years of age must be individualized.
Suggested dosages for children younger than 2 years of age+ for some cough and cold preparations have been published in various references for prescribing and parenting. Using recommended dosages for adults and older children, some clinicians have extrapolated dosages for these preparations based on the weight or age of children younger than 2 years of age. However, these extrapolations were based on assumptions that pathology of the disease and pharmacology of the drugs are similar in adults and pediatric patients.
There currently are no specific dosage recommendations (i.e., approved by the US Food and Drug Administration (FDA)) for cough and cold preparations for this patient population. (See Cautions: Pediatric Precautions.)
The usual dosage of dextromethorphan hydrobromide as the extended-release oral suspension containing the polistirex for adults and children 12 years of age or older is 60 mg twice daily. The usual dosage as the extended-release oral suspension for children 6 to younger than 12 years of age is 30 mg twice daily; children 2 to younger than 6 years of age may receive 15 mg twice daily.
Acetaminophen is relatively safe when used at recommended dosages. However, acetaminophen overdosage has been the leading cause of acute liver failure in the US, United Kingdom, and most of Europe, with about 50% of US cases in recent years resulting from inadvertent overdosage (e.g., in patients not recognizing the presence of the drug in multiple over-the-counter (OTC) and/or prescription products that they may be taking). Therefore, patients should be warned about the importance of determining whether acetaminophen is present in their medications (e.g., by examining labels carefully, by consulting their clinician and pharmacist) and of not exceeding recommended dosages or combining acetaminophen-containing preparations.
Acetaminophen should not be used for self-medication of pain for longer than 10 days (in adults or children 12 years of age and older) or 5 days (in children 2-11 years of age), unless directed by a clinician because pain of such intensity and duration may indicate a pathologic condition requiring medical evaluation and supervised treatment.
Acetaminophen should not be used in adults or children for self-medication of marked fever (greater than 39.5degreesC), fever persisting longer than 3 days, or recurrent fever, unless directed by a clinician because such fevers may indicate serious illness requiring prompt medical evaluation.
Acetaminophen should not be used in adults or children for self-medication of sore throat pain (pharyngitis, laryngitis, tonsillitis) for longer than 2 days.
To minimize the risk of overdosage, recommended age-appropriate daily dosages of acetaminophen should not be exceeded. Because severe liver toxicity and death have occurred in children who received multiple excessive doses of acetaminophen as part of therapeutic administration, parents or caregivers should be instructed to use weight-based dosing for acetaminophen, to use only the calibrated measuring device provided with the particular acetaminophen formulation for measuring dosage, to ensure that the correct number of tablets required for the intended dose is removed from the package, and not to exceed the recommended daily dosage because serious adverse effects could result. In addition, patients should be warned that the risk of overdosage and severe liver damage is increased if more than one preparation containing acetaminophen are used concomitantly.
Pharmacists have an important role in preventing acetaminophen-induced hepatotoxicity by advising consumers about the risk of failing to recognize that a wide variety of OTC and prescription preparations contain acetaminophen. Failure to recognize acetaminophen as an ingredient may be particularly likely with prescription drugs because the label of the dispensed drug may not clearly state its presence. Educating consumers about the risk of exceeding recommended acetaminophen dosages also is important.
The US Food and Drug Administration (FDA) recommends that pharmacists receiving prescriptions for fixed-combination preparations containing more than 325 mg of acetaminophen per dosage unit contact the prescriber to discuss use of a preparation containing no more than 325 mg of the drug per dosage unit. (See Preparations.)
Clinicians should exercise caution when prescribing, preparing, and administering IV acetaminophen to avoid dosing errors that could result in accidental overdosage and death. In particular, clinicians should ensure that the dose (in mg) and the volume (in mL) are not confused, the dose for patients weighing less than 50 kg is based on body weight, the infusion pump is programmed correctly, and the total daily dosage of acetaminophen from all sources does not exceed the maximum recommended daily dosage.
In patients with hepatic impairment or active liver disease, reduction of the total daily dosage of acetaminophen may be warranted. In patients with severe renal impairment (creatinine clearance of 30 mL/minute or less), longer dosing intervals and a reduced total daily dosage of acetaminophen may be warranted. (See Cautions: Precautions and Contraindications.)
The usual dosage of dextromethorphan hydrobromide for adults and children 12 years of age or older is 10-20 mg every 4 hours or 30 mg every 6-8 hours, not to exceed 120 mg daily, or as directed by a clinician. The usual dosage for children 6 to younger than 12 years of age is 5-10 mg every 4 hours or 15 mg every 6-8 hours, not to exceed 60 mg daily, or as directed by a clinician. Children 2 to younger than 6 years of age may receive 2.5-5
mg every 4 hours or 7.5 mg every 6-8 hours, not to exceed 30 mg daily, or as directed by a clinician. Dosage in children younger than 2 years of age must be individualized.
Suggested dosages for children younger than 2 years of age+ for some cough and cold preparations have been published in various references for prescribing and parenting. Using recommended dosages for adults and older children, some clinicians have extrapolated dosages for these preparations based on the weight or age of children younger than 2 years of age. However, these extrapolations were based on assumptions that pathology of the disease and pharmacology of the drugs are similar in adults and pediatric patients.
There currently are no specific dosage recommendations (i.e., approved by the US Food and Drug Administration (FDA)) for cough and cold preparations for this patient population. (See Cautions: Pediatric Precautions.)
The usual dosage of dextromethorphan hydrobromide as the extended-release oral suspension containing the polistirex for adults and children 12 years of age or older is 60 mg twice daily. The usual dosage as the extended-release oral suspension for children 6 to younger than 12 years of age is 30 mg twice daily; children 2 to younger than 6 years of age may receive 15 mg twice daily.
Acetaminophen is relatively safe when used at recommended dosages. However, acetaminophen overdosage has been the leading cause of acute liver failure in the US, United Kingdom, and most of Europe, with about 50% of US cases in recent years resulting from inadvertent overdosage (e.g., in patients not recognizing the presence of the drug in multiple over-the-counter (OTC) and/or prescription products that they may be taking). Therefore, patients should be warned about the importance of determining whether acetaminophen is present in their medications (e.g., by examining labels carefully, by consulting their clinician and pharmacist) and of not exceeding recommended dosages or combining acetaminophen-containing preparations.
Acetaminophen should not be used for self-medication of pain for longer than 10 days (in adults or children 12 years of age and older) or 5 days (in children 2-11 years of age), unless directed by a clinician because pain of such intensity and duration may indicate a pathologic condition requiring medical evaluation and supervised treatment.
Acetaminophen should not be used in adults or children for self-medication of marked fever (greater than 39.5degreesC), fever persisting longer than 3 days, or recurrent fever, unless directed by a clinician because such fevers may indicate serious illness requiring prompt medical evaluation.
Acetaminophen should not be used in adults or children for self-medication of sore throat pain (pharyngitis, laryngitis, tonsillitis) for longer than 2 days.
To minimize the risk of overdosage, recommended age-appropriate daily dosages of acetaminophen should not be exceeded. Because severe liver toxicity and death have occurred in children who received multiple excessive doses of acetaminophen as part of therapeutic administration, parents or caregivers should be instructed to use weight-based dosing for acetaminophen, to use only the calibrated measuring device provided with the particular acetaminophen formulation for measuring dosage, to ensure that the correct number of tablets required for the intended dose is removed from the package, and not to exceed the recommended daily dosage because serious adverse effects could result. In addition, patients should be warned that the risk of overdosage and severe liver damage is increased if more than one preparation containing acetaminophen are used concomitantly.
Pharmacists have an important role in preventing acetaminophen-induced hepatotoxicity by advising consumers about the risk of failing to recognize that a wide variety of OTC and prescription preparations contain acetaminophen. Failure to recognize acetaminophen as an ingredient may be particularly likely with prescription drugs because the label of the dispensed drug may not clearly state its presence. Educating consumers about the risk of exceeding recommended acetaminophen dosages also is important.
The US Food and Drug Administration (FDA) recommends that pharmacists receiving prescriptions for fixed-combination preparations containing more than 325 mg of acetaminophen per dosage unit contact the prescriber to discuss use of a preparation containing no more than 325 mg of the drug per dosage unit. (See Preparations.)
Clinicians should exercise caution when prescribing, preparing, and administering IV acetaminophen to avoid dosing errors that could result in accidental overdosage and death. In particular, clinicians should ensure that the dose (in mg) and the volume (in mL) are not confused, the dose for patients weighing less than 50 kg is based on body weight, the infusion pump is programmed correctly, and the total daily dosage of acetaminophen from all sources does not exceed the maximum recommended daily dosage.
In patients with hepatic impairment or active liver disease, reduction of the total daily dosage of acetaminophen may be warranted. In patients with severe renal impairment (creatinine clearance of 30 mL/minute or less), longer dosing intervals and a reduced total daily dosage of acetaminophen may be warranted. (See Cautions: Precautions and Contraindications.)
Dextromethorphan preparations are administered orally. Lozenges containing dextromethorphan hydrobromide should not be used in children younger than 6 years of age and liquid-filled capsules containing the drug should not be used in children younger than 12 years of age, unless otherwise directed by a clinician. Doxylamine succinate is administered orally.
Pseudoephedrine hydrochloride and sulfate are administered orally. Pseudoephedrine hydrochloride 240-mg extended-release tablets should be The fixed combination of doxylamine/pyridoxine delayed-release Diclegis(R) administered orally once daily and swallowed whole with water; the and extended-release Bonjesta(R) tablets should be taken on an empty extended-release tablets should not be divided, crushed, chewed, or stomach with a glass of water; the tablets should be swallowed whole and dissolved. Patients should be advised that the tablet does not completely should not be crushed, chewed, or split.
dissolve and may be passed in the stool. Acetaminophen is administered orally, rectally as suppositories, and by IV infusion over 15 minutes. Acetaminophen preparations for self-medication should not be used unless seals on the tamper-resistant packaging are intact.
Pseudoephedrine hydrochloride and sulfate are administered orally. Pseudoephedrine hydrochloride 240-mg extended-release tablets should be The fixed combination of doxylamine/pyridoxine delayed-release Diclegis(R) administered orally once daily and swallowed whole with water; the and extended-release Bonjesta(R) tablets should be taken on an empty extended-release tablets should not be divided, crushed, chewed, or stomach with a glass of water; the tablets should be swallowed whole and dissolved. Patients should be advised that the tablet does not completely should not be crushed, chewed, or split.
dissolve and may be passed in the stool. Acetaminophen is administered orally, rectally as suppositories, and by IV infusion over 15 minutes. Acetaminophen preparations for self-medication should not be used unless seals on the tamper-resistant packaging are intact.
No dosing information available.
No generic dosing information available.
The following drug interaction information is available for ALKA-SELTZER PLUS COLD+FLU (dextromethorphan/pseudoephrine hcl/acetaminophen/doxylamine):
There are 0 contraindications.
There are 0 severe interactions.
There are 0 moderate interactions.
The following contraindication information is available for ALKA-SELTZER PLUS COLD+FLU (dextromethorphan/pseudoephrine hcl/acetaminophen/doxylamine):
Drug contraindication overview.
Doxylamine succinate is contraindicated in patients with known hypersensitivity to doxylamine, other ethanolamine derivative antihistamines, or any ingredient in the formulation. Doxylamine in fixed combination with pyridoxine is contraindicated in patients receiving monoamine oxidase (MAO) inhibitors.
Doxylamine succinate is contraindicated in patients with known hypersensitivity to doxylamine, other ethanolamine derivative antihistamines, or any ingredient in the formulation. Doxylamine in fixed combination with pyridoxine is contraindicated in patients receiving monoamine oxidase (MAO) inhibitors.
There are 0 contraindications.
There are 0 severe contraindications.
There are 0 moderate contraindications.
The following adverse reaction information is available for ALKA-SELTZER PLUS COLD+FLU (dextromethorphan/pseudoephrine hcl/acetaminophen/doxylamine):
Adverse reaction overview.
No enhanced Common Adverse Effects information available for this drug.
No enhanced Common Adverse Effects information available for this drug.
There are 0 severe adverse reactions.
There are 0 less severe adverse reactions.
The following precautions are available for ALKA-SELTZER PLUS COLD+FLU (dextromethorphan/pseudoephrine hcl/acetaminophen/doxylamine):
No enhanced Pediatric Use information available for this drug.
Contraindicated
Severe Precaution
Management or Monitoring Precaution
Contraindicated
| None |
Severe Precaution
| None |
Management or Monitoring Precaution
| None |
Doxylamine succinate in fixed combination with pyridoxine hydrochloride is intended for use in the management of nausea and vomiting of pregnancy. Numerous epidemiologic studies (including cohort studies, case-control studies, and meta-analyses) have been performed to investigate possible teratogenic effects of doxylamine in fixed combination with pyridoxine in pregnant women. A meta-analysis of 16 cohort and 11 case-control studies published between 1963 and 1991 reported no increased risk for malformations from first trimester exposures to doxylamine succinate and pyridoxine hydrochloride in fixed combination, with or without dicyclomine hydrochloride (a drug included in a combination product that was previously commercially available for nausea and vomiting of pregnancy).
Another meta-analysis of 12 cohort and 5 case-control studies published between 1963 and 1985 reported no clinically important associations between fetal abnormalities and first trimester exposure to doxylamine succinate and pyridoxine hydrochloride with or without dicyclomine hydrochloride. A reanalysis of data from another meta-analysis supporting the safety of doxylamine during pregnancy found that the strength of the data had been overstated, both in terms of the numbers of patients exposed to doxylamine succinate and the reported odds ratio, which suggested a potential protective effect of antihistamines with regard to fetal malformations. However, the reanalysis did not find evidence of an increased risk of fetal malformations associated with doxylamine use.
Historically, there was considerable controversy regarding the teratogenic potential, if any, of doxylamine; however, after evaluating extensive data and information concerning the possible teratogenicity of the drug, FDA concluded that it is unlikely that doxylamine is teratogenic. FDA recognized, however, that despite the large number of pregnancies evaluated to date the possibility that doxylamine may be weakly teratogenic cannot be excluded. Doxylamine was commercially available in the US for the treatment of nausea and vomiting associated with pregnancy in combination with dicyclomine and pyridoxine until 1976, and then in combination with only pyridoxine until 1983 when the manufacturer voluntarily discontinued manufacturing and distributing the combination.
FDA stated that the removal of products containing doxylamine and pyridoxine that previously were commercially available for the management of nausea and vomiting of pregnancy was not for reasons of safety or effectiveness. Most epidemiologic studies (case-control and cohort) in which fixed combinations of doxylamine and pyridoxine with or without dicyclomine were used during pregnancy indicate that an association between use of these combinations and adverse fetal effects does not appear to exist. In a few studies, a weak association between use of the fixed combinations during pregnancy and specific fetal abnormalities (e.g., pyloric stenosis, cardiac defects, oral clefts) was reported, but a causal relationship with the drugs was not established and these findings have not been confirmed by many other studies.
Women considering self-medication with doxylamine during pregnancy should consult a health professional for advice regarding the relative risks and benefits of such therapy. Most reproduction studies in various animal species using doxylamine and pyridoxine alone or in fixed combination have not revealed evidence of harm to the fetus. Studies in rats and mice using doxylamine succinate dosages up to 125 times the maximum human dosage did not reveal evidence of observable congenital abnormalities, but wavy ribs and diaphragmatic hernias occurred in rats at dosages 125-375 times the maximum human dosage; an overall increase in fetal wastage, varying from zero to threefold, occurred in most rodents receiving dosages 125 or more times greater than the maximum human dosage.
Once daily administration of doxylamine succinate and pyridoxine hydrochloride in pregnant rats during organogenesis (gestational day 6-15) resulted in increased fetal resorptions, decreased fetal body weight, and increased skeletal variations with reduced ossification at dosages 60-100 times the highest clinical dosage based on body surface area. In a study in pregnant cynomolgus monkeys receiving doxylamine succinate and pyridoxine hydrochloride once daily during organogenesis (gestational day 22-50) at dosages up to 3.2 times the highest proposed clinical dosage based on body surface area, there were no observed malformations and no evidence of embryo, fetal, or maternal toxicity.
In another study in pregnant cynomolgus and rhesus monkeys and baboons receiving doxylamine succinate and pyridoxine hydrochloride at dosages 0.5-20 times higher than the clinical dosage based on body surface area, ventricular septal defects were observed in preterm (gestational day 100) fetuses; no relationship between dosage and incidence of ventricular septal defects was observed, and no ventricular septal defects were observed in infant monkeys at term. In addition, no ventricular septal defects were observed at gestational day 100 in cynomolgus monkeys administered the combination of doxylamine succinate and pyridoxine hydrochloride for 4-day periods between 22 and 41 days of gestation.
In a small study in monkeys receiving a fixed combination of doxylamine succinate and pyridoxine hydrochloride throughout fetal organogenesis at dosages 10-20 times the maximum human dosage, intraventricular septal defects were present in 4 of 7 fetuses delivered on day 100 of gestation (full-term gestation is about 160 days), while 2 fetuses aborted on the 46th and 56th day of gestation appeared to be developing normally and 3 other fetuses allowed to develop to term were normal. The importance of septal defects in these monkeys is not known, since an opening in the septum is usually present early during fetal development in monkeys. In other studies in monkeys receiving the fixed combination for shorter periods of time, there was no evidence of fetal toxicity.
Epidemiologic data regarding oral acetaminophen use in pregnant women have shown no increased risk of major congenital malformations in infants exposed in utero to the drug. In a large population-based prospective cohort study involving more than 26,000 women with live-born singleton infants who were exposed to oral acetaminophen during the first trimester of pregnancy, no increase in the risk of congenital malformations was observed in exposed children compared with a control group of unexposed children; the rate of congenital malformations (4.3%) was similar to the rate in the general population. A population-based, case-control study from the National Birth Defects Prevention Study also found no increase in the risk of major birth defects in a group of 11,610 children who had been exposed to acetaminophen during the first trimester of pregnancy compared with a control group of 4500 children.
Animal reproduction studies in pregnant rats given oral acetaminophen during organogenesis at dosages up to 0.85 times the maximum recommended human daily dosage (4 g daily, based on body surface area comparison) showed evidence of fetotoxicity (reduced fetal weight and length) and a dose-related increase in bone variations (reduced ossification and rudimentary rib changes); the offspring showed no evidence of external, visceral, or skeletal malformations. When pregnant rats received oral acetaminophen throughout gestation at a dosage of 1.2
times the maximum recommended human daily dosage, areas of necrosis occurred in both the liver and kidney of pregnant rats and fetuses; these effects did not occur in animals given acetaminophen at dosages of 0.3 times the maximum recommended human dosage. In a continuous breeding study in which pregnant mice were given acetaminophen at dosages approximately equivalent to 0.43,
0.87, or 1.7 times the maximum recommended human daily dosage (based on body surface area comparison), a dose-related reduction in body weight of the fourth and fifth litter offspring of the treated mating pair occurred during lactation and following weaning at all dosages studied.
Animals receiving the highest dosage had a reduced number of litters per mating pair, male offspring with an increased percentage of abnormal sperm, and reduced birth weights in the next-generation pups. Acetaminophen is commonly used during all stages of pregnancy for its analgesic and antipyretic effects. Although acetaminophen has been thought not to be associated with risk in offspring, some recent reports have questioned this assessment, especially with frequent maternal use or in cases involving genetic variability.
FDA reviewed data on a possible association between acetaminophen use during pregnancy and risk of attention deficit hyperactivity disorder (ADHD) in children and announced in January 2015 that the data were inconclusive. Some experts state that as with all drug use during pregnancy, routine use of acetaminophen should be avoided. The manufacturer states that there are no studies of IV acetaminophen in pregnant women and animal reproduction studies have not been conducted with this preparation.
Therefore, the manufacturer states that IV acetaminophen should be used during pregnancy only when clearly needed. Because there are no adequate and well-controlled studies of IV acetaminophen during labor and delivery, the manufacturer states that IV acetaminophen should be used in this setting only after careful assessment of potential benefits and risks.
Another meta-analysis of 12 cohort and 5 case-control studies published between 1963 and 1985 reported no clinically important associations between fetal abnormalities and first trimester exposure to doxylamine succinate and pyridoxine hydrochloride with or without dicyclomine hydrochloride. A reanalysis of data from another meta-analysis supporting the safety of doxylamine during pregnancy found that the strength of the data had been overstated, both in terms of the numbers of patients exposed to doxylamine succinate and the reported odds ratio, which suggested a potential protective effect of antihistamines with regard to fetal malformations. However, the reanalysis did not find evidence of an increased risk of fetal malformations associated with doxylamine use.
Historically, there was considerable controversy regarding the teratogenic potential, if any, of doxylamine; however, after evaluating extensive data and information concerning the possible teratogenicity of the drug, FDA concluded that it is unlikely that doxylamine is teratogenic. FDA recognized, however, that despite the large number of pregnancies evaluated to date the possibility that doxylamine may be weakly teratogenic cannot be excluded. Doxylamine was commercially available in the US for the treatment of nausea and vomiting associated with pregnancy in combination with dicyclomine and pyridoxine until 1976, and then in combination with only pyridoxine until 1983 when the manufacturer voluntarily discontinued manufacturing and distributing the combination.
FDA stated that the removal of products containing doxylamine and pyridoxine that previously were commercially available for the management of nausea and vomiting of pregnancy was not for reasons of safety or effectiveness. Most epidemiologic studies (case-control and cohort) in which fixed combinations of doxylamine and pyridoxine with or without dicyclomine were used during pregnancy indicate that an association between use of these combinations and adverse fetal effects does not appear to exist. In a few studies, a weak association between use of the fixed combinations during pregnancy and specific fetal abnormalities (e.g., pyloric stenosis, cardiac defects, oral clefts) was reported, but a causal relationship with the drugs was not established and these findings have not been confirmed by many other studies.
Women considering self-medication with doxylamine during pregnancy should consult a health professional for advice regarding the relative risks and benefits of such therapy. Most reproduction studies in various animal species using doxylamine and pyridoxine alone or in fixed combination have not revealed evidence of harm to the fetus. Studies in rats and mice using doxylamine succinate dosages up to 125 times the maximum human dosage did not reveal evidence of observable congenital abnormalities, but wavy ribs and diaphragmatic hernias occurred in rats at dosages 125-375 times the maximum human dosage; an overall increase in fetal wastage, varying from zero to threefold, occurred in most rodents receiving dosages 125 or more times greater than the maximum human dosage.
Once daily administration of doxylamine succinate and pyridoxine hydrochloride in pregnant rats during organogenesis (gestational day 6-15) resulted in increased fetal resorptions, decreased fetal body weight, and increased skeletal variations with reduced ossification at dosages 60-100 times the highest clinical dosage based on body surface area. In a study in pregnant cynomolgus monkeys receiving doxylamine succinate and pyridoxine hydrochloride once daily during organogenesis (gestational day 22-50) at dosages up to 3.2 times the highest proposed clinical dosage based on body surface area, there were no observed malformations and no evidence of embryo, fetal, or maternal toxicity.
In another study in pregnant cynomolgus and rhesus monkeys and baboons receiving doxylamine succinate and pyridoxine hydrochloride at dosages 0.5-20 times higher than the clinical dosage based on body surface area, ventricular septal defects were observed in preterm (gestational day 100) fetuses; no relationship between dosage and incidence of ventricular septal defects was observed, and no ventricular septal defects were observed in infant monkeys at term. In addition, no ventricular septal defects were observed at gestational day 100 in cynomolgus monkeys administered the combination of doxylamine succinate and pyridoxine hydrochloride for 4-day periods between 22 and 41 days of gestation.
In a small study in monkeys receiving a fixed combination of doxylamine succinate and pyridoxine hydrochloride throughout fetal organogenesis at dosages 10-20 times the maximum human dosage, intraventricular septal defects were present in 4 of 7 fetuses delivered on day 100 of gestation (full-term gestation is about 160 days), while 2 fetuses aborted on the 46th and 56th day of gestation appeared to be developing normally and 3 other fetuses allowed to develop to term were normal. The importance of septal defects in these monkeys is not known, since an opening in the septum is usually present early during fetal development in monkeys. In other studies in monkeys receiving the fixed combination for shorter periods of time, there was no evidence of fetal toxicity.
Epidemiologic data regarding oral acetaminophen use in pregnant women have shown no increased risk of major congenital malformations in infants exposed in utero to the drug. In a large population-based prospective cohort study involving more than 26,000 women with live-born singleton infants who were exposed to oral acetaminophen during the first trimester of pregnancy, no increase in the risk of congenital malformations was observed in exposed children compared with a control group of unexposed children; the rate of congenital malformations (4.3%) was similar to the rate in the general population. A population-based, case-control study from the National Birth Defects Prevention Study also found no increase in the risk of major birth defects in a group of 11,610 children who had been exposed to acetaminophen during the first trimester of pregnancy compared with a control group of 4500 children.
Animal reproduction studies in pregnant rats given oral acetaminophen during organogenesis at dosages up to 0.85 times the maximum recommended human daily dosage (4 g daily, based on body surface area comparison) showed evidence of fetotoxicity (reduced fetal weight and length) and a dose-related increase in bone variations (reduced ossification and rudimentary rib changes); the offspring showed no evidence of external, visceral, or skeletal malformations. When pregnant rats received oral acetaminophen throughout gestation at a dosage of 1.2
times the maximum recommended human daily dosage, areas of necrosis occurred in both the liver and kidney of pregnant rats and fetuses; these effects did not occur in animals given acetaminophen at dosages of 0.3 times the maximum recommended human dosage. In a continuous breeding study in which pregnant mice were given acetaminophen at dosages approximately equivalent to 0.43,
0.87, or 1.7 times the maximum recommended human daily dosage (based on body surface area comparison), a dose-related reduction in body weight of the fourth and fifth litter offspring of the treated mating pair occurred during lactation and following weaning at all dosages studied.
Animals receiving the highest dosage had a reduced number of litters per mating pair, male offspring with an increased percentage of abnormal sperm, and reduced birth weights in the next-generation pups. Acetaminophen is commonly used during all stages of pregnancy for its analgesic and antipyretic effects. Although acetaminophen has been thought not to be associated with risk in offspring, some recent reports have questioned this assessment, especially with frequent maternal use or in cases involving genetic variability.
FDA reviewed data on a possible association between acetaminophen use during pregnancy and risk of attention deficit hyperactivity disorder (ADHD) in children and announced in January 2015 that the data were inconclusive. Some experts state that as with all drug use during pregnancy, routine use of acetaminophen should be avoided. The manufacturer states that there are no studies of IV acetaminophen in pregnant women and animal reproduction studies have not been conducted with this preparation.
Therefore, the manufacturer states that IV acetaminophen should be used during pregnancy only when clearly needed. Because there are no adequate and well-controlled studies of IV acetaminophen during labor and delivery, the manufacturer states that IV acetaminophen should be used in this setting only after careful assessment of potential benefits and risks.
Doxylamine succinate is expected to be distributed into human milk, because of its low molecular weight. Adverse effects (e.g., excitement, irritability, and sedation) have been reported in infants presumably exposed to doxylamine through human milk. Infants with apnea or other respiratory syndromes may be particularly vulnerable to the sedative effects of doxylamine.
Because of the potential for serious adverse reactions to antihistamines in nursing infants, a decision should be made whether to discontinue nursing or doxylamine, taking into account the importance of the drug to the woman. The manufacturer of doxylamine/pyridoxine in fixed combination states that this preparation should notbe used in nursing women. Acetaminophen is distributed into human milk in small quantities after oral administration.
Data from more than 15 nursing women suggest that approximately 1-2% of the maternal daily dosage would be ingested by a nursing infant. A case of maculopapular rash in a breast-fed infant has been reported; the rash resolved when the mother discontinued acetaminophen use and recurred when she resumed acetaminophen therapy. The American Academy of Pediatrics and other experts state that acetaminophen is an acceptable choice for use in nursing women. The manufacturer states that IV acetaminophen should be used with caution in nursing women.
Precaution Exists
Precaution exists. (No data or inconclusive human data.) Use of this drug by breast feeding mothers should be evaluated carefully.
No Known Risk
No known risk. This drug has no known risks to nursing infants and does not adversely affect lactation.
Because of the potential for serious adverse reactions to antihistamines in nursing infants, a decision should be made whether to discontinue nursing or doxylamine, taking into account the importance of the drug to the woman. The manufacturer of doxylamine/pyridoxine in fixed combination states that this preparation should notbe used in nursing women. Acetaminophen is distributed into human milk in small quantities after oral administration.
Data from more than 15 nursing women suggest that approximately 1-2% of the maternal daily dosage would be ingested by a nursing infant. A case of maculopapular rash in a breast-fed infant has been reported; the rash resolved when the mother discontinued acetaminophen use and recurred when she resumed acetaminophen therapy. The American Academy of Pediatrics and other experts state that acetaminophen is an acceptable choice for use in nursing women. The manufacturer states that IV acetaminophen should be used with caution in nursing women.
Precaution Exists
Precaution exists. (No data or inconclusive human data.) Use of this drug by breast feeding mothers should be evaluated carefully.
| Drug Name | Excretion Potential | Effect on Infant | Notes |
|---|---|---|---|
| Dextromethorphan | Excreted.This drug is known to be excreted in human breast milk. | It is not known whether this drug has an adverse effect on the nursing infant. (No data or inconclusive human data) | Low levels excreted, no adverse effects in infants expected |
| Doxylamine | Unknown. It is unknown whether the drug is excreted in human breast milk. | It is not known whether this drug has an adverse effect on the nursing infant. (No data or inconclusive human data) | Low mw, excretion possible; monitor infant for excessive drowsiness |
| Pseudoephedrine | Excreted.This drug is known to be excreted in human breast milk. | This drug has been shown to have an adverse effect on the nursing infant. | May decrease milk supply and cause irritability |
No Known Risk
No known risk. This drug has no known risks to nursing infants and does not adversely affect lactation.
| Drug Name | Excretion Potential | Effect on Infant | Notes |
|---|---|---|---|
| Acetaminophen | Excreted.This drug is known to be excreted in human breast milk. | This drug has been shown not to have an adverse effect on the nursing infant. | Low levels excreted with low risk for adverse effects in infant |
No enhanced Geriatric Use information available for this drug.
Precaution Exists
Geriatric management or monitoring precaution exists.
Precaution Exists
Geriatric management or monitoring precaution exists.
| Drug Name | Narrative | REN | HEP | CARDIO | NEURO | PULM | ENDO |
|---|---|---|---|---|---|---|---|
| Acetaminophen (oral,rectal) | Hepatic-Elderly may be more susceptible to hepatotoxicity. Strict adherence to a maximum daily dose is recommended; maximum dose 3000-3800 mg depending on dose form strength used and recommendation source. | N | Y | N | N | N | N |
| Doxylamine | Neuro/Psych-Anticholinergic effects may cause sedation, worsen cognitive impairment and increase fall risk. Non-sedating antihistamine preferred. Gastrointestinal-May cause or worsen pre-existing constipation. Genitourinary-Best avoided in patients with urinary retention from any cause. | N | N | N | Y | N | N |
| Pseudoephedrine | Cardiovascular-Elderly are more sensitive to tachycardia and hypertensive effects. May exacerbate symptomatic coronary insufficiency. Genitourinary-May cause urinary retention. Neuro/Psych-May worsen cognitive impairment in some elderly with dementia. Insomnia risk. | Y | N | Y | Y | N | N |
The following prioritized warning is available for ALKA-SELTZER PLUS COLD+FLU (dextromethorphan/pseudoephrine hcl/acetaminophen/doxylamine):
WARNING: One ingredient in this product is acetaminophen. Taking too much acetaminophen may cause serious (possibly fatal) liver disease. Adults should not take more than 4000 milligrams (4 grams) of acetaminophen a day.
People with liver problems and children should take less acetaminophen. Ask your doctor or pharmacist how much acetaminophen is safe to take. Do not use with any other drug containing acetaminophen without asking your doctor or pharmacist first.
Acetaminophen is in many nonprescription and prescription medications (such as pain/fever drugs or cough-and-cold products). Check the labels on all your medicines to see if they contain acetaminophen, and ask your pharmacist if you are unsure. Get medical help right away if you take too much acetaminophen (overdose), even if you feel well.
Overdose symptoms may include nausea, vomiting, loss of appetite, sweating, stomach/abdominal pain, extreme tiredness, yellowing eyes/skin, and dark urine. Daily alcohol use, especially when combined with acetaminophen, may damage your liver. Avoid alcohol.
WARNING: One ingredient in this product is acetaminophen. Taking too much acetaminophen may cause serious (possibly fatal) liver disease. Adults should not take more than 4000 milligrams (4 grams) of acetaminophen a day.
People with liver problems and children should take less acetaminophen. Ask your doctor or pharmacist how much acetaminophen is safe to take. Do not use with any other drug containing acetaminophen without asking your doctor or pharmacist first.
Acetaminophen is in many nonprescription and prescription medications (such as pain/fever drugs or cough-and-cold products). Check the labels on all your medicines to see if they contain acetaminophen, and ask your pharmacist if you are unsure. Get medical help right away if you take too much acetaminophen (overdose), even if you feel well.
Overdose symptoms may include nausea, vomiting, loss of appetite, sweating, stomach/abdominal pain, extreme tiredness, yellowing eyes/skin, and dark urine. Daily alcohol use, especially when combined with acetaminophen, may damage your liver. Avoid alcohol.
The following icd codes are available for ALKA-SELTZER PLUS COLD+FLU (dextromethorphan/pseudoephrine hcl/acetaminophen/doxylamine)'s list of indications:
No ICD codes found for this drug.
No ICD codes found for this drug.
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