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Drug overview for COLD & FLU RELIEF (diphenhydramine hcl/phenylephrine hcl/acetaminophen):
Generic name: DIPHENHYDRAMINE HCL/PHENYLEPHRINE HCL/ACETAMINOPHEN
Drug class: Amphetamines/Anorexiants/Stimulants
Therapeutic class: Respiratory Therapy Agents
Acetaminophen is a synthetic nonopiate derivative of p-aminophenol that Diphenhydramine is an ethanolamine-derivative, first generation Phenylephrine hydrochloride is a sympathomimetic amine that predominantly acts by a direct effect on alpha1-adrenergic receptors. antihistamine. produces analgesia and antipyresis.
Acetaminophen is used extensively in the treatment of mild to moderate pain Diphenhydramine shares the actions and uses of other antihistamines. and fever. Diphenhydramine also is used as an antitussive for temporary relief of cough caused by minor throat and bronchial irritation such as may occur with common colds or inhaled irritants.
Diphenhydramine is effective for the prevention and treatment of nausea, vomiting, and/or vertigo associated with motion sickness. Diphenhydramine may be useful as an adjunctive antiemetic agent to prevent chemotherapy-induced nausea and vomiting+; however, the American Society of Clinical Oncology (ASCO) currently does not recommend that antihistamines be used alone as antiemetic agents in patients receiving chemotherapy. Diphenhydramine also is used as a nighttime sleep aid for the short-term management of insomnia.
In individuals who experience occasional sleeplessness or those who have difficulty falling asleep, the drug is more effective than placebo in reducing sleep onset (i.e., time to fall asleep) and increasing the depth and quality of sleep. Diphenhydramine, alone or in conjunction with other antiparkinsonian agents, may be useful as alternative therapy in the management of tremor early in the course of parkinsonian syndrome. The drug also may be useful in the management of drug-induced extrapyramidal reactions.
Diphenhydramine may be used topically for temporary relief of pruritus and pain associated with various skin conditions including minor burns, sunburn, minor cuts or scrapes, insect bites, minor skin irritations, or rashes associated with poison oak, poison ivy, or poison sumac. However, because systemic diphenhydramine toxicity (e.g., psychosis) has been reported in pediatric patients following topical application of the drug to large areas of the body (often areas with broken skin), many clinicians suggest that topical diphenhydramine be used only on limited areas of skin and not used more often than directed to avoid excessive percutaneous absorption of the drug. (See Acute Toxicity: Manifestations, in the Antihistamines General Statement 4:00.) Topical diphenhydramine also should not be used for self-medication in the management of varicella (chickenpox) or measles without first consulting a clinician.
Generic name: DIPHENHYDRAMINE HCL/PHENYLEPHRINE HCL/ACETAMINOPHEN
Drug class: Amphetamines/Anorexiants/Stimulants
Therapeutic class: Respiratory Therapy Agents
Acetaminophen is a synthetic nonopiate derivative of p-aminophenol that Diphenhydramine is an ethanolamine-derivative, first generation Phenylephrine hydrochloride is a sympathomimetic amine that predominantly acts by a direct effect on alpha1-adrenergic receptors. antihistamine. produces analgesia and antipyresis.
Acetaminophen is used extensively in the treatment of mild to moderate pain Diphenhydramine shares the actions and uses of other antihistamines. and fever. Diphenhydramine also is used as an antitussive for temporary relief of cough caused by minor throat and bronchial irritation such as may occur with common colds or inhaled irritants.
Diphenhydramine is effective for the prevention and treatment of nausea, vomiting, and/or vertigo associated with motion sickness. Diphenhydramine may be useful as an adjunctive antiemetic agent to prevent chemotherapy-induced nausea and vomiting+; however, the American Society of Clinical Oncology (ASCO) currently does not recommend that antihistamines be used alone as antiemetic agents in patients receiving chemotherapy. Diphenhydramine also is used as a nighttime sleep aid for the short-term management of insomnia.
In individuals who experience occasional sleeplessness or those who have difficulty falling asleep, the drug is more effective than placebo in reducing sleep onset (i.e., time to fall asleep) and increasing the depth and quality of sleep. Diphenhydramine, alone or in conjunction with other antiparkinsonian agents, may be useful as alternative therapy in the management of tremor early in the course of parkinsonian syndrome. The drug also may be useful in the management of drug-induced extrapyramidal reactions.
Diphenhydramine may be used topically for temporary relief of pruritus and pain associated with various skin conditions including minor burns, sunburn, minor cuts or scrapes, insect bites, minor skin irritations, or rashes associated with poison oak, poison ivy, or poison sumac. However, because systemic diphenhydramine toxicity (e.g., psychosis) has been reported in pediatric patients following topical application of the drug to large areas of the body (often areas with broken skin), many clinicians suggest that topical diphenhydramine be used only on limited areas of skin and not used more often than directed to avoid excessive percutaneous absorption of the drug. (See Acute Toxicity: Manifestations, in the Antihistamines General Statement 4:00.) Topical diphenhydramine also should not be used for self-medication in the management of varicella (chickenpox) or measles without first consulting a clinician.
DRUG IMAGES
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The following indications for COLD & FLU RELIEF (diphenhydramine hcl/phenylephrine hcl/acetaminophen) have been approved by the FDA:
Indications:
Allergic conjunctivitis
Allergic rhinitis
Flu-like symptoms
Nasal congestion
Rhinorrhea
Sinus headache
Professional Synonyms:
Allergy eye itch
Atopic conjunctivitis
Itchy eyes due to allergies
Nasal stuffiness
Ocular itching due to allergies
Sinus pain
Indications:
Allergic conjunctivitis
Allergic rhinitis
Flu-like symptoms
Nasal congestion
Rhinorrhea
Sinus headache
Professional Synonyms:
Allergy eye itch
Atopic conjunctivitis
Itchy eyes due to allergies
Nasal stuffiness
Ocular itching due to allergies
Sinus pain
The following dosing information is available for COLD & FLU RELIEF (diphenhydramine hcl/phenylephrine hcl/acetaminophen):
Dosage should be individualized according to the patient's response and tolerance.
The usual adult oral dosage of diphenhydramine hydrochloride is 25-50 mg 3 or 4 times daily at 4- to 6-hour intervals, not to exceed 300 mg in 24 hours.
The usual adult IM or IV dose of diphenhydramine hydrochloride is 10-50 mg; in a few patients, up to 100 mg may be required. Some experts recommend a dose of 25-50 mg. The rate of IV administration should not exceed 25 mg/minute.
The maximum adult IM or IV dosage of diphenhydramine hydrochloride is 400 mg daily.
Acetaminophen is relatively safe when used at recommended dosages. However, When diphenhydramine was available only by prescription, the prescribing acetaminophen overdosage has been the leading cause of acute liver failure information for the drug indicated a usual oral diphenhydramine in the US, United Kingdom, and most of Europe, with about 50% of US cases hydrochloride dosage for children weighing more than 9.1 kg of 12.5-25
mg 3 in recent years resulting from inadvertent overdosage (e.g., in patients or 4 times daily at 4- to 6-hour intervals and for children weighing 9.1 kg not recognizing the presence of the drug in multiple over-the-counter (OTC) or less an oral diphenhydramine hydrochloride dosage of 6.25-12.5 mg 3 or 4 and/or prescription products that they may be taking).
Therefore, patients times daily at 4- to 6-hour intervals. However, these dosage should be warned about the importance of determining whether acetaminophen recommendations are not included in the current labeling of nonprescription is present in their medications (e.g., by examining labels carefully, by oral diphenhydramine preparations, and clinicians should use caution when consulting their clinician and pharmacist) and of not exceeding recommended considering use of nonprescription oral diphenhydramine in children younger dosages or combining acetaminophen-containing preparations. than 4 years of age.
(See Cautions: Pediatric Precautions.)
Acetaminophen should not be used for self-medication of pain for longer Alternatively, for oral, deep IM, or IV therapy, children (other than than 10 days (in adults or children 12 years of age and older) or 5 days premature or full-term neonates) may be given 5 mg/kg daily or 150 mg/m2 (in children 2-11 years of age), unless directed by a clinician because daily divided in 4 doses; some experts recommend a dosage of 1-2 mg/kg pain of such intensity and duration may indicate a pathologic condition daily. The rate of IV administration should not exceed 25 mg/minute. requiring medical evaluation and supervised treatment.
The maximum oral, IM, or IV dosage of diphenhydramine hydrochloride in Acetaminophen should not be used in adults or children for self-medication children older than 1 month of age is 300 mg daily. 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.
Phenylephrine hydrochloride should be administered in the lowest effective dosage for the shortest possible time. When used to increase blood pressure in patients with acute hypotensive states, dosage should be individualized based on the pressor response.
For temporary relief of pruritus and pain associated with various skin conditions in adults and children 2 years of age or older, creams, lotions, or solutions containing 1-2% diphenhydramine hydrochloride are applied to the affected areas 3 or 4 times daily or as directed by a clinician; topical diphenhydramine should not be used more often than directed.
If the condition worsens, or if symptoms persist for longer than 7 days or resolve and then recur within a few days, topical therapy with diphenhydramine hydrochloride should be discontinued and a clinician consulted; the possibility of sensitization by, or hypersensitivity to, the drug should be considered.
Topical preparations containing diphenhydramine hydrochloride should not be used on large areas of the body or concomitantly with other preparations containing the antihistamine, including those used orally, since increased serum concentrations of diphenhydramine may occur that can result in systemic toxicity. (See Acute Toxicity: Manifestations, in the Antihistamines General Statement 4:00.) The drug also should not be used for topical self-medication in the management of varicella (chickenpox) or measles without first consulting a clinician.
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 adult oral dosage of diphenhydramine hydrochloride is 25-50 mg 3 or 4 times daily at 4- to 6-hour intervals, not to exceed 300 mg in 24 hours.
The usual adult IM or IV dose of diphenhydramine hydrochloride is 10-50 mg; in a few patients, up to 100 mg may be required. Some experts recommend a dose of 25-50 mg. The rate of IV administration should not exceed 25 mg/minute.
The maximum adult IM or IV dosage of diphenhydramine hydrochloride is 400 mg daily.
Acetaminophen is relatively safe when used at recommended dosages. However, When diphenhydramine was available only by prescription, the prescribing acetaminophen overdosage has been the leading cause of acute liver failure information for the drug indicated a usual oral diphenhydramine in the US, United Kingdom, and most of Europe, with about 50% of US cases hydrochloride dosage for children weighing more than 9.1 kg of 12.5-25
mg 3 in recent years resulting from inadvertent overdosage (e.g., in patients or 4 times daily at 4- to 6-hour intervals and for children weighing 9.1 kg not recognizing the presence of the drug in multiple over-the-counter (OTC) or less an oral diphenhydramine hydrochloride dosage of 6.25-12.5 mg 3 or 4 and/or prescription products that they may be taking).
Therefore, patients times daily at 4- to 6-hour intervals. However, these dosage should be warned about the importance of determining whether acetaminophen recommendations are not included in the current labeling of nonprescription is present in their medications (e.g., by examining labels carefully, by oral diphenhydramine preparations, and clinicians should use caution when consulting their clinician and pharmacist) and of not exceeding recommended considering use of nonprescription oral diphenhydramine in children younger dosages or combining acetaminophen-containing preparations. than 4 years of age.
(See Cautions: Pediatric Precautions.)
Acetaminophen should not be used for self-medication of pain for longer Alternatively, for oral, deep IM, or IV therapy, children (other than than 10 days (in adults or children 12 years of age and older) or 5 days premature or full-term neonates) may be given 5 mg/kg daily or 150 mg/m2 (in children 2-11 years of age), unless directed by a clinician because daily divided in 4 doses; some experts recommend a dosage of 1-2 mg/kg pain of such intensity and duration may indicate a pathologic condition daily. The rate of IV administration should not exceed 25 mg/minute. requiring medical evaluation and supervised treatment.
The maximum oral, IM, or IV dosage of diphenhydramine hydrochloride in Acetaminophen should not be used in adults or children for self-medication children older than 1 month of age is 300 mg daily. 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.
Phenylephrine hydrochloride should be administered in the lowest effective dosage for the shortest possible time. When used to increase blood pressure in patients with acute hypotensive states, dosage should be individualized based on the pressor response.
For temporary relief of pruritus and pain associated with various skin conditions in adults and children 2 years of age or older, creams, lotions, or solutions containing 1-2% diphenhydramine hydrochloride are applied to the affected areas 3 or 4 times daily or as directed by a clinician; topical diphenhydramine should not be used more often than directed.
If the condition worsens, or if symptoms persist for longer than 7 days or resolve and then recur within a few days, topical therapy with diphenhydramine hydrochloride should be discontinued and a clinician consulted; the possibility of sensitization by, or hypersensitivity to, the drug should be considered.
Topical preparations containing diphenhydramine hydrochloride should not be used on large areas of the body or concomitantly with other preparations containing the antihistamine, including those used orally, since increased serum concentrations of diphenhydramine may occur that can result in systemic toxicity. (See Acute Toxicity: Manifestations, in the Antihistamines General Statement 4:00.) The drug also should not be used for topical self-medication in the management of varicella (chickenpox) or measles without first consulting a clinician.
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.)
Diphenhydramine hydrochloride usually is administered orally. Diphenhydramine citrate usually is administered orally. When oral therapy is not feasible, diphenhydramine hydrochloride may be given by deep IM or, preferably, IV injection.
The drug should not be given subcutaneously, intradermally, or perivascularly because of its irritating effects; local necrosis has been reported following subcutaneous or intradermal administration of parenteral diphenhydramine. IV use of the drug in a home-care setting should be employed under careful supervision. Use of diphenhydramine for local anesthesia via local infiltration is discouraged because of the risk of local tissue necrosis.
Diphenhydramine hydrochloride should not be given to premature or full-term neonates. (See Cautions: Pediatric Precautions.) For the temporary relief of pruritus associated with various skin conditions and disorders, diphenhydramine hydrochloride-containing preparations are applied topically in the form of a cream, lotion, or topical solution. The possibility of clinically important percutaneous absorption of the drug following topical application should be considered.
(See Cautions.) 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.
The drug should not be given subcutaneously, intradermally, or perivascularly because of its irritating effects; local necrosis has been reported following subcutaneous or intradermal administration of parenteral diphenhydramine. IV use of the drug in a home-care setting should be employed under careful supervision. Use of diphenhydramine for local anesthesia via local infiltration is discouraged because of the risk of local tissue necrosis.
Diphenhydramine hydrochloride should not be given to premature or full-term neonates. (See Cautions: Pediatric Precautions.) For the temporary relief of pruritus associated with various skin conditions and disorders, diphenhydramine hydrochloride-containing preparations are applied topically in the form of a cream, lotion, or topical solution. The possibility of clinically important percutaneous absorption of the drug following topical application should be considered.
(See Cautions.) 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 COLD & FLU RELIEF (diphenhydramine hcl/phenylephrine hcl/acetaminophen):
There are 1 contraindications.
These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.
| Drug Interaction | Drug Names |
|---|---|
| Sympathomimetics (Indirect & Mixed Acting)/MAOIs SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Catecholamine stores increased by MAOIs can be released by indirect acting sympathomimetics such as ephedrine and amphetamine. MAO inhibitors also interfere with gut and liver metabolism of direct acting sympathomimetics (e.g oral phenylephrine). CLINICAL EFFECTS: Concurrent use of MAOIs may result in potentiation of sympathomimetic effects, which may result in headaches, hypertensive crisis, toxic neurological effects, and malignant hyperpyrexia. Fatalities have occurred. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of monoamine oxidase inhibitors and sympathomimetics is contraindicated. The manufacturers of sympathomimetic agents recommend waiting 14 days after discontinuation of MAO inhibitors before initiating the sympathomimetic. DISCUSSION: Indirect acting sympathomimetic amines may cause abrupt elevation of blood pressure when administered to patients taking monoamine oxidase inhibitors, resulting in a potentially fatal hypertensive crisis. Mixed (direct and indirect) acting sympathomimetics have also been shown to interact with monoamine oxidase inhibitors depending on their degree of indirect action. The direct-acting sympathomimetics have not been reported to interact. Dopamine is metabolized by monoamine oxidase, and its pressor effect is enhanced by monoamine oxidase inhibitors. Since procarbazine, an antineoplastic agent, is a weak monoamine oxidase inhibitor, hypertensive reactions may result from its concurrent use with indirect and mixed acting sympathomimetics. Furazolidone, an antibacterial with monoamine oxidase inhibitor action, has also been shown to interact with indirect acting sympathomimetics. Linezolid is another antibacterial with monoamine oxidase inhibitor properties. Metaxalone is a weak inhibitor of MAO. Foods containing large amounts of tyramine have also been implicated in this interaction. Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A. At recommended dosages, rasagiline, oral selegiline, and transdermal selegiline up to 6mg/day are selective for MAO-B; however, at higher dosages they have been shown to lose their selectivity. One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology. |
EMSAM, FURAZOLIDONE, MARPLAN, MATULANE, METAXALONE, METHYLENE BLUE, NARDIL, PARNATE, PHENELZINE SULFATE, PROCARBAZINE HCL, PROVAYBLUE, SELEGILINE HCL, TRANYLCYPROMINE SULFATE |
There are 15 severe interactions.
These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.
| Drug Interaction | Drug Names |
|---|---|
| Ergot Alkaloids/Sympathomimetics SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Concurrent use of ergot alkaloids and sympathomimetics may result in additive or synergistic effect on peripheral blood vessels. CLINICAL EFFECTS: Concurrent use of ergot alkaloids and sympathomimetics may result in increased blood pressure due to peripheral vasoconstriction. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: When possible, avoid the concurrent use of ergot alkaloids and sympathomimetics. If concurrent use is warranted, monitor blood pressure and for signs of vasoconstriction. Decreasing the dose of one or both drugs may be necessary. DISCUSSION: There have been reports of severe vasoconstriction resulting in gangrene in patients receiving intravenous ergonovine with dopamine or norepinephrine. |
DIHYDROERGOTAMINE MESYLATE, ERGOLOID MESYLATES, ERGOMAR, ERGOTAMINE TARTRATE, ERGOTAMINE-CAFFEINE, METHYLERGONOVINE MALEATE, METHYSERGIDE MALEATE, MIGERGOT, MIGRANAL, TRUDHESA |
| Selected Inhalation Anesthetic Agents/Sympathomimetics SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: The exact mechanism is unknown. The anesthetics produce conduction changes that increase impulse re-entry into the myocardial tissue.(1) The anesthetics' ability to precipitate arrhythmias is enhanced by elevated arterial blood pressure, tachycardia, hypercapnia, and/or hypoxia, events that stimulate the release of endogenous catecholamines.(1) CLINICAL EFFECTS: Concurrent use of inhalation anesthetic agents and sympathomimetics may result in ventricular arrhythmias or sudden blood pressure and heart rate increase during surgery.(2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Monitor blood pressure and avoid use of sympathomimetics in patients being treated with anesthetics on the day of surgery.(2) Intravenous use of epinephrine during surgery with halothane and related halogenated general anesthetics should be strongly discouraged. When intravenous epinephrine is necessary, nitrous oxide anesthesia supplemented with ether, muscle relaxants, or opioids should be used instead of halothane.(3,4) Epinephrine may safely be used subcutaneously with the following precautions: the patient is adequately ventilated to prevent hypoxia or respiratory acidosis; the total dose of epinephrine is limited to 100 mcg/10 minute period or 300 mcg/hour in adults, 3.5 mcg/Kg in infants, 2.5 mcg/Kg in children up to two years of age, and 1.45 mcg/Kg in children over two years of age; a minimum effective concentration of anesthetic is maintained; the drugs are not co-administered in patients with hypertension or other cardiovascular disorders; and the cardiac rhythm is continuously monitored during and after injection.(3-10) If arrhythmias occur after the administration of the epinephrine, the drugs of choice are lidocaine or propranolol, depending on the type of arrhythmia.(1) DISCUSSION: Administration of epinephrine during halothane anesthesia may may lead to serious ventricular arrhythmias.(3-6,11-18) This has occurred when epinephrine was administered intravenously,(6) when it was administered with lidocaine as a dental block,(11,14) or when it was administered supraperiosteally.(5) Norepinephrine has been shown to interact with halothane in a manner similar to epinephrine.(1) In two case reports, patients were given terbutaline (0.25 to 0.35 mg) for wheezing following induction of anesthesia with halothane. One patient's heart rate increased from 68 to 100 beats/minute, and the ECG showed premature ventricular contractions and bigeminy, while the other patient developed multiple unifocal premature ventricular contractions and bigeminy. The arrhythmias resolved in both patients following lidocaine administration.(19) Although not documented, isoproterenol causes effects on the heart similar to terbutaline(20) and would probably interact with halothane in a similar manner. Other inhalation anesthetics that increase the incidence of arrhythmias with epinephrine include chloroform,(20) methoxyflurane,(20) and enflurane.(12) A similar interaction may be expected between the other inhalation anesthetics and sympathomimetics. |
DESFLURANE, FORANE, ISOFLURANE, SEVOFLURANE, SUPRANE, TERRELL, ULTANE |
| Solid Oral Potassium Tablets/Anticholinergics SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Concentrated potassium may damage the lining of the GI tract. Anticholinergics delay gastric emptying, resulting in the potassium product remaining in the gastrointestinal tract for a longer period of time.(1-16) CLINICAL EFFECTS: Use of solid oral dosage forms of potassium in patients treated with anticholinergics may result in gastrointestinal erosions, ulcers, stenosis and bleeding.(1-16) PREDISPOSING FACTORS: Diseases or conditions which may increase risk for GI damage include: preexisting dysphagia, strictures, cardiomegaly, diabetic gastroparesis, elderly status, or insufficient oral intake to allow dilution of potassium.(1-10,21) Other drugs which may add to risk for GI damage include: nonsteroidal anti-inflammatory drugs (NSAIDs), bisphosphonates, or tetracyclines.(21) PATIENT MANAGEMENT: Regulatory agency and manufacturer recommendations regarding this interaction: - In the US, all solid oral dosage forms (including tablets and extended release capsules) of potassium are contraindicated in patients receiving anticholinergics at sufficient dosages to result in systemic effects.(2-8) Patients receiving such anticholinergic therapy should use a liquid form of potassium chloride.(2) - In Canada, solid oral potassium is contraindicated in any patient with a cause for arrest or delay in tablet/capsule passage through the gastrointestinal tract and the manufacturers recommend caution with concurrent anticholinergic medications.(1,9-10) Evaluate each patient for predisposing factors which may increase risk for GI damage. In patients with multiple risk factors for harm, consider use of liquid potassium supplements, if tolerated. For patients receiving concomitant therapy, assure any potassium dose form is taken after meals with a large glass of water or other fluid. To decrease potassium concentration in the GI tract, limit each dose to 20 meq; if more than 20 meq daily is required, give in divided doses.(2) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Patients should be instructed to immediately report any difficulty swallowing, abdominal pain, distention, severe vomiting, or gastrointestinal bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. DISCUSSION: In clinical trials, there was a higher incidence of gastric and duodenal lesions in patients receiving a high dose of a wax-matrix controlled-release formulation with a concurrent anticholinergic agent. Some lesions were asymptomatic and not accompanied by bleeding, as shown by a lack of positive Hemoccult tests.(1-17) Several studies suggest that the incidence of gastric and duodenal lesions may be less with the microencapsulated formulation of potassium chloride.(14-17) |
K-TAB ER, KLOR-CON 10, KLOR-CON 8, KLOR-CON M10, KLOR-CON M15, KLOR-CON M20, POTASSIUM CHLORIDE, POTASSIUM CITRATE ER, UROCIT-K |
| Solid Oral Potassium Capsules/Anticholinergics SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Concentrated potassium may damage the lining of the GI tract. Anticholinergics delay gastric emptying, resulting in the potassium product remaining in the gastrointestinal tract for a longer period of time.(1-16)) CLINICAL EFFECTS: Use of solid oral dosage forms of potassium in patients treated with anticholinergics may result in gastrointestinal erosions, ulcers, stenosis and bleeding.(1-16) PREDISPOSING FACTORS: Diseases or conditions which may increase risk for GI damage include: preexisting dysphagia, strictures, cardiomegaly, diabetic gastroparesis, elderly status, or insufficient oral intake to allow dilution of potassium.(1-10,21) Other drugs which may add to risk for GI damage include: nonsteroidal anti-inflammatory drugs (NSAIDs), bisphosphonates, or tetracyclines.(21) PATIENT MANAGEMENT: Regulatory agency and manufacturer recommendations regarding this interaction: - In the US, all solid oral dosage forms (including tablets and extended release capsules) of potassium are contraindicated in patients receiving anticholinergics at sufficient dosages to result in systemic effects.(2-8) Patients receiving such anticholinergic therapy should use a liquid form of potassium chloride.(2) - In Canada, solid oral potassium is contraindicated in any patient with a cause for arrest or delay in tablet/capsule passage through the gastrointestinal tract and the manufacturers recommend caution with concurrent anticholinergic medications.(1,9-10) Evaluate each patient for predisposing factors which may increase risk for GI damage. In patients with multiple risk factors for harm, consider use of liquid potassium supplements, if tolerated. For patients receiving concomitant therapy, assure any potassium dose form is taken after meals with a large glass of water or other fluid. To decrease potassium concentration in the GI tract, limit each dose to 20 meq; if more than 20 meq daily is required, give in divided doses.(2) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Patients should be instructed to immediately report any difficulty swallowing, abdominal pain, distention, severe vomiting, or gastrointestinal bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. DISCUSSION: In clinical trials, there was a higher incidence of gastric and duodenal lesions in patients receiving a high dose of a wax-matrix controlled-release formulation with a concurrent anticholinergic agent. The lesions were asymptomatic and not accompanied by bleeding, as shown by a lack of positive Hemoccult tests.(1-17) Several studies suggest that the incidence of gastric and duodenal lesions may be less with the microencapsulated formulation of potassium chloride.(14-17) |
POTASSIUM CHLORIDE |
| Mixed;Indirect Sympathomimetics/Selected MAOIs SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Catecholamine stores increased by MAOIs can be released by indirect acting sympathomimetics such as ephedrine and amphetamine. MAO inhibitors also interfere with gut and liver metabolism of direct acting sympathomimetics (e.g oral phenylephrine). CLINICAL EFFECTS: Concurrent use of MAOIs may result in potentiation of sympathomimetic effects, which may result in headaches, hypertensive crisis, toxic neurological effects, and malignant hyperpyrexia. Fatalities have occurred with combinations of sympathomimetics and MAO-A inhibitors. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of MAO-A inhibitors and sympathomimetics is contraindicated. The manufacturers of sympathomimetic agents recommend waiting 14 days after discontinuation of MAO inhibitors before initiating the sympathomimetic. Patients receiving direct or indirect acting sympathomimetics should not receive linezolid unless they are monitored for potential increases in blood pressure. Initial dosages of dopamine and epinephrine should be reduced. At recommended dosages, oral selegiline and transdermal selegiline up to 6mg/day are selective for MAO-B; however, at higher dosages they have been shown to lose their selectivity. Patients receiving higher dosages of selegiline should be considered susceptive to this interaction. DISCUSSION: Indirect acting sympathomimetic amines may cause abrupt elevation of blood pressure when administered to patients taking monoamine oxidase inhibitors, resulting in a potentially fatal hypertensive crisis. Mixed (direct and indirect) acting sympathomimetics have also been shown to interact with monoamine oxidase inhibitors depending on their degree of indirect action. The direct-acting sympathomimetics have not been reported to interact. Dopamine is metabolized by monoamine oxidase, and its pressor effect is enhanced by monoamine oxidase inhibitors. Furazolidone, an antibacterial with monoamine oxidase inhibitor action, has also been shown to interact with indirect acting sympathomimetics. Foods containing large amounts of tyramine have also been implicated in this interaction. A significant pressor response was observed in normal subjects receiving linezolid and tyramine doses of more than 100 mg. Administration of linezolid (600 mg BID for 3 days) with pseudoephedrine (60 mg q 4 hours for 2 doses) increased blood pressure by 32 mmHg. Administration of linezolid (600 mg BID for 3 days) with phenylpropanolamine (25 mg q 4 hours for 2 doses) increased blood pressure by 38 mmHg. One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology. |
EMSAM, LINEZOLID, LINEZOLID-0.9% NACL, LINEZOLID-D5W, SELEGILINE HCL, XADAGO, ZELAPAR, ZYVOX |
| Radioactive Iodide/Agents that Affect Iodide SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Many compounds can affect iodide protein binding and alter iodide pharmacokinetics and pharmacodynamics.(1,2) CLINICAL EFFECTS: Compounds that affect iodide pharmacokinetics and pharmacodynamics may impact the effectiveness of radioactive iodide.(1,2 PREDISPOSING FACTORS: Compounds that affect iodide pharmacokinetics and pharmacodynamics are expected to have the most impact during therapy using radioactive iodide. Diagnostic procedures would be expected to be impacted less. PATIENT MANAGEMENT: Discuss the use of agents that affect iodide pharmacokinetics and pharmacodynamics with the patient's oncologist.(1,2) DISCUSSION: Many agents interact with radioactive iodine. The average duration of effect is: anticoagulants - 1 week antihistamines - 1 week anti-thyroid drugs, e.g: carbimazole, methimazole, propylthiouracil - 3-5 days corticosteroids - 1 week iodide-containing medications, e.g: amiodarone - 1-6 months expectorants - 2 weeks Lugol solution - 3 weeks saturated solution of potassium iodine - 3 weeks vitamins - 10-14 days iodide-containing X-ray contrast agents - up to 1 year lithium - 4 weeks phenylbutazone - 1-2 weeks sulfonamides - 1 week thyroid hormones (natural or synthetic), e.g.: thyroxine - 4 weeks tri-iodothyronine - 2 weeks tolbutamide - 1 week topical iodide - 1-9 months (1,2) |
ADREVIEW, HICON, JEANATOPE, MEGATOPE, SODIUM IODIDE I-123, SODIUM IODIDE I-131 |
| Selected Direct-Acting Sympathomimetics/Tricyclic Compounds SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Unknown. However, it is speculated that direct-acting sympathomimetic amines have an enhanced effect due to tricyclic blockage of norepinephrine reuptake. CLINICAL EFFECTS: Increased effect of direct acting sympathomimetics. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Consider avoiding the concurrent use of direct-acting sympathomimetics and tricyclic compounds. If concurrent use of direct-acting sympathomimetics and tricyclic compounds is warranted, the initial dose of the sympathomimetic should be lowered and the patient should be monitored for adverse cardiovascular effects. Use of tricyclic compounds and other sympathomimetics should be approached with caution. DISCUSSION: Epinephrine and other direct-acting sympathomimetic amines exert enhanced cardiovascular effects (e.g., arrhythmias, hypertension, and tachycardia) in individuals concurrently receiving or previously treated with tricyclic antidepressants. Other direct and mixed acting sympathomimetic amines have also been reported to interact with tricyclic antidepressants. These include norepinephrine, phenylephrine, dopamine, and methoxamine. Protriptyline, amitriptyline, and desipramine have also been reported to interact with direct-acting sympathomimetics. |
AMITRIPTYLINE HCL, AMOXAPINE, ANAFRANIL, CHLORDIAZEPOXIDE-AMITRIPTYLINE, CLOMIPRAMINE HCL, DESIPRAMINE HCL, DOXEPIN HCL, IMIPRAMINE HCL, IMIPRAMINE PAMOATE, NORPRAMIN, NORTRIPTYLINE HCL, PAMELOR, PERPHENAZINE-AMITRIPTYLINE, PROTRIPTYLINE HCL, SILENOR, TRIMIPRAMINE MALEATE |
| Iobenguane I 123/Agents that Affect Catecholamines SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Many compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells.(1) CLINICAL EFFECTS: Compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with imaging completed with iobenguane.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Discuss the use of agents that affect catecholamines. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores prior to imaging with iobenguane. Before imaging with iobenguane, discontinue agents that affect catecholamines for at least 5 biological half-lives, as clinically tolerated.(1) DISCUSSION: Many agents may reduce catecholamine uptake or deplete catecholamine stores.(1) Examples include: - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine) - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) - monoamine oxidase inhibitors (e.g. phenelzine, linezolid) - central monoamine depleting drugs (e.g. reserpine) - non-select beta adrenergic blocking drugs (e.g. labetalol) - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine) - botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine) |
ADREVIEW |
| Eliglustat/Weak CYP2D6 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Weak inhibitors of CYP2D6 may inhibit the metabolism of eliglustat. If the patient is also taking an inhibitor of CYP3A4, eliglustat metabolism can be further inhibited.(1) CLINICAL EFFECTS: Concurrent use of an agent that is a weak inhibitor of CYP2D6 may result in elevated levels of and clinical effects of eliglustat, including prolongation of the PR, QTc, and/or QRS intervals, which may result in life-threatening cardiac arrhythmias.(1) PREDISPOSING FACTORS: If the patient is also taking an inhibitor of CYP3A4 and/or has hepatic impairment, eliglustat metabolism can be further inhibited.(1) The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) PATIENT MANAGEMENT: The dosage of eliglustat with weak inhibitors of CYP2D6 in poor CYP2D6 metabolizers should be limited to 84 mg daily.(1) The dosage of eliglustat with weak inhibitors of CYP2D6 in extensive CYP2D6 metabolizers with mild (Child-Pugh Class A) hepatic impairment should be limited to 84 mg daily.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: Paroxetine (30 mg daily), a strong inhibitor of CYP2D6, increased eliglustat (84 mg BID) maximum concentration (Cmax) and area-under-curve (AUC) by 7-fold and 8.4-fold, respectively, in extensive metabolizers. Physiologically-based pharmacokinetic (PKPB) models suggested paroxetine would increase eliglustat Cmax and AUC by 2.1-fold and 2.3-fold, respectively, in intermediate metabolizers. PKPB models suggested ketoconazole may increase the Cmax and AUC of eliglustat (84 mg daily) by 4.3-fold and 6.2-fold, respectively, in poor metabolizers.(1) PKPB models suggested terbinafine, a moderate inhibitor of CYP2D6, would increase eliglustat Cmax and AUC by 3.8-fold and 4.5-fold, respectively, in extensive metabolizers and by 1.6-fold and 1.6-fold, respectively in intermediate metabolizers. PKPB models suggest that concurrent eliglustat (84 mg BID), paroxetine (a strong inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax and AUC by 16.7-fold and 24.2-fold, respectively, in extensive metabolizers. In intermediate metabolizers, eliglustat Cmax and AUC would be expected to increase 7.5-fold and 9.8-fold, respectively.(1) PKPB models suggest that concurrent eliglustat (84 mg BID), terbinafine (a moderate inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax and AUC by 10.2-fold and 13.6-fold, respectively, in extensive metabolizers. In intermediate metabolizers, eliglustat Cmax and AUC would be expected to increase 4.2-fold and 5-fold, respectively.(1) A single dose of rolapitant increased dextromethorphan, a CYP2D6 substrate, about 3-fold on days 8 and day 22 following administration. Dextromethorphan levels remained elevated by 2.3-fold on day 28 after single dose rolapitant. The inhibitory effects of rolapitant on CYP2D6 are expected to persist beyond 28 days.(5) Weak inhibitors of CYP2D6 include: alogliptin, artesunate, celecoxib, clobazam, desvenlafaxine, diphenhydramine, dronabinol, dupilumab, echinacea, felodipine, gefitinib, hydralazine, hydroxychloroquine, lorcaserin, methadone, panobinostat, propafenone, sertraline, vemurafenib, and venlafaxine.(3,4) |
CERDELGA |
| Clozapine/Anticholinergics SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Clozapine has potent anticholinergic properties and inhibits serotonin receptors, including 5-HT3.(1-4) Both of these properties may cause inhibition of gastrointestinal (GI) smooth muscle contraction, resulting in decreased peristalsis.(3,4) These effects may be compounded by concurrent use of anticholinergic agents.(1-6) CLINICAL EFFECTS: Concurrent use of clozapine with other anticholinergic agents may increase the risk of constipation (common) and serious bowel complications (uncommon), including complete bowel obstruction, fecal impaction, paralytic ileus and intestinal ischemia or infarction.(1-6) PREDISPOSING FACTORS: The risk for serious bowel complications is higher with increasing age, higher frequency of constipation, and in patients on higher doses of clozapine or multiple anticholinergic agents.(1,5) PATIENT MANAGEMENT: Avoid the use of other anticholinergic agents with clozapine.(1-6) If concurrent use is necessary, evaluate the patient's bowel function regularly. Monitor for symptoms of constipation and GI hypomotility, including having bowel movements less than three times weekly or less than usual, difficulty having a bowel movement or passing gas, nausea, vomiting, and abdominal pain or distention.(2) Consider a prophylactic laxative in those with a history of constipation or bowel obstruction.(2) Review patient medication list for other anticholinergic agents. When possible, decrease the dosage or number of prescribed anticholinergic agents, particularly in the elderly. Counsel the patient about the importance of maintaining adequate hydration. Encourage regular exercise and eating a high-fiber diet.(2) DISCUSSION: In a prospective cohort study of 26,720 schizophrenic patients in the Danish Central Psychiatric Research Registry, the odds ratio (OR) for ileus was 1.99 with clozapine and 1.48 with anticholinergics. The OR for fatal ileus was 6.73 with clozapine and 5.88 with anticholinergics. Use of anticholinergics with 1st generation antipsychotics (FGA) increased the risk of ileus compare to FGA alone, but this analysis was not done with clozapine.(5) A retrospective cohort study of 24,970 schizophrenic patients from the Taiwanese National Health Insurance Research Database found that the hazard ratio (HR) for clozapine-induced constipation increased from 1.64 when clozapine is used alone, to 2.15 when used concomitantly with anticholinergics. However, there was no significant difference in the HR for ileus when clozapine is used with and without anticholinergics (1.95 and 2.02, respectively).(6) In the French Pharmacovigilance Database, 7 of 38 cases of antipsychotic-associated ischemic colitis or intestinal necrosis involved clozapine, and 5 of these cases involved use of concomitant anticholinergic agents. Three patients died, one of whom was on concomitant anticholinergics.(3) In a case series, 4 of 9 cases of fatal clozapine-associated GI dysfunction involved concurrent anticholinergic agents.(4) |
CLOZAPINE, CLOZAPINE ODT, CLOZARIL, VERSACLOZ |
| Zonisamide/Anticholinergics SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Zonisamide can cause decreased sweating and elevated body temperature. Agents with anticholinergic activity can predispose patients to heat-related disorders.(1-2) CLINICAL EFFECTS: Concurrent use of zonisamide with agents with anticholinergic activity may increase the incidence of oligohidrosis and hyperthermia, especially in pediatric or adolescent patients.(1-2) Overheating and dehydration can lead to brain damage and death. PREDISPOSING FACTORS: Pediatric and adolescent patients and patients with dehydration may be more likely to experience heat-related disorders.(1) PATIENT MANAGEMENT: The UK and US manufacturers of zonisamide state that caution should be used in adults when zonisamide is prescribed with other medicinal products that predispose to heat-related disorders, such as agents with anticholinergic activity.(1-2) Pediatric and adolescent patients must not take anticholinergic agents (e.g. clomipramine, hydroxyzine, diphenhydramine, haloperidol, imipramine, and oxybutynin) concurrently with zonisamide.(1) Monitor for signs and symptoms of heat stroke: skin feels very hot with little or no sweating, confusion, muscle cramps, rapid heartbeat, or rapid breathing. Monitor for signs and symptoms of dehydration: dry mouth, urinating less than usual, dark-colored urine, dry skin, feeling tired, dizziness, or irritability. If signs or symptoms of dehydration, oligohidrosis, or elevated body temperature occur, discontinuation of zonisamide should be considered. DISCUSSION: Case reports of decreased sweating and elevated temperature have been reported, especially in pediatric patients. Some cases resulted in heat stroke that required hospital treatment and resulted in death.(1) |
ZONEGRAN, ZONISADE, ZONISAMIDE |
| Eluxadoline/Anticholinergics; Opioids SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Eluxadoline is a mixed mu-opioid and kappa-opioid agonist and delta-opioid antagonist and may alter or slow down gastrointestinal transit.(1) CLINICAL EFFECTS: Constipation related adverse events that sometimes required hospitalization have been reported, including the development of intestinal obstruction, intestinal perforation, and fecal impaction.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid use with other drugs that may cause constipation. If concurrent use is necessary, evaluate the patient's bowel function regularly. Monitor for symptoms of constipation and GI hypomotility, including having bowel movements less than three times weekly or less than usual, difficulty having a bowel movement or passing gas, nausea, vomiting, and abdominal pain or distention.(1) Instruct patients to stop eluxadoline and immediately contact their healthcare provider if they experience severe constipation. Loperamide may be used occasionally for acute management of severe diarrhea, but must be discontinued if constipation develops.(1) DISCUSSION: In phase 3 clinical trials, constipation was the most commonly reported adverse reaction (8%). Approximately 50% of constipation events occurred within the first 2 weeks of treatment while the majority occurred within the first 3 months of therapy. Rates of severe constipation were less than 1% in patients receiving eluxadoline doses of 75 mg and 100 mg.(1) |
VIBERZI |
| Alprostadil/Acetaminophen; NSAIDs SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Alprostadil is a prostaglandin E1 product used to maintain patency of a patent ductus arteriosus (PDA).(1) Acetaminophen and nonsteroidal anti-inflammatory (NSAID) agents inhibit prostaglandins and may be used for PDA closure in addition to pain/fever management.(2-4) CLINICAL EFFECTS: Simultaneous administration of acetaminophen or NSAIDs may result in decreased clinical effects from alprostadil, including reduction in PDA.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid concurrent administration of acetaminophen or NSAIDs in patients on alprostadil for maintaining patency of a patent ductus arteriosus (PDA).(1) DISCUSSION: NSAIDs and acetaminophen are used as management for patent ductus arteriosus (PDA) closure.(2-4) Alprostadil is used to maintain patency of a PDA.(1) In a case report, a 37-week gestational age neonate with cardiac defects required alprostadil therapy for PDA patency. After multiple doses of acetaminophen for pain, an echocardiogram showed reduction of the PDA requiring increased doses of alprostadil. Additional acetaminophen was discontinued. Follow up echocardiogram showed successful reversal of PDA reduction and alprostadil dose was reduced.(5) |
ALPROSTADIL, PROSTAGLANDIN E1, PROSTIN VR PEDIATRIC |
| Mixed;Indirect Sympathomimetics/Rasagiline SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Catecholamine stores increased by MAOIs can be released by indirect acting sympathomimetics such as ephedrine and amphetamine. MAO inhibitors also interfere with gut and liver metabolism of direct acting sympathomimetics (e.g oral phenylephrine). CLINICAL EFFECTS: Concurrent use of MAOIs may result in potentiation of sympathomimetic effects, which may result in headaches, hypertensive crisis, toxic neurological effects, and malignant hyperpyrexia. Hypertensive crisis has been reported in patients taking recommended doses of rasagiline with sympathomimetic agents. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: At recommended dosages, rasagiline is selective for MAO-B; however, at higher dosages it has been shown to lose its selectivity. Patients receiving higher dosages of rasagiline should be considered susceptive to this interaction. Concurrent use should be approached with caution. DISCUSSION: Indirect acting sympathomimetic amines may cause abrupt elevation of blood pressure when administered to patients taking monoamine oxidase inhibitors, resulting in a potentially fatal hypertensive crisis. Mixed (direct and indirect) acting sympathomimetics have also been shown to interact with monoamine oxidase inhibitors depending on their degree of indirect action. The direct-acting sympathomimetics have not been reported to interact. Dopamine is metabolized by monoamine oxidase, and its pressor effect is enhanced by monoamine oxidase inhibitors. |
AZILECT, RASAGILINE MESYLATE |
| Glucagon (Diagnostic)/Anticholinergics SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Glucagon and anticholinergic agents may have additive effects on inhibition of gastrointestinal motility.(1) CLINICAL EFFECTS: Concurrent use of glucagon with anticholinergic agents may increase the risk of gastrointestinal hypomotility, including constipation and bowel complications.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of glucagon as a diagnotic aid is not recommended with the use of anticholinergic agents.(1) If concurrent use is necessary, evaluate the patient's bowel function. Monitor for symptoms of constipation and gastrointestinal hypomotility. DISCUSSION: Both glucagon and anticholinergic agents may have additive effects on inhibition of gastrointestinal motility and increase the risk of gastrointestinal adverse effects.(1) |
GLUCAGON HCL |
There are 9 moderate interactions.
The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.
| Drug Interaction | Drug Names |
|---|---|
| Sympathomimetics (Direct, Mixed-Acting)/Guanethidine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Direct or mixed-acting sympathomimetics may inhibit uptake of guanethidine at the adrenergic neuron. CLINICAL EFFECTS: Decreased antihypertensive effectiveness. Effects may be seen for several days after discontinuation of the direct or mixed-acting sympathomimetic. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid concomitant administration of these drugs. If both drugs are administered, adjust the guanethidine dose as needed based on blood pressure. DISCUSSION: Documentation supports routine monitoring of this interaction. It should be noted that this interaction can occur quickly. |
GUANETHIDINE HEMISULFATE |
| Sympathomimetics/Rauwolfia Alkaloids SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Reserpine depletes catecholamine stores within the peripheral vascular adrenergic nerve endings, thus indirect acting sympathomimetics are unable to trigger the release of catecholamines. The reserpine-induced catecholamine release increases sensitivity to the effects of direct acting sympathomimetics. CLINICAL EFFECTS: Increased effects of direct acting sympathomimetics. Decreased effects of indirect acting sympathomimetics. Mixed acting sympathomimetics will show effects based on the predominance of either direct or indirect activity. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: If these agents are administered concurrently, monitor blood pressure. The dose of the sympathomimetic may need to be adjusted. DISCUSSION: This interaction has been well documented in animal studies and human case reports have confirmed the interaction. Reserpine has been shown to decrease the response to epinephrine administered for hypotension. Reserpine has also been shown to decrease the effectiveness of ophthalmic epinephrine, a direct acting sympathomimetic. Ophthalmic phenylephrine has been shown to decrease the hypotensive effects of reserpine. |
RESERPINE |
| Sympathomimetics (Direct, Mixed-Acting)/Methyldopa SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Unknown. CLINICAL EFFECTS: The pressor response to sympathomimetics may be increased. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Start with low doses of sympathomimetics and monitor blood pressure of patients during concurrent administration of sympathomimetics and methyldopa. DISCUSSION: The pressor response to sympathomimetics has been reported to be increased during methyldopa administration. In addition to increased duration of pressor response, severe hypertension has been reported. |
METHYLDOPA, METHYLDOPA-HYDROCHLOROTHIAZIDE, METHYLDOPATE HCL |
| Tamoxifen/Selected Weak CYP2D6 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Inhibitors of CYP2D6 may inhibit the conversion of tamoxifen to endoxifen (an active metabolite of tamoxifen).(1-2) The role of endoxifen in tamoxifen's efficacy has been debated and may involve a minimum concentration level.(3-5) CLINICAL EFFECTS: Concurrent use of inhibitors of CYP2D6 may decrease the effectiveness of tamoxifen in preventing breast cancer recurrence. PREDISPOSING FACTORS: Concurrent use of weak CYP2D6 inhibitors in patients who are CYP2D6 intermediate metabolizers should be avoided. Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6 inhibition. PATIENT MANAGEMENT: Although data on this interaction are conflicting, it may be prudent to use alternatives to CYP2D6 inhibitors when possible in patients taking tamoxifen. The US manufacturer of tamoxifen states that the impact on the efficacy of tamoxifen by strong CYP2D6 inhibitors is uncertain and makes no recommendation regarding coadministration with inhibitors of CYP2D6.(12) The manufacturer of paroxetine (a strong CYP2D6 inhibitor) states that alternative agents with little or no CYP2D6 inhibition should be considered.(13) The National Comprehensive Cancer Network's breast cancer guidelines advises caution when coadministering strong CYP2D6 inhibitors with tamoxifen.(14) If concurrent therapy is warranted, the risks versus benefits should be discussed with the patient. DISCUSSION: Some studies have suggested that administration of fluoxetine, paroxetine, and quinidine with tamoxifen or a CYP2D6 poor metabolizer phenotype may result in a decrease in the formation of endoxifen (an active metabolite of tamoxifen) and a shorter time to breast cancer recurrence.(1-2,9) A retrospective study of 630 breast cancer patients found an increasing risk of breast cancer mortality with increasing durations of coadministration of tamoxifen and paroxetine. In the adjusted analysis, absolute increases of 25%, 50%, and 75% in the proportion of time of overlapping use of tamoxifen with paroxetine was associated with 24%, 54%, and 91% increase in the risk of death from breast cancer, respectively.(16) The CYP2D6 genotype of the patient may have a role in the effects of this interaction. Patients with wild-type CYP2D6 genotype may be affected to a greater extent by this interaction. Patients with a variant CYP2D6 genotype may have lower baseline levels of endoxifen and may be affected to a lesser extent by this interaction.(6-10) In a retrospective review, 1,325 patients treated with tamoxifen for breast cancer were classified as being poor 2D6 metabolizers (lacking functional CYP2D6 enzymes), intermediate metabolizers (heterozygous alleles), or extensive metabolizers (possessing 2 functional alleles). After a mean follow-up period of 6.3 years, the recurrence rates were 14.9%, 20.9%, and 29.0%, in extensive metabolizers, intermediate metabolizers, and poor metabolizers, respectively.(11) In October of 2006, the Advisory Committee Pharmaceutical Science, Clinical Pharmacology Subcommittee of the US Food and Drug Administration recommended that the US tamoxifen labeling be updated to include information about the increased risk of breast cancer recurrence in poor CYP2D6 metabolizers (either by genotype or drug interaction).(17-18) The labeling changes were never made due to ongoing uncertainty about the effects of CYP2D6 genotypes on tamoxifen efficacy. In contrast to the above information, two studies have shown no relationship between CYP2D6 genotype and breast cancer outcome.(19-21) As well, a number of studies found no association between use of CYP2D6 inhibitors and/or antidepressants in patients on tamoxifen and breast cancer recurrence,(22-26) though the studies were limited by problematic selection of CYP2D6 inhibitors and short follow-up. Weak inhibitors of CYP2D6 include: alogliptin, artesunate, celecoxib, cimetidine, clobazam, cobicistat, delavirdine, diltiazem, diphenhydramine, dronabinol, dupilumab, echinacea, fedratinib, felodipine, fluvoxamine, gefitinib, hydralazine, imatinib, labetalol, lorcaserin, nicardipine, osilodrostat, ranitidine, ritonavir, sertraline, verapamil and viloxazine.(27) |
SOLTAMOX, TAMOXIFEN CITRATE |
| Acetaminophen/Isoniazid SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Isoniazid may induce the metabolism of acetaminophen to its toxic N-acetyl-p-benzoquinone imine (NAPQI) metabolite by CYP2E1.(1) CLINICAL EFFECTS: Concurrent isoniazid and acetaminophen may result in hepatotoxicity.(1) Symptoms can include nausea, vomiting, jaundice, dark urine, abdominal pain, and unexplained fatigue. PREDISPOSING FACTORS: The interaction may be more severe in fast acetylators. PATIENT MANAGEMENT: Concurrent use of acetaminophen in patients treated with isoniazid should be approached with caution. Consider an alternative analgesic agent. If concurrent therapy is warranted, advise patients not to exceed the maximum recommended daily dose of acetaminophen and to immediately report any symptoms of hepatotoxicity. DISCUSSION: Isoniazid has been shown to induce, after initially inhibiting, the metabolism of acetaminophen to N-acetyl-p-benzoquinone imine (NAPQI), which is hepatotoxicity. Normally, NAPQI is rapidly converted to non-toxic metabolites by glutathione; however, high levels of NAPQI can overwhelm this system.(2-4) In a case report, a patient receiving isoniazid developed severe acetaminophen toxicity following a suicide attempt, despite only having ingested a maximum of 11.5 grams of acetaminophen and having a blood acetaminophen level of 15 mmol/L 13 hours later. Toxicity is usually seen with levels greater than 26 mmol/L.(5) In a retrospective review of 20 deaths in patients taking isoniazid alone or with ethambutol during a 13 year period, two deaths involved patients receiving concurrent isoniazid and acetaminophen.(6,7) |
ISONIAZID |
| Selected Anticoagulants/Acetaminophen SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Acetaminophen may reduce levels of functional Factor VI, thereby increasing the International Normalized Ratio (INR).(1) In one trial factors II and VII levels were also reduced, thereby increasing the INR. (2) CLINICAL EFFECTS: Concurrent use of routine acetaminophen, especially at dosages greater than 2 grams/day, and coumarin anticoagulants may result in elevated anticoagulant effects. PREDISPOSING FACTORS: Routine use of acetaminophen at dosages greater than 2 grams/day may increase the risk of the interaction. PATIENT MANAGEMENT: Patients receiving routine acetaminophen at dosages greater than 2 grams/day with coumarin anticoagulants should be closely monitored for changes in anticoagulant effects. The dosage of the anticoagulant may need to be adjusted. Patients receiving coumarin anticoagulants should be counseled on the use of acetaminophen. DISCUSSION: A large systematic review was performed on 72 warfarin drug-drug interactions studies that reported on bleeding, thromboembolic events, or death. Most studies were retrospective cohorts. A meta-analysis of 4 of those studies found a higher rate of clinically significant bleeding in patients on warfarin and non-NSAID analgesics (OR=2.12; 95% CI 1.65-2.73). Increased bleeding risk was also seen in subgroup analyses with acetaminophen (OR=2.32; 95% CI 1.22-4.44).(3) In a study in 11 patients maintained on warfarin, use of acetaminophen (4 grams daily for 14 days) increased INR values by an average of 1.04.(4) In a study in 36 patients maintained on warfarin, the addition of acetaminophen (2 grams/day or 4 grams/day) increased INR values.(5) In a study in 20 patients maintained on warfarin, the addition of acetaminophen (4 grams/day for 14 days) increased average INR values by 1.20 (from 2.6 to 3.45).(6) In a study, 12 patients maintained on various anticoagulants (anisindione, dicoumarol, phenprocoumon, and warfarin) who received 4 weeks of acetaminophen (2.6 grams/day) were compared to 50 subjects maintained on various anticoagulants who did not receive acetaminophen. By the third week of concurrent acetaminophen, prothrombin times increased from 23 seconds to 28.4 seconds. The average warfarin-equivalent dose decreased by 5.8 mg to 4.4 mg. In another phase, 50 subjects maintained on various anticoagulants received acetaminophen (2.6 grams/day for 14 days). The mean prothrombin increase was 3.6 seconds.(7) There have been case reports of increased INRs following concurrent acetaminophen in patients maintained on warfarin(8-11) and acenocoumarol.(12) In contrast to the above reports, other studies have found no effects on acenocoumarol,(14) phenprocoumon,(13-15) or warfarin(16,17) by acetaminophen. In a study in 45 patients maintained on warfarin, the addition of acetaminophen (2 or 3 grams/day for 10 days) increased average INR by 0.7 and 0.67 with 2 grams/day and 3 grams/day, respectively. This increase was apparent by day 3, and a decrease in factor II and VII was observed.(2) A self-controlled case study of 1,622 oral anticoagulant-precipitant drug pairs were reviewed and found 14% of drug pairs were associated with a statistically significant elevated risk of thromboembolism. Concurrent use of warfarin and acetaminophen resulted in a ratio of rate ratios (95% CI) of 1.28 (1.18-1.38).(18) One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology. |
DICUMAROL, JANTOVEN, WARFARIN SODIUM |
| Busulfan/Acetaminophen SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Busulfan is eliminated from the body via glutathione conjugation. Acetaminophen reduces glutathione levels in the blood and tissues and therefore could decrease the elimination rate of busulfan.(1,2) CLINICAL EFFECTS: Concurrent use of acetaminophen may result in elevated levels of, prolonged exposure to, and toxicity from busulfan, including myelosuppression, granulocytopenia, thrombocytopenia, anemia, seizures, hepatic veno-occlusive disease, cardiac tamponade, bronchopulmonary dysplasia, or cellular dysplasia.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Use acetaminophen concurrent with busulfan with caution.(1) Consider withholding acetaminophen for 72 hours before and during busulfan therapy. If concurrent use cannot be avoided, monitor patients for busulfan toxicity. DISCUSSION: Although a small population study in adult patients found no effect of acetaminophen on busulfan clearance,(3) caution is still warranted.(1) |
BUSULFAN, BUSULFEX, MYLERAN |
| Metoprolol/Selected CYP2D6 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: CYP2D6 inhibitors may inhibit the metabolism of metoprolol.(1,2) CLINICAL EFFECTS: Concurrent use of CYP2D6 inhibitors may result in elevated levels of and toxicity from metoprolol.(1,2) PREDISPOSING FACTORS: The interaction may be more severe in patients who are ultrarapid metabolizers of CYP2D6,(1,2) elderly,(3) and on higher doses of beta-blockers.(3) PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy with metoprolol and inhibitors of CYP2D6. The dosage of metoprolol may need to be adjusted.(1,2) The effects of rolapitant, a moderate CYP2D6 inhibitor, on CYP2D6 are expected to last at least 28 days after administration.(4) DISCUSSION: In a case report, a patient maintained on metoprolol developed bradycardia following the addition of bupropion.(5) In a study in 20 healthy females, diphenhydramine increased the AUC of metoprolol by 21%. Heart rate reduction increased 29%.(6) In a randomized study in 16 healthy subjects, diphenhydramine decreased metoprolol oral and nonrenal clearance by 2-fold in extensive 2D6 metabolizers. In extensive 2D6 metabolizers, metoprolol-induced effects on heart rate, systolic blood pressure, and aortic blood flow peak velocity were all increased. There were no effects of diphenhydramine in poor metabolizers.(7) Fluoxetine has been shown to inhibit metoprolol metabolism in vitro.(8) There is a case report of severe bradycardia following the addition of fluoxetine to metoprolol.(9) In a 3-way, randomized, cross-over study in healthy subjects, paroxetine (20 mg daily) increased the area-under-curve (AUC) of both S- and R-metoprolol by 3-fold, and 4-fold, respectively, regardless of whether the formulation of metoprolol was immediate release or extended release. Concurrent paroxetine also significantly decreased heart rate and blood pressure when compared to metoprolol alone.(10) In an open-label, randomized, cross-over study in 10 healthy subjects, paroxetine increased the AUC of S-metoprolol and R-metoprolol from an immediate release formulation (50 mg)by 4-fold and 5-fold, respectively. Paroxetine increased the AUC of S-metoprolol and R-metoprolol from an extended release formulation (100 mg) by 3-fold and 4-fold, respectively.(11) In a study in patients with acute myocardial infarction and depression, paroxetine (20 mg daily) increased the AUC of metoprolol 3-fold. Mean heart rate was significantly lower following the addition of paroxetine to metoprolol. Two patients experienced bradycardia and severe orthostatic hypotension.(12) In an open trial in 8 healthy males, paroxetine (20 mg daily) increased the AUC of S-metoprolol and R-metoprolol by 4-fold and 7-fold, respectively.(13) There are case reports of complete atrioventricular block(14) and bradycardia(15) with concurrent metoprolol and paroxetine. A systematic review and meta-analysis of CYP2D6 interactions between metoprolol and either paroxetine or fluoxetine reviewed 9 articles including 4 primary and 2 observational studies as well as 3 case reports. Experimental studies noted paroxetine increased the AUC of metoprolol 3-fold to 5-fold and significantly decreased blood pressure and heart rate. Paroxetine and fluoxetine have shown equipotent inhibitor capacity on CYP2D6. The metabolite, norfluoxetine, is also an inhibitor of CYP2D6.(16) A retrospective cohort study evaluated morbidity in patients on a beta-blocker primarily metabolized by CYP2D6 (e.g., nebivolol, metoprolol, carvedilol, propranolol, labetalol) and started on a strong or moderate CYP2D6-inhibiting antidepressant (e.g., fluoxetine, paroxetine, bupropion, duloxetine). Use of such an antidepressant with a beta-blocker was associated with an increased risk of hospitalization or ED visit due to an adverse hemodynamic event (HR 1.53, 95% CI 1.03-2.81, p=0.04).(3) CYP2D6 inhibitors include: abiraterone, bupropion, celecoxib, cinacalcet, citalopram, dacomitinib, diphenhydramine, duloxetine, escitalopram, fedratinib, fluoxetine, hydroxychloroquine, imatinib, lorcaserin, osilodrostat, paroxetine, ranitidine, ranolazine, rolapitant, and sertraline. One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology. |
KAPSPARGO SPRINKLE, LOPRESSOR, METOPROLOL SUCCINATE, METOPROLOL TARTRATE, METOPROLOL-HYDROCHLOROTHIAZIDE, TOPROL XL |
| Topiramate/Anticholinergics SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Topiramate can cause decreased sweating and elevated body temperature. Agents with anticholinergic activity can predispose patients to heat-related disorders.(1-2) CLINICAL EFFECTS: Concurrent use of topiramate with agents with anticholinergic activity may increase the incidence of oligohidrosis and hyperthermia, especially in pediatric or adolescent patients.(1-2) Overheating and dehydration can lead to brain damage and death. PREDISPOSING FACTORS: Pediatric and adolescent patients and patients with dehydration may be more likely to experience heat-related disorders.(1) PATIENT MANAGEMENT: The manufacturer of topiramate states that caution should be used when topiramate is prescribed with other medicinal products that predispose to heat-related disorders, such as agents with anticholinergic activity (e.g. clomipramine, hydroxyzine, diphenhydramine, haloperidol, imipramine, and oxybutynin) concurrently with zonisamide.(1) Monitor for signs and symptoms of heat stroke: skin feels very hot with little or no sweating, confusion, muscle cramps, rapid heartbeat, or rapid breathing. Monitor for signs and symptoms of dehydration: dry mouth, urinating less than usual, dark-colored urine, dry skin, feeling tired, dizziness, or irritability. If signs or symptoms of dehydration, oligohidrosis, or elevated body temperature occur, discontinuation of zonisamide should be considered. DISCUSSION: Case reports of decreased sweating and elevated temperature have been reported, especially in pediatric patients. Some cases resulted in heat stroke that required hospital treatment.(1) A 64-year old woman developed non-exertional hyperthemia while taking multiple psychiatric medications with topiramate.(2) |
EPRONTIA, QSYMIA, QUDEXY XR, TOPAMAX, TOPIRAMATE, TOPIRAMATE ER, TROKENDI XR |
The following contraindication information is available for COLD & FLU RELIEF (diphenhydramine hcl/phenylephrine hcl/acetaminophen):
Drug contraindication overview.
No enhanced Contraindications information available for this drug.
No enhanced Contraindications information available for this drug.
There are 4 contraindications.
Absolute contraindication.
| Contraindication List |
|---|
| Acetaminophen overdose |
| Acute hepatic failure |
| Acute hepatitis C |
| Severe uncontrolled hypertension |
There are 12 severe contraindications.
Adequate patient monitoring is recommended for safer drug use.
| Severe List |
|---|
| Angle-closure glaucoma |
| Benign prostatic hyperplasia |
| Bladder outflow obstruction |
| Chronic idiopathic constipation |
| Coronary artery disease |
| Disease of liver |
| Hypertension |
| Hyperthyroidism |
| Protein-calorie malnutrition |
| Shock |
| Stenosing peptic ulcer |
| Urinary retention |
There are 4 moderate contraindications.
Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.
| Moderate List |
|---|
| Chronic heart failure |
| Hypertension |
| Hyperthyroidism |
| Ocular hypertension |
The following adverse reaction information is available for COLD & FLU RELIEF (diphenhydramine hcl/phenylephrine hcl/acetaminophen):
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 31 severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
| None. |
Abnormal hepatic function tests |
| Rare/Very Rare |
|---|
|
Acute generalized exanthematous pustulosis Acute hepatic failure Agranulocytosis Allergic dermatitis Anaphylaxis Angioedema Blood dyscrasias Cardiac arrhythmia Dizziness Drug-induced hepatitis Extrasystoles Hallucinations Headache disorder Hemolytic anemia Hyperhidrosis Hypersensitivity drug reaction Hypotension Insomnia Laryngeal edema Leukopenia Maculopapular rash Nervousness Neutropenic disorder Pallor Seizure disorder Stevens-johnson syndrome Tachycardia Thrombocytopenic disorder Toxic epidermal necrolysis Tremor |
There are 54 less severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Anticholinergic toxicity Dizziness Drowsy Thick bronchial secretions |
Abnormal hepatic function tests |
| Rare/Very Rare |
|---|
|
Abdominal distension Accidental fall Acute abdominal pain Acute cognitive impairment Agitation Anorexia Ataxia Blurred vision Chest discomfort Chills Constipation Diarrhea Diplopia Dry nose Dry throat Dyspnea Dysuria Erythema Euphoria Excitement Fatigue Headache disorder Hyperhidrosis Insomnia Irritability Maculopapular rash Malaise Medication overuse headache Migraine Nausea Nervousness Nightmares Palpitations Paresthesia Pruritus of skin Skin photosensitivity Skin rash Symptoms of anxiety Tachycardia Tinnitus Tremor Urinary retention Urticaria Vertigo Visual changes Vomiting Wheezing Xerostomia |
The following precautions are available for COLD & FLU RELIEF (diphenhydramine hcl/phenylephrine hcl/acetaminophen):
No enhanced Pediatric Use information available for this drug.
Contraindicated
Contraindicated
Contraindicated
Severe Precaution
Management or Monitoring Precaution
Contraindicated
| Diphenhydramine (Cough-Cold) | 30 Days – 6 Years | Do not use unless as directed by clinician consultation. Risk of adverse CNS effects include sedation or paradoxical excitation; risk of respiratory depression. |
Contraindicated
| Diphenhydramine (oral) | 1 Day – 29 Days | Possible risk of CNS excitation, convulsions in newborns. |
Contraindicated
| Phenylephrine (oral) | 1 Day – 6 Years | Risk of CNS excitation. Do not use age <6 years without clinician consult. |
Severe Precaution
| None |
Management or Monitoring Precaution
| Acetaminophen (oral,rectal) | 1 Day – 12 Years | Use weight based dosing in children less than 12 years. |
Reproduction studies in rats and rabbits receiving diphenhydramine hydrochloride dosages up to 5 times the recommended human dosage have not revealed evidence of harm to the fetus. However, diphenhydramine has been shown to cross the placenta. In one epidemiologic study, use of bromodiphenhydramine (no longer commercially available) but not diphenhydramine was associated with an increased risk of teratogenic effects.
In another epidemiologic study, there also was no evidence of increased risk of teratogenicity associated with diphenhydramine use during the first trimester, although a modest association could not be ruled out. Use of diphenhydramine during the first trimester of pregnancy has been associated with an increased risk of cleft palate alone or combined with other fetal abnormalities, and the drug has been reported to potentiate the teratogenic effect of morphine in mice. The manufacturers state that there are no adequate and controlled studies to date using diphenhydramine in pregnant women, and the drugs should be used during pregnancy only when clearly needed.
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. It is not known whether phenylephrine hydrochloride can cause fetal harm when administered to pregnant women; the drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Animal studies suggest a potential for adverse cardiovascular effects to the fetus if the drug is administered IV during pregnancy. Administration of phenylephrine to patients in late pregnancy or labor may cause fetal anoxia and bradycardia by increasing contractility of the uterus and decreasing uterine blood flow. In studies of IV phenylephrine in pregnant women undergoing cesarean delivery with neuraxial anesthesia, common adverse effects reported in the mother included nausea and vomiting, bradycardia, reactive hypertension, and transient arrhythmias.
The drug did not appear to affect neonatal Apgar scores or umbilical artery blood-gas status. If a vasopressor is used in conjunction with oxytocic drugs, the vasopressor effect is potentiated and may result in potentially serious adverse effects. (See Drug Interactions: Oxytocic Drugs.)
In another epidemiologic study, there also was no evidence of increased risk of teratogenicity associated with diphenhydramine use during the first trimester, although a modest association could not be ruled out. Use of diphenhydramine during the first trimester of pregnancy has been associated with an increased risk of cleft palate alone or combined with other fetal abnormalities, and the drug has been reported to potentiate the teratogenic effect of morphine in mice. The manufacturers state that there are no adequate and controlled studies to date using diphenhydramine in pregnant women, and the drugs should be used during pregnancy only when clearly needed.
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. It is not known whether phenylephrine hydrochloride can cause fetal harm when administered to pregnant women; the drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Animal studies suggest a potential for adverse cardiovascular effects to the fetus if the drug is administered IV during pregnancy. Administration of phenylephrine to patients in late pregnancy or labor may cause fetal anoxia and bradycardia by increasing contractility of the uterus and decreasing uterine blood flow. In studies of IV phenylephrine in pregnant women undergoing cesarean delivery with neuraxial anesthesia, common adverse effects reported in the mother included nausea and vomiting, bradycardia, reactive hypertension, and transient arrhythmias.
The drug did not appear to affect neonatal Apgar scores or umbilical artery blood-gas status. If a vasopressor is used in conjunction with oxytocic drugs, the vasopressor effect is potentiated and may result in potentially serious adverse effects. (See Drug Interactions: Oxytocic Drugs.)
| Drug/Drug Class | Severity | Precaution Description | Pregnancy Category Description |
|---|---|---|---|
| Acetaminophen | 2 | Available data suggest no known risk; otc product, no fda pregnancy warnings | No fda rating but may have precautions or warnings; may have animal and/or human studies or pre or post marketing information. |
| Phenylephrine | 2 | Insufficient human data available | No fda rating but may have precautions or warnings; may have animal and/or human studies or pre or post marketing information. |
| Diphenhydramine | B | Animal studies have failed to demonstrate a risk to the fetus but there are no well-controlled studies in pregnant women; or animal reproduction studies have shown an adverse effect (other than decrease in fertility), but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus during the first trimester of pregnancy (and there is no evidence of a risk in later trimesters). |
Diphenhydramine has been detected in milk. Because of the potential for serious adverse reactions to antihistamines in nursing infants, a decision should be made whether to discontinue nursing or diphenhydramine, taking into account the importance of the drug to the woman. Acetaminophen is distributed into human milk in small quantities after oral It is not known whether phenylephrine is distributed into human milk administration.
Data from more than 15 nursing women suggest that following parenteral administration. The drug should be used with caution approximately 1-2% of the maternal daily dosage would be ingested by a in nursing women. 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.
Data from more than 15 nursing women suggest that following parenteral administration. The drug should be used with caution approximately 1-2% of the maternal daily dosage would be ingested by a in nursing women. 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 |
|---|---|---|---|
| Diphenhydramine | 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) | Limited data suggest increased drowsiness, and irritability |
| Phenylephrine | 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) | Oral bioavailability low; infant exposure may be minimal |
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 |
| Diphenhydramine | Neuro/Psych-Anticholinergic effects may cause sedation, worsen cognitive impairment and increase fall risk. Maximum of 25mg/day. Cardiovascular-May cause orthostatic hypotension at higher doses. 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 |
| Phenylephrine | 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. | N | N | Y | Y | N | N |
The following prioritized warning is available for COLD & FLU RELIEF (diphenhydramine hcl/phenylephrine hcl/acetaminophen):
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 COLD & FLU RELIEF (diphenhydramine hcl/phenylephrine hcl/acetaminophen)'s list of indications:
| Allergic conjunctivitis | |
| H10.1 | Acute atopic conjunctivitis |
| H10.10 | Acute atopic conjunctivitis, unspecified eye |
| H10.11 | Acute atopic conjunctivitis, right eye |
| H10.12 | Acute atopic conjunctivitis, left eye |
| H10.13 | Acute atopic conjunctivitis, bilateral |
| H10.44 | Vernal conjunctivitis |
| H10.45 | Other chronic allergic conjunctivitis |
| H16.26 | Vernal keratoconjunctivitis, with limbar and corneal involvement |
| H16.261 | Vernal keratoconjunctivitis, with limbar and corneal involvement, right eye |
| H16.262 | Vernal keratoconjunctivitis, with limbar and corneal involvement, left eye |
| H16.263 | Vernal keratoconjunctivitis, with limbar and corneal involvement, bilateral |
| H16.269 | Vernal keratoconjunctivitis, with limbar and corneal involvement, unspecified eye |
| Allergic rhinitis | |
| J30.1 | Allergic rhinitis due to pollen |
| J30.2 | Other seasonal allergic rhinitis |
| J30.5 | Allergic rhinitis due to food |
| J30.8 | Other allergic rhinitis |
| J30.81 | Allergic rhinitis due to animal (cat) (dog) hair and dander |
| J30.89 | Other allergic rhinitis |
| J30.9 | Allergic rhinitis, unspecified |
| Flu-like symptoms | |
| J02.9 | Acute pharyngitis, unspecified |
| R05 | Cough |
| R05.1 | Acute cough |
| R05.2 | Subacute cough |
| R05.9 | Cough, unspecified |
| R09.81 | Nasal congestion |
| R50.9 | Fever, unspecified |
| R53.1 | Weakness |
| R53.81 | Other malaise |
| R53.83 | Other fatigue |
| R68.83 | Chills (without fever) |
| Nasal congestion | |
| R09.81 | Nasal congestion |
| Rhinorrhea | |
| R09.82 | Postnasal drip |
| Sinus headache | |
| R51 | Headache |
| R51.9 | Headache, unspecified |
Formulary Reference Tool