Sleep Aid

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The following indications for SLEEP AID (doxylamine succinate) have been approved by the FDA:

Indications:
Allergic conjunctivitis
Allergic reaction
Allergic rhinitis
Anaphylaxis
Cough
Dermatographic urticaria
Idiopathic parkinsonism
Insomnia
Motion sickness
Nasal congestion
Nausea and vomiting
Nausea
Parkinsonism
Pruritus of skin
Rhinorrhea
Sneezing
Urticaria
Vertigo
Vomiting

Professional Synonyms:
Agrypnia
Ahypnia
Allergy eye itch
Anaphylactic reaction
Atopic conjunctivitis
Autographism
Cnidosis
Dermatography
Dermographia
Dermographism
Dermography
Ebbecke's reaction
Emesis
Factitious urticaria
Itching wheals
Itchy eyes due to allergies
Itchy skin eruption
Nasal stuffiness
Nettle rash
Ocular itching due to allergies
Paralysis agitans
Primary Parkinson's disease
Pruritic dermatitis
Queasy
Riders' vertigo
Severe type I hypersensitivity reaction
Skin writing
Trembling palsy
Uredo
Urticaria factitia
Urticarial rash
Urtication
Vomit
Weal

The following dosing information is available for SLEEP AID (doxylamine succinate):

Dosing
Administration
SLEEP AID
DIPHENHYDRAMINE HCL

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.

When diphenhydramine was available only by prescription, the prescribing information for the drug indicated a usual oral diphenhydramine hydrochloride dosage for children weighing more than 9.1 kg of 12.5-25 mg 3 or 4 times daily at 4- to 6-hour intervals and for children weighing 9.1

kg or less an oral diphenhydramine hydrochloride dosage of 6.25-12.5 mg 3 or 4 times daily at 4- to 6-hour intervals.

However, these dosage recommendations are not included in the current labeling of nonprescription oral diphenhydramine preparations, and clinicians should use caution when considering use of nonprescription oral diphenhydramine in children younger than 4 years of age. (See Cautions: Pediatric Precautions.)

Alternatively, for oral, deep IM, or IV therapy, children (other than premature or full-term neonates) may be given 5 mg/kg daily or 150 mg/m2 daily divided in 4 doses; some experts recommend a dosage of 1-2 mg/kg daily. The rate of IV administration should not exceed 25 mg/minute.

The maximum oral, IM, or IV dosage of diphenhydramine hydrochloride in children older than 1 month of age is 300 mg daily.

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.

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.) Doxylamine succinate is administered orally. The fixed combination of doxylamine/pyridoxine delayed-release Diclegis(R) and extended-release Bonjesta(R) tablets should be taken on an empty stomach with a glass of water; the tablets should be swallowed whole and should not be crushed, chewed, or split.

Dosing information for SLEEP AID
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
SLEEP AID 25 MG CAPLET	Maintenance	Adults take 1 tablet (25 mg) by oral route every 4-6 hours as needed

Generic dosing information for DIPHENHYDRAMINE HCL
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
DIPHENHYDRAMINE 25 MG CAPLET	Maintenance	Adults take 1 tablet (25 mg) by oral route every 4-6 hours as needed

The following drug interaction information is available for SLEEP AID (doxylamine succinate):

Contraindicated
Severe
Moderate

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
Selected Antihistamines/Selected 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: MAOIs prolong and intensify the effects of antihistamines.(1-6) CLINICAL EFFECTS: Concurrent use of antihistamines and a MAOI may result in severe hypotension.(1-6) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of antihistamines and a MAOI is contraindicated.(1-6) DISCUSSION: MAOIs may prolong and intensify the effects of antihistamines, resulting in severe hypotension.(1-6) A case report describes a patient having cyproheptadine added to their phenelzine therapy in an attempt to relieve the patients anorgasmia. The patient began to suddenly experience visual hallucination after taking the cyproheptadine for two months. Once the medication was terminated, the hallucinations stopped occurring within 48 hours.(7) Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A.(8,9)	AZILECT, EMSAM, FURAZOLIDONE, MARPLAN, MATULANE, METHYLENE BLUE, NARDIL, PARNATE, PHENELZINE SULFATE, PROCARBAZINE HCL, PROVAYBLUE, RASAGILINE MESYLATE, SELEGILINE HCL, TRANYLCYPROMINE SULFATE, XADAGO, ZELAPAR

Drug Interaction

Drug Names

Selected Antihistamines/Selected 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: MAOIs prolong and intensify the effects of antihistamines.(1-6)

CLINICAL EFFECTS: Concurrent use of antihistamines and a MAOI may result in severe hypotension.(1-6)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of antihistamines and a MAOI is contraindicated.(1-6)

DISCUSSION: MAOIs may prolong and intensify the effects of antihistamines, resulting in severe hypotension.(1-6) A case report describes a patient having cyproheptadine added to their phenelzine therapy in an attempt to relieve the patients anorgasmia. The patient began to suddenly experience visual hallucination after taking the cyproheptadine for two months.

Once the medication was terminated, the hallucinations stopped occurring within 48 hours.(7) Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A.(8,9)

AZILECT, EMSAM, FURAZOLIDONE, MARPLAN, MATULANE, METHYLENE BLUE, NARDIL, PARNATE, PHENELZINE SULFATE, PROCARBAZINE HCL, PROVAYBLUE, RASAGILINE MESYLATE, SELEGILINE HCL, TRANYLCYPROMINE SULFATE, XADAGO, ZELAPAR

There are 5 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
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)	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
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
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
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 6 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
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, dimenhydrinate, diphenhydramine, dronabinol, dupilumab, echinacea, enasidenib, fedratinib, felodipine, fluvoxamine, gefitinib, hydralazine, imatinib, labetalol, lorcaserin, nicardipine, osilodrostat, ranitidine, ritonavir, sertraline, verapamil and viloxazine.(27)	SOLTAMOX, TAMOXIFEN CITRATE
Eliglustat/Weak CYP2D6 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. 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, dimenhydrinate, diphenhydramine, dronabinol, dupilumab, echinacea, enasidenib, felodipine, gefitinib, hydralazine, hydroxychloroquine, lorcaserin, methadone, panobinostat, propafenone, sertraline, vemurafenib, and venlafaxine.(3,4)	CERDELGA
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, dimenhydrinate, 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
Zonisamide/Anticholinergics SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. 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
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
Propranolol/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 propranolol.(1) CLINICAL EFFECTS: Concurrent use of CYP2D6 inhibitors may result in elevated levels of and toxicity from propranolol, including hypotension and bradycardia.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy with propranolol and CYP2D6 inhibitors. The dosage of propranolol may need to be adjusted.(1) DISCUSSION: In a pharmacokinetic study in 16 healthy volunteers, concurrent use of quinidine 200 mg (a CYP2D6 inhibitor) increased the area-under-curve (AUC) of propranolol by 2.29-fold.(2) In a pharmacokinetic study in 6 healthy subjects, concurrent use of quinidine increased propranolol AUC 2-fold.(3) A retrospective review of concurrent use of propranolol and antidepressants evaluated the risk of hospitalization or emergency room visit within 30 days of concurrent prescription. In patients receiving antidepressants with moderate to strong CYP2D6 inhibitory effects, patient were an increased risk compared to patients receiving no antidepressants (Hazard Ratio (HR) = 1.53; 95% CI 1.03-2.81 vs. HR = 1.24; 95% CI 0.82-1.88).(4) Case reports of bradycardia and cardiac adverse effects have been reported with concurrent use of propranolol and the antidepressants fluoxetine and paroxetine (strong CYP2D6 inhibitors).(5) Strong CYP2D6 inhibitors include: bupropion, dacomitinib, fluoxetine, mavorixafor, and paroxetine. Moderate CYP2D6 inhibitors include: abiraterone, asunaprevir, berotralstat, capivasertib, cinacalcet, duloxetine, eliglustat, escitalopram, lorcaserin, mirabegron, moclobemide, quinine, ranolazine, and rolapitant. Weak CYP2D6 inhibitors include: celecoxib, desvenlafaxine, diphenhydramine, dimenhydrinate, dronabinol, fedratinib, hydroxychloroquine, imatinib, osilodrostat, ranitidine, and sertraline.(6)	HEMANGEOL, INDERAL LA, INDERAL XL, INNOPRAN XL, PROPRANOLOL HCL, PROPRANOLOL HCL ER, PROPRANOLOL-HYDROCHLOROTHIAZID

The following contraindication information is available for SLEEP AID (doxylamine succinate):

Overview
Contraindicated
Severe
Moderate

Drug contraindication overview.

Doxylamine succinate is contraindicated in patients with known hypersensitivity to doxylamine, other ethanolamine derivative antihistamines, or any ingredient in the formulation. Doxylamine in fixed combination with pyridoxine is contraindicated in patients receiving monoamine oxidase (MAO) inhibitors.

There are 0 contraindications.

There are 6 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
Stenosing peptic ulcer
Urinary retention

There are 6 moderate contraindications. Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.

Moderate List
Coronary artery disease
Hypertension
Hyperthyroidism
Ocular hypertension
Pyloroduodenal obstruction
Seizure disorder

The following adverse reaction information is available for SLEEP AID (doxylamine succinate):

Overview
Severe
Less Severe

Adverse reaction overview.

No enhanced Common Adverse Effects information available for this drug.

There are 8 severe adverse reactions.

More Frequent	Less Frequent
None.	None.

Rare/Very Rare
Anaphylaxis Blood dyscrasias Extrasystoles Hallucinations Hemolytic anemia Hypersensitivity drug reaction Hypotension Seizure disorder

There are 52 less severe adverse reactions.

More Frequent	Less Frequent
Anticholinergic toxicity Dizziness Drowsy Thick bronchial secretions	Muscle weakness Sedation

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 Euphoria Excitement Fatigue Headache disorder Hyperhidrosis Insomnia Irritability Maculopapular rash Malaise 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

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
Euphoria
Excitement
Fatigue
Headache disorder
Hyperhidrosis
Insomnia
Irritability
Maculopapular rash
Malaise
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 SLEEP AID (doxylamine succinate):

Pediatric
Pregnant
Lactation
Geriatric

No enhanced Pediatric Use information available for this drug.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None

Doxylamine succinate in fixed combination with pyridoxine hydrochloride is intended for use in the management of nausea and vomiting of pregnancy. Numerous epidemiologic studies (including cohort studies, case-control studies, and meta-analyses) have been performed to investigate possible teratogenic effects of doxylamine in fixed combination with pyridoxine in pregnant women. A meta-analysis of 16 cohort and 11 case-control studies published between 1963 and 1991 reported no increased risk for malformations from first trimester exposures to doxylamine succinate and pyridoxine hydrochloride in fixed combination, with or without dicyclomine hydrochloride (a drug included in a combination product that was previously commercially available for nausea and vomiting of pregnancy).

Another meta-analysis of 12 cohort and 5 case-control studies published between 1963 and 1985 reported no clinically important associations between fetal abnormalities and first trimester exposure to doxylamine succinate and pyridoxine hydrochloride with or without dicyclomine hydrochloride. A reanalysis of data from another meta-analysis supporting the safety of doxylamine during pregnancy found that the strength of the data had been overstated, both in terms of the numbers of patients exposed to doxylamine succinate and the reported odds ratio, which suggested a potential protective effect of antihistamines with regard to fetal malformations. However, the reanalysis did not find evidence of an increased risk of fetal malformations associated with doxylamine use.

Historically, there was considerable controversy regarding the teratogenic potential, if any, of doxylamine; however, after evaluating extensive data and information concerning the possible teratogenicity of the drug, FDA concluded that it is unlikely that doxylamine is teratogenic. FDA recognized, however, that despite the large number of pregnancies evaluated to date the possibility that doxylamine may be weakly teratogenic cannot be excluded. Doxylamine was commercially available in the US for the treatment of nausea and vomiting associated with pregnancy in combination with dicyclomine and pyridoxine until 1976, and then in combination with only pyridoxine until 1983 when the manufacturer voluntarily discontinued manufacturing and distributing the combination.

FDA stated that the removal of products containing doxylamine and pyridoxine that previously were commercially available for the management of nausea and vomiting of pregnancy was not for reasons of safety or effectiveness. Most epidemiologic studies (case-control and cohort) in which fixed combinations of doxylamine and pyridoxine with or without dicyclomine were used during pregnancy indicate that an association between use of these combinations and adverse fetal effects does not appear to exist. In a few studies, a weak association between use of the fixed combinations during pregnancy and specific fetal abnormalities (e.g., pyloric stenosis, cardiac defects, oral clefts) was reported, but a causal relationship with the drugs was not established and these findings have not been confirmed by many other studies.

Women considering self-medication with doxylamine during pregnancy should consult a health professional for advice regarding the relative risks and benefits of such therapy. Most reproduction studies in various animal species using doxylamine and pyridoxine alone or in fixed combination have not revealed evidence of harm to the fetus. Studies in rats and mice using doxylamine succinate dosages up to 125 times the maximum human dosage did not reveal evidence of observable congenital abnormalities, but wavy ribs and diaphragmatic hernias occurred in rats at dosages 125-375 times the maximum human dosage; an overall increase in fetal wastage, varying from zero to threefold, occurred in most rodents receiving dosages 125 or more times greater than the maximum human dosage.

Once daily administration of doxylamine succinate and pyridoxine hydrochloride in pregnant rats during organogenesis (gestational day 6-15) resulted in increased fetal resorptions, decreased fetal body weight, and increased skeletal variations with reduced ossification at dosages 60-100 times the highest clinical dosage based on body surface area. In a study in pregnant cynomolgus monkeys receiving doxylamine succinate and pyridoxine hydrochloride once daily during organogenesis (gestational day 22-50) at dosages up to 3.2 times the highest proposed clinical dosage based on body surface area, there were no observed malformations and no evidence of embryo, fetal, or maternal toxicity.

In another study in pregnant cynomolgus and rhesus monkeys and baboons receiving doxylamine succinate and pyridoxine hydrochloride at dosages 0.5-20 times higher than the clinical dosage based on body surface area, ventricular septal defects were observed in preterm (gestational day 100) fetuses; no relationship between dosage and incidence of ventricular septal defects was observed, and no ventricular septal defects were observed in infant monkeys at term. In addition, no ventricular septal defects were observed at gestational day 100 in cynomolgus monkeys administered the combination of doxylamine succinate and pyridoxine hydrochloride for 4-day periods between 22 and 41 days of gestation.

In a small study in monkeys receiving a fixed combination of doxylamine succinate and pyridoxine hydrochloride throughout fetal organogenesis at dosages 10-20 times the maximum human dosage, intraventricular septal defects were present in 4 of 7 fetuses delivered on day 100 of gestation (full-term gestation is about 160 days), while 2 fetuses aborted on the 46th and 56th day of gestation appeared to be developing normally and 3 other fetuses allowed to develop to term were normal. The importance of septal defects in these monkeys is not known, since an opening in the septum is usually present early during fetal development in monkeys. In other studies in monkeys receiving the fixed combination for shorter periods of time, there was no evidence of fetal toxicity.

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.

Doxylamine succinate is expected to be distributed into human milk, because of its low molecular weight. Adverse effects (e.g., excitement, irritability, and sedation) have been reported in infants presumably exposed to doxylamine through human milk. Infants with apnea or other respiratory syndromes may be particularly vulnerable to the sedative effects of doxylamine.

Because of the potential for serious adverse reactions to antihistamines in nursing infants, a decision should be made whether to discontinue nursing or doxylamine, taking into account the importance of the drug to the woman. The manufacturer of doxylamine/pyridoxine in fixed combination states that this preparation should notbe used in nursing women. 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.

No enhanced Geriatric Use information available for this drug.

The following icd codes are available for SLEEP AID (doxylamine succinate)'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 reaction
T78.40	Allergy, unspecified
T78.40xA	Allergy, unspecified, initial encounter
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
Anaphylaxis
T78.0	Anaphylactic reaction due to food
T78.00	Anaphylactic reaction due to unspecified food
T78.00xA	Anaphylactic reaction due to unspecified food, initial encounter
T78.01	Anaphylactic reaction due to peanuts
T78.01xA	Anaphylactic reaction due to peanuts, initial encounter
T78.02	Anaphylactic reaction due to shellfish (crustaceans)
T78.02xA	Anaphylactic reaction due to shellfish (crustaceans), initial encounter
T78.03	Anaphylactic reaction due to other fish
T78.03xA	Anaphylactic reaction due to other fish, initial encounter
T78.04	Anaphylactic reaction due to fruits and vegetables
T78.04xA	Anaphylactic reaction due to fruits and vegetables, initial encounter
T78.05	Anaphylactic reaction due to tree nuts and seeds
T78.05xA	Anaphylactic reaction due to tree nuts and seeds, initial encounter
T78.06	Anaphylactic reaction due to food additives
T78.06xA	Anaphylactic reaction due to food additives, initial encounter
T78.07	Anaphylactic reaction due to milk and dairy products
T78.07xA	Anaphylactic reaction due to milk and dairy products, initial encounter
T78.08	Anaphylactic reaction due to eggs
T78.08xA	Anaphylactic reaction due to eggs, initial encounter
T78.09	Anaphylactic reaction due to other food products
T78.09xA	Anaphylactic reaction due to other food products, initial encounter
T78.2	Anaphylactic shock, unspecified
T78.2xxA	Anaphylactic shock, unspecified, initial encounter
T80.5	Anaphylactic reaction due to serum
T80.51	Anaphylactic reaction due to administration of blood and blood products
T80.51xA	Anaphylactic reaction due to administration of blood and blood products, initial encounter
T80.52	Anaphylactic reaction due to vaccination
T80.52xA	Anaphylactic reaction due to vaccination, initial encounter
T80.59	Anaphylactic reaction due to other serum
T80.59xA	Anaphylactic reaction due to other serum, initial encounter
T88.6	Anaphylactic reaction due to adverse effect of correct drug or medicament properly administered
T88.6xxA	Anaphylactic reaction due to adverse effect of correct drug or medicament properly administered, initial encounter
Cough
R05	Cough
R05.1	Acute cough
R05.2	Subacute cough
R05.3	Chronic cough
R05.9	Cough, unspecified
Dermatographic urticaria
L50.3	Dermatographic urticaria
Idiopathic parkinsonism
G20	Parkinson's disease
G20.A	Parkinson's disease without dyskinesia
G20.A1	Parkinson's disease without dyskinesia, without mention of fluctuations
G20.A2	Parkinson's disease without dyskinesia, with fluctuations
G20.B	Parkinson's disease with dyskinesia
G20.B1	Parkinson's disease with dyskinesia, without mention of fluctuations
G20.B2	Parkinson's disease with dyskinesia, with fluctuations
G20.C	Parkinsonism, unspecified
Insomnia
F51.0	Insomnia not due to a substance or known physiological condition
F51.01	Primary insomnia
F51.02	Adjustment insomnia
F51.03	Paradoxical insomnia
F51.04	Psychophysiologic insomnia
F51.05	Insomnia due to other mental disorder
F51.09	Other insomnia not due to a substance or known physiological condition
G47.0	Insomnia
G47.00	Insomnia, unspecified
G47.01	Insomnia due to medical condition
G47.09	Other insomnia
Motion sickness
T75.3xxA	Motion sickness, initial encounter
Nasal congestion
R09.81	Nasal congestion
Nausea
R11	Nausea and vomiting
R11.0	Nausea
R11.2	Nausea with vomiting, unspecified
Nausea and vomiting
R11	Nausea and vomiting
R11.2	Nausea with vomiting, unspecified
Parkinsonism
G20	Parkinson's disease
G20.A	Parkinson's disease without dyskinesia
G20.A1	Parkinson's disease without dyskinesia, without mention of fluctuations
G20.A2	Parkinson's disease without dyskinesia, with fluctuations
G20.B	Parkinson's disease with dyskinesia
G20.B1	Parkinson's disease with dyskinesia, without mention of fluctuations
G20.B2	Parkinson's disease with dyskinesia, with fluctuations
G20.C	Parkinsonism, unspecified
G21	Secondary parkinsonism
G21.2	Secondary parkinsonism due to other external agents
G21.3	Postencephalitic parkinsonism
G21.4	Vascular parkinsonism
G21.8	Other secondary parkinsonism
G21.9	Secondary parkinsonism, unspecified
Pruritus of skin
L29.8	Other pruritus
L29.81	Cholestatic pruritus
L29.89	Other pruritus
L29.9	Pruritus, unspecified
Rhinorrhea
R09.82	Postnasal drip
Sneezing
R06.7	Sneezing
Urticaria
L50	Urticaria
L50.0	Allergic urticaria
L50.1	Idiopathic urticaria
L50.2	Urticaria due to cold and heat
L50.3	Dermatographic urticaria
L50.4	Vibratory urticaria
L50.5	Cholinergic urticaria
L50.6	Contact urticaria
L50.8	Other urticaria
L50.9	Urticaria, unspecified
L56.3	Solar urticaria
O26.86	Pruritic urticarial papules and plaques of pregnancy (PUPPp)
Vertigo
A88.1	Epidemic vertigo
H81.1	Benign paroxysmal vertigo
H81.10	Benign paroxysmal vertigo, unspecified ear
H81.11	Benign paroxysmal vertigo, right ear
H81.12	Benign paroxysmal vertigo, left ear
H81.13	Benign paroxysmal vertigo, bilateral
H81.2	Vestibular neuronitis
H81.20	Vestibular neuronitis, unspecified ear
H81.21	Vestibular neuronitis, right ear
H81.22	Vestibular neuronitis, left ear
H81.23	Vestibular neuronitis, bilateral
H81.3	Other peripheral vertigo
H81.31	Aural vertigo
H81.311	Aural vertigo, right ear
H81.312	Aural vertigo, left ear
H81.313	Aural vertigo, bilateral
H81.319	Aural vertigo, unspecified ear
H81.39	Other peripheral vertigo
H81.391	Other peripheral vertigo, right ear
H81.392	Other peripheral vertigo, left ear
H81.393	Other peripheral vertigo, bilateral
H81.399	Other peripheral vertigo, unspecified ear
H81.4	Vertigo of central origin
H82	Vertiginous syndromes in diseases classified elsewhere
H82.1	Vertiginous syndromes in diseases classified elsewhere, right ear
H82.2	Vertiginous syndromes in diseases classified elsewhere, left ear
H82.3	Vertiginous syndromes in diseases classified elsewhere, bilateral
H82.9	Vertiginous syndromes in diseases classified elsewhere, unspecified ear
R42	Dizziness and giddiness
T75.23	Vertigo from infrasound
T75.23xA	Vertigo from infrasound, initial encounter
Vomiting
K91.0	Vomiting following gastrointestinal surgery
R11	Nausea and vomiting
R11.1	Vomiting
R11.10	Vomiting, unspecified
R11.11	Vomiting without nausea
R11.12	Projectile vomiting
R11.13	Vomiting of fecal matter
R11.14	Bilious vomiting
R11.15	Cyclical vomiting syndrome unrelated to migraine
R11.2	Nausea with vomiting, unspecified