Monday, May 17, 2010

Acetic acid

MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Acetic acid for irrigation may be confused with glacial acetic acid
VoSol® may be confused with Vexol®

PHARMACOLOGIC CATEGORY
Otic Agent, Anti-infective
Topical Skin Product

DOSING: ADULTS
Irrigation (Note: Dosage of an irrigating solution depends on the capacity or surface area of the structure being irrigated):
For continuous irrigation of the urinary bladder with 0.25% acetic acid irrigation, the rate of administration will approximate the rate of urine flow; usually 500-1500 mL/24 hours
For periodic irrigation of an indwelling urinary catheter to maintain patency, about 50 mL of 0.25% acetic acid irrigation is required

Otitis externa: Otic: Insert saturated wick; keep moist 24 hours; remove wick and instill 5 drops 3-4 times/day

DOSING: ELDERLY — Refer to adult dosing.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution for irrigation: 0.25% (250 mL, 500 mL, 1000 mL)

Solution, otic: 2% (15 mL)

DOSAGE FORMS: CONCISE
Solution for irrigation: 0.25% (250 mL, 500 mL, 1000 mL)

Solution, otic: 2% (15 mL)

GENERIC EQUIVALENT AVAILABLE — Yes

ADMINISTRATION — Not for internal intake or I.V. infusion; topical use or irrigation use only.

USE — Irrigation of the bladder; treatment of superficial bacterial infections of the external auditory canal

ADVERSE REACTIONS SIGNIFICANT — <1% (Limited to important or life-threatening): Hematuria, systemic acidosis, urologic pain

CONTRAINDICATIONS — Hypersensitivity to acetic acid or any component of the formulation; during transurethral procedures

WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Acidosis: Systemic acidosis may result from absorption. Bladder irritation: Use of irrigation in patients with mucosal lesions of urinary bladder may cause irritation.

Other warnings/precautions: Administration: Not for internal intake or I.V. infusion; topical use or irrigation use only.

DRUG INTERACTIONS — There are no known significant interactions.

PREGNANCY RISK FACTOR — C (show table)

INTERNATIONAL BRAND NAMES — Aquaear (AU); Earcalm (GB, IE); Suym Otico (PE)

Acetic acid

MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Acetic acid for irrigation may be confused with glacial acetic acid
VoSol® may be confused with Vexol®

PHARMACOLOGIC CATEGORY
Otic Agent, Anti-infective
Topical Skin Product

DOSING: ADULTS
Irrigation (Note: Dosage of an irrigating solution depends on the capacity or surface area of the structure being irrigated):
For continuous irrigation of the urinary bladder with 0.25% acetic acid irrigation, the rate of administration will approximate the rate of urine flow; usually 500-1500 mL/24 hours
For periodic irrigation of an indwelling urinary catheter to maintain patency, about 50 mL of 0.25% acetic acid irrigation is required

Otitis externa: Otic: Insert saturated wick; keep moist 24 hours; remove wick and instill 5 drops 3-4 times/day

DOSING: ELDERLY — Refer to adult dosing.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution for irrigation: 0.25% (250 mL, 500 mL, 1000 mL)

Solution, otic: 2% (15 mL)

DOSAGE FORMS: CONCISE
Solution for irrigation: 0.25% (250 mL, 500 mL, 1000 mL)

Solution, otic: 2% (15 mL)

GENERIC EQUIVALENT AVAILABLE — Yes

ADMINISTRATION — Not for internal intake or I.V. infusion; topical use or irrigation use only.

USE — Irrigation of the bladder; treatment of superficial bacterial infections of the external auditory canal

ADVERSE REACTIONS SIGNIFICANT — <1% (Limited to important or life-threatening): Hematuria, systemic acidosis, urologic pain

CONTRAINDICATIONS — Hypersensitivity to acetic acid or any component of the formulation; during transurethral procedures

WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Acidosis: Systemic acidosis may result from absorption. Bladder irritation: Use of irrigation in patients with mucosal lesions of urinary bladder may cause irritation.

Other warnings/precautions: Administration: Not for internal intake or I.V. infusion; topical use or irrigation use only.

DRUG INTERACTIONS — There are no known significant interactions.

PREGNANCY RISK FACTOR — C (show table)

INTERNATIONAL BRAND NAMES — Aquaear (AU); Earcalm (GB, IE); Suym Otico (PE)

Acetazolamide

MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
AcetaZOLAMIDE may be confused with acetoHEXAMIDE
Diamox® Sequels® may be confused with Diabinese®, Dobutrex®, Trimox®

U.S. BRAND NAMES — Diamox® Sequels®

PHARMACOLOGIC CATEGORY
Anticonvulsant, Miscellaneous
Carbonic Anhydrase Inhibitor
Diuretic, Carbonic Anhydrase Inhibitor
Ophthalmic Agent, Antiglaucoma

DOSING: ADULTS — Note: I.M. administration is not recommended.

Glaucoma:
Chronic simple (open-angle): Oral: 250 mg 1-4 times/day or 500 mg extended release capsule twice daily
Secondary, acute (closed-angle): I.V.: 250-500 mg, may repeat in 2-4 hours to a maximum of 1 g/day

Edema: Oral, I.V.: 250-375 mg once daily

Epilepsy: Oral: 8-30 mg/kg/day in 1-4 divided doses, not to exceed 1 g/day. Note: Extended release capsule is not recommended for treatment of epilepsy.

Metabolic alkalosis (unlabeled use): I.V. 250 mg every 6 hours for 4 doses or 500 mg single dose; reassess need based upon acid-base status

Mountain sickness: Oral: 250 mg every 8-12 hours (or 500 mg extended release capsules every 12-24 hours). Therapy should begin 24-48 hours before and continue during ascent and for at least 48 hours after arrival at the high altitude.
Note: In situations of rapid ascent (such as rescue or military operations), 1000 mg/day is recommended.

Urine alkalinization (unlabeled use): Oral: 5 mg/kg/dose repeated 2-3 times over 24 hours

Respiratory stimulant in COPD (unlabeled use): Oral, I.V.: 250 mg twice daily

DOSING: PEDIATRIC — Note: I.M. administration is not recommended.

(For additional information see "Acetazolamide: Pediatric drug information")

Glaucoma:
Oral: 8-30 mg/kg/day or 300-900 mg/m2/day divided every 8 hours
I.V.: 20-40 mg/kg/24 hours divided every 6 hours, not to exceed 1 g/day

Edema: Oral, I.V.: 5 mg/kg or 150 mg/m2 once every day

Epilepsy: Oral: Refer to adult dosing.

DOSING: ELDERLY — Oral: Initial: 250 mg once or twice daily; use lowest effective dose possible.

DOSING: RENAL IMPAIRMENT
Clcr 10-50 mL/minute: Administer every 12 hours.

Clcr <10 mL/minute: Avoid use (ineffective).

Moderately dialyzable (20% to 50%)

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, extended release: 500 mg
Diamox® Sequels®: 500 mg

Injection, powder for reconstitution: 500 mg

Tablet: 125 mg, 250 mg

DOSAGE FORMS: CONCISE
Capsule, extended release: 500 mg
Diamox® Sequels®: 500 mg

Injection, powder for reconstitution: 500 mg

Tablet: 125 mg, 250 mg

GENERIC EQUIVALENT AVAILABLE — Yes

ADMINISTRATION
Oral: May cause an alteration in taste, especially carbonated beverages. Short-acting tablets may be crushed and suspended in cherry or chocolate syrup to disguise the bitter taste of the drug; do not use fruit juices. Alternatively, submerge tablet in 10 mL of hot water and add 10 mL honey or syrup.

I.M.: I.M. administration is painful because of the alkaline pH of the drug; use by this route is not recommended.

I.V.: No specific guidance given by manufacturer, but I.V. push at a rate of up to 500 mg over 3 minutes has been reported in a clinical trial (Mazur, 1999); a study to assess cerebrovascular reserve has used rapid I.V. push of up to 1 g over ≤ 1 minute (Piepgras, 1990)

COMPATIBILITY — Stable in dextran 6% in D5W, dextran 6% in NS, D5LR, D5NS, D51/2NS, D51/4NS, D5W, D10W, LR, NS, 1/2NS.

Y-site administration: Variable (consult detailed reference): Diltiazem, TPN.

Compatibility when admixed: Compatible: Cimetidine, ranitidine. Incompatible: Multivitamins.

USE — Treatment of glaucoma (chronic simple open-angle, secondary glaucoma, preoperatively in acute angle-closure); drug-induced edema or edema due to congestive heart failure (adjunctive therapy); centrencephalic epilepsies (immediate release dosage form); prevention or amelioration of symptoms associated with acute mountain sickness

USE - UNLABELED / INVESTIGATIONAL — Metabolic alkalosis; respiratory stimulant in COPD; urine alkalinization

ADVERSE REACTIONS SIGNIFICANT — Frequency not defined.

Cardiovascular: Flushing

Central nervous system: Ataxia, confusion, convulsions, depression, dizziness, drowsiness, excitement, fatigue, fever, headache, malaise

Dermatologic: Allergic skin reactions, photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria

Endocrine & metabolic: Electrolyte imbalance, growth retardation (children), hyperglycemia, hypoglycemia, hypokalemia, hyponatremia, metabolic acidosis

Gastrointestinal: Appetite decreased, diarrhea, melena, nausea, taste alteration, vomiting

Genitourinary: Crystalluria, glycosuria, hematuria, polyuria, renal failure

Hematologic: Agranulocytosis, aplastic anemia, leukopenia, thrombocytopenia, thrombocytopenic purpura

Hepatic: Cholestatic jaundice, fulminant hepatic necrosis, hepatic insufficiency, liver function tests abnormal

Local: Pain at injection site

Neuromuscular & skeletal: Flaccid paralysis, paresthesia

Ocular: Myopia

Otic: Hearing disturbance, tinnitus

Miscellaneous: Anaphylaxis

CONTRAINDICATIONS — Hypersensitivity to acetazolamide, sulfonamides, or any component of the formulation; hepatic disease or insufficiency; decreased sodium and/or potassium levels; adrenocortical insufficiency, cirrhosis; hyperchloremic acidosis, severe renal disease or dysfunction; severe pulmonary obstruction; long-term use in noncongestive angle-closure glaucoma

WARNINGS / PRECAUTIONS
Concerns related to adverse effects: CNS effects: Impairment of mental alertness and/or physical coordination may occur. Sulfa allergy: Chemical similarities are present among sulfonamides, sulfonylureas, carbonic anhydrase inhibitors, thiazides, and loop diuretics (except ethacrynic acid). Use in patients with sulfonylurea allergy is specifically contraindicated in product labeling, however, a risk of cross-reaction exists in patients with allergy to any of these compounds; avoid use when previous reaction has been severe. Discontinue if signs of hypersensitivity are noted.

Disease-related concerns: Diabetes: Use with caution in patients with prediabetes or diabetes mellitus; may see a change in glucose control. Hepatic impairment: Use with caution in patients with hepatic dysfunction; in cirrhosis, avoid electrolyte and acid/base imbalances that might lead to hepatic encephalopathy. Respiratory acidosis: Use with caution in patients with respiratory acidosis.

Special populations: Elderly: Use with caution in the elderly; may be more sensitive to side effects.

Other warnings/precautions: I.M. administration: Painful because of the alkaline pH of the drug; use by this route is not recommended.

METABOLISM / TRANSPORT EFFECTS — Inhibits CYP3A4 (weak)

DRUG INTERACTIONS
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Alpha-/Beta-Agonists: Carbonic Anhydrase Inhibitors may decrease the excretion of Alpha-/Beta-Agonists. Exceptions: Dipivefrin. Risk C: Monitor therapy

Amifostine: Antihypertensives may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, antihypertensive medications should be withheld for 24 hours prior to amifostine administration. If antihypertensive therapy can not be withheld, amifostine should not be administered. Risk D: Consider therapy modification

Amphetamines: Carbonic Anhydrase Inhibitors may decrease the excretion of Amphetamines. Risk C: Monitor therapy

Anticonvulsants (Barbiturate): Carbonic Anhydrase Inhibitors may enhance the adverse/toxic effect of Anticonvulsants (Barbiturate). Specifically, osteomalacia and rickets. Risk C: Monitor therapy

Anticonvulsants (Hydantoin): Carbonic Anhydrase Inhibitors may enhance the adverse/toxic effect of Anticonvulsants (Hydantoin). Specifically, osteomalacia and rickets. Risk C: Monitor therapy

Antihypertensives: May enhance the hypotensive effect of other Antihypertensives. Risk C: Monitor therapy

CarBAMazepine: Carbonic Anhydrase Inhibitors may increase the serum concentration of CarBAMazepine. Risk C: Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

Diazoxide: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

Flecainide: Carbonic Anhydrase Inhibitors may decrease the excretion of Flecainide. Risk C: Monitor therapy

Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

Ketorolac: May diminish the therapeutic effect of Anticonvulsants. Risk C: Monitor therapy

MAO Inhibitors: May enhance the orthostatic effect of Orthostasis Producing Agents. Risk C: Monitor therapy

Mefloquine: May diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of convulsions. Monitor anticonvulsant concentrations and treatment response closely with concurrent use. Risk D: Consider therapy modification

Memantine: Carbonic Anhydrase Inhibitors may decrease the excretion of Memantine. Risk C: Monitor therapy

Methenamine: Carbonic Anhydrase Inhibitors may diminish the therapeutic effect of Methenamine. Risk D: Consider therapy modification

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce dosage of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Risk D: Consider therapy modification

Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

Primidone: Carbonic Anhydrase Inhibitors may enhance the adverse/toxic effect of Primidone. Specifically, osteomalacia and rickets. Carbonic Anhydrase Inhibitors may decrease the serum concentration of Primidone. Risk C: Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

QuiNIDine: Carbonic Anhydrase Inhibitors may decrease the excretion of QuiNIDine. Risk C: Monitor therapy

RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification

Salicylates: May enhance the adverse/toxic effect of Carbonic Anhydrase Inhibitors. Salicylate toxicity might be enhanced by this same combination. Risk D: Consider therapy modification

Trientine: Carbonic Anhydrase Inhibitor Diuretics may decrease the serum concentration of Trientine. Risk C: Monitor therapy

Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

PREGNANCY RISK FACTOR — C (show table)

PREGNANCY IMPLICATIONS — Teratogenic in animal studies, however, there are no adequate and well-controlled studies in pregnant women.

LACTATION — Enters breast milk/not recommended (AAP rates "compatible")

DIETARY CONSIDERATIONS — May be taken with food to decrease GI upset. May have additive effects with other folic acid antagonists. Sodium content of 500 mg injection: 47.2 mg (2.05 mEq).

PRICING — (data from drugstore.com)
Capsule, 12-hour (AcetaZOLAMIDE)
500 mg (100): $299.97

Capsule, 12-hour (Diamox Sequels)
500 mg (60): $314.98

Tablets (AcetaZOLAMIDE)
125 mg (90): $29.99
250 mg (60): $29.99

MONITORING PARAMETERS — Intraocular pressure, potassium, serum bicarbonate; serum electrolytes, periodic CBC with differential; monitor growth in pediatric patients

CANADIAN BRAND NAMES — Apo-Acetazolamide®; Diamox®

INTERNATIONAL BRAND NAMES — Acetadiazol (MX); Acetak (PE); Albox (JP); Apo-Acetazolamide (MY); Azol (TW); Carbinib (PT); Cetamid (PH); Diamox (AE, AR, AT, AU, BD, BE, BG, BH, BR, CH, CL, CO, CY, CZ, DE, DK, EG, ES, FI, FR, GB, GR, HK, HN, HR, ID, IE, IL, IN, IQ, IR, IT, JO, JP, KP, KW, LB, LU, LY, MY, NL, NO, OM, PH, PK, PT, QA, RU, SA, SE, SG, SY, TH, TR, TW, VE, YE, ZA); Diamox Sustets (CO); Diluran (CZ); Diural (UY); Diuramid (PL); Evamox (PK); Fonurit (HU); Glaupax (CH, DE, HR, JP, TH); Huma-Zolamide (HN, HU); Ledamox (JP); Lediamox (PT); Medene (TH); Optamide (PH); Renamid (HR); Stazol (PY); Synomax (IN); Uramox (IL); Zolmide (PH)

MECHANISM OF ACTION — Reversible inhibition of the enzyme carbonic anhydrase resulting in reduction of hydrogen ion secretion at renal tubule and an increased renal excretion of sodium, potassium, bicarbonate, and water to decrease production of aqueous humor; also inhibits carbonic anhydrase in central nervous system to retard abnormal and excessive discharge from CNS neurons

PHARMACODYNAMICS / KINETICS
Onset of action: Capsule, extended release: 2 hours; I.V.: 2 minutes
Peak effect: Capsule, extended release: 8-12 hours; I.V.: 15 minutes; Tablet: 2-4 hours

Duration: Inhibition of aqueous humor secretion: Capsule, extended release: 18-24 hours; I.V.: 4-5 hours; Tablet: 8-12 hours

Distribution: Erythrocytes, kidneys; blood-brain barrier and placenta; distributes into milk (~30% of plasma concentrations)

Excretion: Urine (70% to 100% as unchanged drug)

PATIENT INFORMATION — Report numbness or tingling of extremities. Do not crush, chew, or swallow contents of long-acting capsule; may be opened and sprinkled on soft food. Ability to perform tasks requiring mental alertness and/or physical coordination may be impaired. Take with food; drug may cause substantial increase in blood glucose in some patients with diabetes.

Acetazolamide

MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
AcetaZOLAMIDE may be confused with acetoHEXAMIDE
Diamox® Sequels® may be confused with Diabinese®, Dobutrex®, Trimox®

U.S. BRAND NAMES — Diamox® Sequels®

PHARMACOLOGIC CATEGORY
Anticonvulsant, Miscellaneous
Carbonic Anhydrase Inhibitor
Diuretic, Carbonic Anhydrase Inhibitor
Ophthalmic Agent, Antiglaucoma

DOSING: ADULTS — Note: I.M. administration is not recommended.

Glaucoma:
Chronic simple (open-angle): Oral: 250 mg 1-4 times/day or 500 mg extended release capsule twice daily
Secondary, acute (closed-angle): I.V.: 250-500 mg, may repeat in 2-4 hours to a maximum of 1 g/day

Edema: Oral, I.V.: 250-375 mg once daily

Epilepsy: Oral: 8-30 mg/kg/day in 1-4 divided doses, not to exceed 1 g/day. Note: Extended release capsule is not recommended for treatment of epilepsy.

Metabolic alkalosis (unlabeled use): I.V. 250 mg every 6 hours for 4 doses or 500 mg single dose; reassess need based upon acid-base status

Mountain sickness: Oral: 250 mg every 8-12 hours (or 500 mg extended release capsules every 12-24 hours). Therapy should begin 24-48 hours before and continue during ascent and for at least 48 hours after arrival at the high altitude.
Note: In situations of rapid ascent (such as rescue or military operations), 1000 mg/day is recommended.

Urine alkalinization (unlabeled use): Oral: 5 mg/kg/dose repeated 2-3 times over 24 hours

Respiratory stimulant in COPD (unlabeled use): Oral, I.V.: 250 mg twice daily

DOSING: PEDIATRIC — Note: I.M. administration is not recommended.

(For additional information see "Acetazolamide: Pediatric drug information")

Glaucoma:
Oral: 8-30 mg/kg/day or 300-900 mg/m2/day divided every 8 hours
I.V.: 20-40 mg/kg/24 hours divided every 6 hours, not to exceed 1 g/day

Edema: Oral, I.V.: 5 mg/kg or 150 mg/m2 once every day

Epilepsy: Oral: Refer to adult dosing.

DOSING: ELDERLY — Oral: Initial: 250 mg once or twice daily; use lowest effective dose possible.

DOSING: RENAL IMPAIRMENT
Clcr 10-50 mL/minute: Administer every 12 hours.

Clcr <10 mL/minute: Avoid use (ineffective).

Moderately dialyzable (20% to 50%)

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, extended release: 500 mg
Diamox® Sequels®: 500 mg

Injection, powder for reconstitution: 500 mg

Tablet: 125 mg, 250 mg

DOSAGE FORMS: CONCISE
Capsule, extended release: 500 mg
Diamox® Sequels®: 500 mg

Injection, powder for reconstitution: 500 mg

Tablet: 125 mg, 250 mg

GENERIC EQUIVALENT AVAILABLE — Yes

ADMINISTRATION
Oral: May cause an alteration in taste, especially carbonated beverages. Short-acting tablets may be crushed and suspended in cherry or chocolate syrup to disguise the bitter taste of the drug; do not use fruit juices. Alternatively, submerge tablet in 10 mL of hot water and add 10 mL honey or syrup.

I.M.: I.M. administration is painful because of the alkaline pH of the drug; use by this route is not recommended.

I.V.: No specific guidance given by manufacturer, but I.V. push at a rate of up to 500 mg over 3 minutes has been reported in a clinical trial (Mazur, 1999); a study to assess cerebrovascular reserve has used rapid I.V. push of up to 1 g over ≤ 1 minute (Piepgras, 1990)

COMPATIBILITY — Stable in dextran 6% in D5W, dextran 6% in NS, D5LR, D5NS, D51/2NS, D51/4NS, D5W, D10W, LR, NS, 1/2NS.

Y-site administration: Variable (consult detailed reference): Diltiazem, TPN.

Compatibility when admixed: Compatible: Cimetidine, ranitidine. Incompatible: Multivitamins.

USE — Treatment of glaucoma (chronic simple open-angle, secondary glaucoma, preoperatively in acute angle-closure); drug-induced edema or edema due to congestive heart failure (adjunctive therapy); centrencephalic epilepsies (immediate release dosage form); prevention or amelioration of symptoms associated with acute mountain sickness

USE - UNLABELED / INVESTIGATIONAL — Metabolic alkalosis; respiratory stimulant in COPD; urine alkalinization

ADVERSE REACTIONS SIGNIFICANT — Frequency not defined.

Cardiovascular: Flushing

Central nervous system: Ataxia, confusion, convulsions, depression, dizziness, drowsiness, excitement, fatigue, fever, headache, malaise

Dermatologic: Allergic skin reactions, photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria

Endocrine & metabolic: Electrolyte imbalance, growth retardation (children), hyperglycemia, hypoglycemia, hypokalemia, hyponatremia, metabolic acidosis

Gastrointestinal: Appetite decreased, diarrhea, melena, nausea, taste alteration, vomiting

Genitourinary: Crystalluria, glycosuria, hematuria, polyuria, renal failure

Hematologic: Agranulocytosis, aplastic anemia, leukopenia, thrombocytopenia, thrombocytopenic purpura

Hepatic: Cholestatic jaundice, fulminant hepatic necrosis, hepatic insufficiency, liver function tests abnormal

Local: Pain at injection site

Neuromuscular & skeletal: Flaccid paralysis, paresthesia

Ocular: Myopia

Otic: Hearing disturbance, tinnitus

Miscellaneous: Anaphylaxis

CONTRAINDICATIONS — Hypersensitivity to acetazolamide, sulfonamides, or any component of the formulation; hepatic disease or insufficiency; decreased sodium and/or potassium levels; adrenocortical insufficiency, cirrhosis; hyperchloremic acidosis, severe renal disease or dysfunction; severe pulmonary obstruction; long-term use in noncongestive angle-closure glaucoma

WARNINGS / PRECAUTIONS
Concerns related to adverse effects: CNS effects: Impairment of mental alertness and/or physical coordination may occur. Sulfa allergy: Chemical similarities are present among sulfonamides, sulfonylureas, carbonic anhydrase inhibitors, thiazides, and loop diuretics (except ethacrynic acid). Use in patients with sulfonylurea allergy is specifically contraindicated in product labeling, however, a risk of cross-reaction exists in patients with allergy to any of these compounds; avoid use when previous reaction has been severe. Discontinue if signs of hypersensitivity are noted.

Disease-related concerns: Diabetes: Use with caution in patients with prediabetes or diabetes mellitus; may see a change in glucose control. Hepatic impairment: Use with caution in patients with hepatic dysfunction; in cirrhosis, avoid electrolyte and acid/base imbalances that might lead to hepatic encephalopathy. Respiratory acidosis: Use with caution in patients with respiratory acidosis.

Special populations: Elderly: Use with caution in the elderly; may be more sensitive to side effects.

Other warnings/precautions: I.M. administration: Painful because of the alkaline pH of the drug; use by this route is not recommended.

METABOLISM / TRANSPORT EFFECTS — Inhibits CYP3A4 (weak)

DRUG INTERACTIONS
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Alpha-/Beta-Agonists: Carbonic Anhydrase Inhibitors may decrease the excretion of Alpha-/Beta-Agonists. Exceptions: Dipivefrin. Risk C: Monitor therapy

Amifostine: Antihypertensives may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, antihypertensive medications should be withheld for 24 hours prior to amifostine administration. If antihypertensive therapy can not be withheld, amifostine should not be administered. Risk D: Consider therapy modification

Amphetamines: Carbonic Anhydrase Inhibitors may decrease the excretion of Amphetamines. Risk C: Monitor therapy

Anticonvulsants (Barbiturate): Carbonic Anhydrase Inhibitors may enhance the adverse/toxic effect of Anticonvulsants (Barbiturate). Specifically, osteomalacia and rickets. Risk C: Monitor therapy

Anticonvulsants (Hydantoin): Carbonic Anhydrase Inhibitors may enhance the adverse/toxic effect of Anticonvulsants (Hydantoin). Specifically, osteomalacia and rickets. Risk C: Monitor therapy

Antihypertensives: May enhance the hypotensive effect of other Antihypertensives. Risk C: Monitor therapy

CarBAMazepine: Carbonic Anhydrase Inhibitors may increase the serum concentration of CarBAMazepine. Risk C: Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

Diazoxide: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

Flecainide: Carbonic Anhydrase Inhibitors may decrease the excretion of Flecainide. Risk C: Monitor therapy

Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

Ketorolac: May diminish the therapeutic effect of Anticonvulsants. Risk C: Monitor therapy

MAO Inhibitors: May enhance the orthostatic effect of Orthostasis Producing Agents. Risk C: Monitor therapy

Mefloquine: May diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of convulsions. Monitor anticonvulsant concentrations and treatment response closely with concurrent use. Risk D: Consider therapy modification

Memantine: Carbonic Anhydrase Inhibitors may decrease the excretion of Memantine. Risk C: Monitor therapy

Methenamine: Carbonic Anhydrase Inhibitors may diminish the therapeutic effect of Methenamine. Risk D: Consider therapy modification

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce dosage of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Risk D: Consider therapy modification

Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

Primidone: Carbonic Anhydrase Inhibitors may enhance the adverse/toxic effect of Primidone. Specifically, osteomalacia and rickets. Carbonic Anhydrase Inhibitors may decrease the serum concentration of Primidone. Risk C: Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

QuiNIDine: Carbonic Anhydrase Inhibitors may decrease the excretion of QuiNIDine. Risk C: Monitor therapy

RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification

Salicylates: May enhance the adverse/toxic effect of Carbonic Anhydrase Inhibitors. Salicylate toxicity might be enhanced by this same combination. Risk D: Consider therapy modification

Trientine: Carbonic Anhydrase Inhibitor Diuretics may decrease the serum concentration of Trientine. Risk C: Monitor therapy

Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

PREGNANCY RISK FACTOR — C (show table)

PREGNANCY IMPLICATIONS — Teratogenic in animal studies, however, there are no adequate and well-controlled studies in pregnant women.

LACTATION — Enters breast milk/not recommended (AAP rates "compatible")

DIETARY CONSIDERATIONS — May be taken with food to decrease GI upset. May have additive effects with other folic acid antagonists. Sodium content of 500 mg injection: 47.2 mg (2.05 mEq).

PRICING — (data from drugstore.com)
Capsule, 12-hour (AcetaZOLAMIDE)
500 mg (100): $299.97

Capsule, 12-hour (Diamox Sequels)
500 mg (60): $314.98

Tablets (AcetaZOLAMIDE)
125 mg (90): $29.99
250 mg (60): $29.99

MONITORING PARAMETERS — Intraocular pressure, potassium, serum bicarbonate; serum electrolytes, periodic CBC with differential; monitor growth in pediatric patients

CANADIAN BRAND NAMES — Apo-Acetazolamide®; Diamox®

INTERNATIONAL BRAND NAMES — Acetadiazol (MX); Acetak (PE); Albox (JP); Apo-Acetazolamide (MY); Azol (TW); Carbinib (PT); Cetamid (PH); Diamox (AE, AR, AT, AU, BD, BE, BG, BH, BR, CH, CL, CO, CY, CZ, DE, DK, EG, ES, FI, FR, GB, GR, HK, HN, HR, ID, IE, IL, IN, IQ, IR, IT, JO, JP, KP, KW, LB, LU, LY, MY, NL, NO, OM, PH, PK, PT, QA, RU, SA, SE, SG, SY, TH, TR, TW, VE, YE, ZA); Diamox Sustets (CO); Diluran (CZ); Diural (UY); Diuramid (PL); Evamox (PK); Fonurit (HU); Glaupax (CH, DE, HR, JP, TH); Huma-Zolamide (HN, HU); Ledamox (JP); Lediamox (PT); Medene (TH); Optamide (PH); Renamid (HR); Stazol (PY); Synomax (IN); Uramox (IL); Zolmide (PH)

MECHANISM OF ACTION — Reversible inhibition of the enzyme carbonic anhydrase resulting in reduction of hydrogen ion secretion at renal tubule and an increased renal excretion of sodium, potassium, bicarbonate, and water to decrease production of aqueous humor; also inhibits carbonic anhydrase in central nervous system to retard abnormal and excessive discharge from CNS neurons

PHARMACODYNAMICS / KINETICS
Onset of action: Capsule, extended release: 2 hours; I.V.: 2 minutes
Peak effect: Capsule, extended release: 8-12 hours; I.V.: 15 minutes; Tablet: 2-4 hours

Duration: Inhibition of aqueous humor secretion: Capsule, extended release: 18-24 hours; I.V.: 4-5 hours; Tablet: 8-12 hours

Distribution: Erythrocytes, kidneys; blood-brain barrier and placenta; distributes into milk (~30% of plasma concentrations)

Excretion: Urine (70% to 100% as unchanged drug)

PATIENT INFORMATION — Report numbness or tingling of extremities. Do not crush, chew, or swallow contents of long-acting capsule; may be opened and sprinkled on soft food. Ability to perform tasks requiring mental alertness and/or physical coordination may be impaired. Take with food; drug may cause substantial increase in blood glucose in some patients with diabetes.

Acetaminophen, isometheptene, and dichloralphenazone

MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Midrin® may be confused with midodrine, Mydfrin®

Duplicate therapy issues: This product contains acetaminophen, which may be a component of other combination products. Do not exceed the maximum recommended daily dose of acetaminophen.

U.S. BRAND NAMES — Amidrine [DSC]; Duradrin® [DSC]; Epidrin; Midrin®; Migquin [DSC]; Migratine; Migrazone® [DSC]; Migrin-A [DSC]

PHARMACOLOGIC CATEGORY
Analgesic, Miscellaneous

DOSING: ADULTS
Migraine headache: Oral: 2 capsules to start, followed by 1 capsule every hour until relief is obtained (maximum: 5 capsules/12 hours)

Tension headache: Oral: 1-2 capsules every 4 hours (maximum: 8 capsules/24 hours)

DOSING: ELDERLY — Refer to adult dosing.

DOSING: HEPATIC IMPAIRMENT — Use with caution. Limited, low-dose therapy usually well tolerated in hepatic disease/cirrhosis; however, cases of hepatotoxicity at daily acetaminophen dosages <4 g/day have been reported. Avoid chronic use in hepatic impairment.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule: Acetaminophen 325 mg, isometheptene mucate 65 mg, dichloralphenazone 100 mg [DSC]
Amidrine [DSC], Duradrin® [DSC], Epidrin, Midrin®, Migquin [DSC], Migrazone® [DSC], Migratine, Migrin-A [DSC]: Acetaminophen 325 mg, isometheptene mucate 65 mg, and dichloralphenazone 100 mg

DOSAGE FORMS: CONCISE
Capsule:
Epidrin, Midrin®, Migratine: Acetaminophen 325 mg, isometheptene 65 mg, and dichloralphenazone 100 mg

GENERIC EQUIVALENT AVAILABLE — Yes

USE — Relief of migraine and tension headache

ADVERSE REACTIONS SIGNIFICANT — Frequency not defined.

Central nervous system: Dizziness (transient)

Dermatological: Rash

CONTRAINDICATIONS — Hypersensitivity to acetaminophen, isometheptene, dichloralphenazone, or any component of the formulation; glaucoma; severe renal disease; hypertension; organic heart disease; hepatic disease; MAO inhibitor therapy

RESTRICTIONS — C-IV

METABOLISM / TRANSPORT EFFECTS — Acetaminophen: Substrate (minor) of CYP1A2, 2A6, 2C9, 2D6, 2E1, 3A4; Inhibits CYP3A4 (weak)

DRUG INTERACTIONS
Antacids: May decrease the excretion of Alpha-/Beta-Agonists. Exceptions: Aluminum Hydroxide. Risk C: Monitor therapy

Anticonvulsants (Hydantoin): May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy

Atomoxetine: May enhance the hypertensive effect of Sympathomimetics. Atomoxetine may enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy

Barbiturates: May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy

Beta-Blockers: May enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting). Epinephrine used as a local anesthetic for dental procedures will not likely cause clinically relevant problems. Management: Cardioselective beta-blockers and lower doses of epinephrine may confer a more limited risk. Patients who may require acute subcutaneous epinephrine (e.g., bee sting kits) should probably avoid beta blockers. Risk D: Consider therapy modification

Bromocriptine: Alpha-/Beta-Agonists may enhance the adverse/toxic effect of Bromocriptine. Including increased blood pressure, ventricular arrhythmias, and seizure. Risk C: Monitor therapy

Cannabinoids: May enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy

CarBAMazepine: May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy

Carbonic Anhydrase Inhibitors: May decrease the excretion of Alpha-/Beta-Agonists. Exceptions: Brinzolamide; Dorzolamide. Risk C: Monitor therapy

Cholestyramine Resin: May decrease the absorption of Acetaminophen. Effect is minimal if cholestyramine is administered 1 hour after acetaminophen. Risk D: Consider therapy modification

Imatinib: May increase the serum concentration of Acetaminophen. Risk D: Consider therapy modification

Iobenguane I 123: Sympathomimetics may diminish the therapeutic effect of Iobenguane I 123. Risk X: Avoid combination

Isoniazid: May enhance the adverse/toxic effect of Acetaminophen. Risk C: Monitor therapy

MAO Inhibitors: May enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting). Primarily with oral administration of phenylephrine. Risk D: Consider therapy modification

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy

Serotonin/Norepinephrine Reuptake Inhibitors: May enhance the tachycardic effect of Alpha-/Beta-Agonists. Serotonin/Norepinephrine Reuptake Inhibitors may enhance the vasopressor effect of Alpha-/Beta-Agonists. Risk D: Consider therapy modification

Spironolactone: May diminish the vasoconstricting effect of Alpha-/Beta-Agonists. Risk C: Monitor therapy

Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Risk C: Monitor therapy

Tricyclic Antidepressants: May enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting). Risk D: Consider therapy modification

Vitamin K Antagonists (eg, warfarin): Acetaminophen may enhance the anticoagulant effect of Vitamin K Antagonists. Most likely with daily acetaminophen doses >1.3 g for >1 week. Risk C: Monitor therapy

ETHANOL / NUTRITION / HERB INTERACTIONS — Ethanol: Excessive intake of ethanol may increase the risk of acetaminophen-induced hepatotoxicity. Avoid ethanol or limit to <3 drinks/day.

LACTATION — Excretion in breast milk unknown/use caution

BREAST-FEEDING CONSIDERATIONS — Acetaminophen and dichloralphenazone are excreted in breast milk; excretion of isometheptene is not known.

PRICING — (data from drugstore.com)
Capsules (Epidrin)
325-65-100 mg (100): $63.99

Capsules (Isometheptene-APAP-Dichloral)
65-325-100 mg (30): $22.99

Capsules (Migratine)
325-65-100 mg (100): $37.57

Acetaminophen, isometheptene, and dichloralphenazone

MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Midrin® may be confused with midodrine, Mydfrin®

Duplicate therapy issues: This product contains acetaminophen, which may be a component of other combination products. Do not exceed the maximum recommended daily dose of acetaminophen.

U.S. BRAND NAMES — Amidrine [DSC]; Duradrin® [DSC]; Epidrin; Midrin®; Migquin [DSC]; Migratine; Migrazone® [DSC]; Migrin-A [DSC]

PHARMACOLOGIC CATEGORY
Analgesic, Miscellaneous

DOSING: ADULTS
Migraine headache: Oral: 2 capsules to start, followed by 1 capsule every hour until relief is obtained (maximum: 5 capsules/12 hours)

Tension headache: Oral: 1-2 capsules every 4 hours (maximum: 8 capsules/24 hours)

DOSING: ELDERLY — Refer to adult dosing.

DOSING: HEPATIC IMPAIRMENT — Use with caution. Limited, low-dose therapy usually well tolerated in hepatic disease/cirrhosis; however, cases of hepatotoxicity at daily acetaminophen dosages <4 g/day have been reported. Avoid chronic use in hepatic impairment.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule: Acetaminophen 325 mg, isometheptene mucate 65 mg, dichloralphenazone 100 mg [DSC]
Amidrine [DSC], Duradrin® [DSC], Epidrin, Midrin®, Migquin [DSC], Migrazone® [DSC], Migratine, Migrin-A [DSC]: Acetaminophen 325 mg, isometheptene mucate 65 mg, and dichloralphenazone 100 mg

DOSAGE FORMS: CONCISE
Capsule:
Epidrin, Midrin®, Migratine: Acetaminophen 325 mg, isometheptene 65 mg, and dichloralphenazone 100 mg

GENERIC EQUIVALENT AVAILABLE — Yes

USE — Relief of migraine and tension headache

ADVERSE REACTIONS SIGNIFICANT — Frequency not defined.

Central nervous system: Dizziness (transient)

Dermatological: Rash

CONTRAINDICATIONS — Hypersensitivity to acetaminophen, isometheptene, dichloralphenazone, or any component of the formulation; glaucoma; severe renal disease; hypertension; organic heart disease; hepatic disease; MAO inhibitor therapy

RESTRICTIONS — C-IV

METABOLISM / TRANSPORT EFFECTS — Acetaminophen: Substrate (minor) of CYP1A2, 2A6, 2C9, 2D6, 2E1, 3A4; Inhibits CYP3A4 (weak)

DRUG INTERACTIONS
Antacids: May decrease the excretion of Alpha-/Beta-Agonists. Exceptions: Aluminum Hydroxide. Risk C: Monitor therapy

Anticonvulsants (Hydantoin): May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy

Atomoxetine: May enhance the hypertensive effect of Sympathomimetics. Atomoxetine may enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy

Barbiturates: May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy

Beta-Blockers: May enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting). Epinephrine used as a local anesthetic for dental procedures will not likely cause clinically relevant problems. Management: Cardioselective beta-blockers and lower doses of epinephrine may confer a more limited risk. Patients who may require acute subcutaneous epinephrine (e.g., bee sting kits) should probably avoid beta blockers. Risk D: Consider therapy modification

Bromocriptine: Alpha-/Beta-Agonists may enhance the adverse/toxic effect of Bromocriptine. Including increased blood pressure, ventricular arrhythmias, and seizure. Risk C: Monitor therapy

Cannabinoids: May enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy

CarBAMazepine: May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy

Carbonic Anhydrase Inhibitors: May decrease the excretion of Alpha-/Beta-Agonists. Exceptions: Brinzolamide; Dorzolamide. Risk C: Monitor therapy

Cholestyramine Resin: May decrease the absorption of Acetaminophen. Effect is minimal if cholestyramine is administered 1 hour after acetaminophen. Risk D: Consider therapy modification

Imatinib: May increase the serum concentration of Acetaminophen. Risk D: Consider therapy modification

Iobenguane I 123: Sympathomimetics may diminish the therapeutic effect of Iobenguane I 123. Risk X: Avoid combination

Isoniazid: May enhance the adverse/toxic effect of Acetaminophen. Risk C: Monitor therapy

MAO Inhibitors: May enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting). Primarily with oral administration of phenylephrine. Risk D: Consider therapy modification

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy

Serotonin/Norepinephrine Reuptake Inhibitors: May enhance the tachycardic effect of Alpha-/Beta-Agonists. Serotonin/Norepinephrine Reuptake Inhibitors may enhance the vasopressor effect of Alpha-/Beta-Agonists. Risk D: Consider therapy modification

Spironolactone: May diminish the vasoconstricting effect of Alpha-/Beta-Agonists. Risk C: Monitor therapy

Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Risk C: Monitor therapy

Tricyclic Antidepressants: May enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting). Risk D: Consider therapy modification

Vitamin K Antagonists (eg, warfarin): Acetaminophen may enhance the anticoagulant effect of Vitamin K Antagonists. Most likely with daily acetaminophen doses >1.3 g for >1 week. Risk C: Monitor therapy

ETHANOL / NUTRITION / HERB INTERACTIONS — Ethanol: Excessive intake of ethanol may increase the risk of acetaminophen-induced hepatotoxicity. Avoid ethanol or limit to <3 drinks/day.

LACTATION — Excretion in breast milk unknown/use caution

BREAST-FEEDING CONSIDERATIONS — Acetaminophen and dichloralphenazone are excreted in breast milk; excretion of isometheptene is not known.

PRICING — (data from drugstore.com)
Capsules (Epidrin)
325-65-100 mg (100): $63.99

Capsules (Isometheptene-APAP-Dichloral)
65-325-100 mg (30): $22.99

Capsules (Migratine)
325-65-100 mg (100): $37.57

Acetaminophen, diphenhydramine, and phenylephrine

MEDICATION SAFETY ISSUES
Duplicate therapy issues: This product contains acetaminophen, which may be a component of combination products. Do not exceed the maximum recommended daily dose of acetaminophen.

SPECIAL ALERTS
Health Canada: Labeling Changes for OTC Cough and Cold Preparations - December, 2008

Health Canada has issued an advisory to Canadian consumers regarding upcoming labeling changes for the use of over-the-counter (OTC) cough and cold medicines in children. Specific labeling changes as well as other important information may be found at http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2008/2008_184-eng.php.

Manufacturers Voluntarily Change Pediatric OTC Product Labeling - October 7, 2008

Leading manufacturers of over-the-counter (OTC) pediatric cough and cold products, in consultation with the Food and Drug Administration (FDA), have announced that they are voluntarily transitioning product labeling as it relates to children <4 years of age. The decision to change the labeling followed a meeting on October 2, 2008, conducted by the FDA to gather additional information related to the use of these products in children. The safety of the ingredients in these products was not in question. It was found that dosing errors and accidental ingestions were the leading cause of rare adverse events in children. The new product labeling will state "Do not use in children under four years of age." In addition, products with certain antihistamines will warn parents not to use these products to sedate or make a child sleepy. Labeling of adult products will not change. New product labels will be introduced during the 2008-2009 cough and cold season and some products will have the updated labeling by mid-October. Products with the old labeling will not be removed from the market. Prescription products are not affected.

It is important to note that these medications have not been shown to be unsafe when used correctly. Pharmacists may continue to see health care practitioners recommending these agents for use in pediatric patients, and should help to ensure that they are being used safely and at appropriate dosages. Parents should be advised that OTC cough and cold products are safe and effective when used as directed, but that they should not be used in children <4 years of age unless instructed to do so by their healthcare provider. Counseling tips from the Consumer Healthcare Products Association (CHPA) also include: Always follow dosing instructions exactly and use measuring devices provided with the medicine. Never give 2 medicines at the same time that contain the same active ingredient. Do not give a medicine intended for use in adults to a child.

Additional tips and information related to the labeling changes can be found on the following educational website of the CHPA: http://www.otcsafety.org.

The FDA had previously issued a Public Health Advisory reminding patients and caregivers that OTC cough and cold medications should not be used to treat infants and children <2 years of age. This is in response to the Centers for Disease Control and Prevention (CDC) report which noted that during 2004 and 2005, ~1519 children <2 years of age were seen in emergency departments for adverse effects, including overdose, associated with products containing nasal decongestants (eg, pseudoephedrine), antihistamines (eg, carbinoxamine), and cough suppressants (eg, dextromethorphan). In October of 2007, several manufacturers voluntarily removed these products in order to help reduce dosing errors and overdose in this age group.

For additional information, refer to the following websites:

http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm094913.htm

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116839.htm

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5601a1.htm, Centers for Disease Control, "Infant Deaths Associated with Cough and Cold Medications - Two States, 2005,"MMWR Morb Mortal Wkly Rep, 2007, 56(01):1-4.

U.S. BRAND NAMES — Benadryl® Allergy and Cold [OTC]; Benadryl® Allergy and Sinus Headache [OTC]; Benadry® Maximum Strength Severe Allergy and Sinus Headache [OTC]; Cold Control PE [OTC]; Sudafed PE® Nighttime Cold [OTC]; Sudafed PE® Severe Cold [OTC]; Theraflu® Nighttime Severe Cold & Cough [OTC]; Theraflu® Sugar-Free Nighttime Severe Cold & Cough [OTC]; Theraflu® Warming Relief Flu & Sore Throat [OTC]; Theraflu® Warming Relief Nighttime Severe Cold & Cough [OTC]; Tylenol® Allergy Multi-Symptom Nighttime [OTC]; Tylenol® Children's Plus Cold and Allergy [OTC]

PHARMACOLOGIC CATEGORY
Analgesic, Miscellaneous
Decongestant
Histamine H1 Antagonist

DOSING: ADULTS — Hay fever/cold symptoms: Oral: General dosing guidelines; refer to specific product labeling (Benadryl® Allergy and Cold, Benadryl® Allergy and Sinus Headache, Sudafed PE® Nighttime Cold, Sudafed PE® Severe Cold, Tylenol® Allergy Multi-Symptom Nighttime): Two caplets every 4 hours as needed; maximum: 12 caplets/24 hours

DOSING: PEDIATRIC — Hay fever/cold symptoms: Oral: General dosing guidelines; refer to specific product labeling:

Children 6-11 years (Benadryl® Allergy and Cold, Benadryl® Allergy and Sinus Headache, Sudafed PE® Severe Cold): One caplet every 4 hours as needed; maximum: 5 caplets/24 hours

Children 6-11 years; 48-95 lbs (Tylenol® Children's Plus Cold and Allergy): 10 mL every 4 hours as needed; maximum: 5 doses/24 hours

Children ≥ 12 years: Refer to adult dosing.

DOSING: ELDERLY — Refer to adult dosing.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Caplet:
Benadryl® Allergy and Cold, Benadryl® Allergy and Sinus Headache, Sudafed PE® Severe Cold: Acetaminophen 325 mg, diphenhydramine hydrochloride 12.5 mg, and phenylephrine hydrochloride 5 mg
Benadry® Maximum Strength Severe Allergy and Sinus Headache: Acetaminophen 325 mg, diphenhydramine hydrochloride 25 mg, and phenylephrine hydrochloride 5 mg
Cold Control PE: Acetaminophen 650 mg, diphenhydramine hydrochloride 25 mg, and phenylephrine hydrochloride 10 mg
Sudafed PE® Nighttime Cold: Acetaminophen 325 mg, diphenhydramine hydrochloride 25 mg, and phenylephrine hydrochloride 5 mg
Tylenol® Allergy Multi-Symptom Nighttime: Acetaminophen 325 mg, diphenhydramine hydrochloride 25 mg, and phenylephrine hydrochloride 5 mg [Cool Burst™ flavor]

Liquid:
Tylenol® Children's Plus Cold and Allergy: Acetaminophen 160 mg, diphenhydramine hydrochloride 12.5 mg, and phenylephrine hydrochloride 2.5 mg per 5 mL (120 mL) [contains sodium benzoate; bubble gum flavor]

Powder for solution, oral:
Theraflu® Nighttime Severe Cold & Cough: Acetaminophen 650 mg, diphenhydramine hydrochloride 25 mg, and phenylephrine hydrochloride 10 mg per packet (6s) [contains phenylalanine 13 mg, potassium 10 mg, and sodium 23 mg per packet; honey lemon flavor]
Theraflu® Sugar-Free Nighttime Severe Cold & Cough: Acetaminophen 650 mg, diphenhydramine hydrochloride 25 mg, and phenylephrine hydrochloride 10 mg per packet (6s) [sugar free; contains phenylalanine 13 mg, potassium 10 mg, and sodium 23 mg per packet; honey lemon flavor]

Syrup, oral:
Theraflu® Warming Relief Flu & Sore Throat: Acetaminophen 325 mg, diphenhydramine hydrochloride 12.5 mg, and phenylephrine hydrochloride 5 mg per 15 mL (245.5 mL) [contains ethanol, potassium 5 mg/15 mL, propylene glycol, sodium 5 mg/15 mL, sodium benzoate; cherry flavor]
Theraflu® Warming Relief Nighttime Severe Cold & Cough: Acetaminophen 325 mg, diphenhydramine hydrochloride 12.5 mg, and phenylephrine hydrochloride 5 mg per 15 mL (245.5 mL) [contains ethanol 10%, potassium 5 mg/15 mL, propylene glycol, sodium 5 mg/15 mL, sodium benzoate; cherry flavor]

DOSAGE FORMS: CONCISE
Caplet:
Benadryl® Allergy and Cold [OTC], Benadryl® Allergy and Sinus Headache [OTC], Sudafed PE® Severe Cold [OTC]: Acetaminophen 325 mg, diphenhydramine 12.5 mg, and phenylephrine 5 mg
Benadry® Maximum Strength Severe Allergy and Sinus Headache, Sudafed PE® Nighttime Cold [OTC], Tylenol® Allergy Multi-Symptom Nighttime [OTC]: Acetaminophen 325 mg, diphenhydramine 25 mg, and phenylephrine 5 mg
Cold Control PE: Acetaminophen 650 mg, diphenhydramine 25 mg, and phenylephrine 10 mg

Liquid:
Tylenol® Children's Plus Cold and Allergy [OTC]: Acetaminophen 160 mg, diphenhydramine 12.5 mg, and phenylephrine 2.5 mg per 5 mL

Powder for solution, oral:
Theraflu® Nighttime Severe Cold & Cough [OTC], Theraflu® Sugar-Free Nighttime Severe Cold & Cough [OTC]: Acetaminophen 650 mg, diphenhydramine 25 mg, and phenylephrine 10 mg per packet (6s)

Syrup, oral:
Theraflu® Warming Relief Flu & Sore Throat [OTC], Theraflu® Warming Relief Nighttime Severe Cold & Cough [OTC]: Acetaminophen 325 mg, diphenhydramine 12.5 mg, and phenylephrine 5 mg per 15 mL (245.5 mL)

GENERIC EQUIVALENT AVAILABLE — No

ADMINISTRATION — Administer without regard to meals.

Liquid: Shake well before use. Only use enclosed dosing cup; do not use other devices.

Tylenol® Allergy Multi-Symptom Nighttime: Swallow whole; do not crush, chew, or dissolve.

USE — Temporary relief of symptoms of hay fever and the common cold, including sinus/nasal congestion and pain/pressure, headache, sneezing, runny nose, itchy/watery eyes, sore throat, cough, and minor aches and pains

ADVERSE REACTIONS SIGNIFICANT — See individual agents.

CONTRAINDICATIONS — Use with or within 14 days of MAO inhibitor therapy; concurrent use with other products containing acetaminophen, diphenhydramine (including topical) or phenylephrine

WARNINGS / PRECAUTIONS
Concerns related to adverse effects: CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

Disease-related concerns: Ethanol use: Use with caution in patients with alcoholic liver disease; consuming ≥ 3 alcoholic drinks/day may increase the risk of liver damage. Hepatic impairment: Use caution in patients with hepatic impairment; acetaminophen may cause severe hepatic toxicity with acute overdose.

Concurrent drug therapy issues: Sedatives: Effects may be potentiated when used with other sedative drugs or ethanol.

Special populations: Pediatrics: Use with caution in children; may cause excitability. Do not exceed pediatric dosing recommendations. If no recommendations exist on OTC labeling for patient's age, the product should not be administered without the guidance of a physician.

Other warnings/precautions: Dosage limit: Limit acetaminophen dose to <4>7 days in adults (or >5 days in children) during use, consult a physician. If redness, swelling, or rash occurs or if fever worsens or persists >3 days during therapy, consult healthcare provider. If sore throat is severe, accompanied by fever, nausea/vomiting, headache, swelling or rash, or last >2 days, discontinue use and consult healthcare provider.

DRUG INTERACTIONS
Acetylcholinesterase Inhibitors (Central): Anticholinergics may diminish the therapeutic effect of Acetylcholinesterase Inhibitors (Central). Acetylcholinesterase Inhibitors (Central) may diminish the therapeutic effect of Anticholinergics. If the anticholinergic action is a side effect of the agent, the result may be beneficial. Risk C: Monitor therapy

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Amphetamines: May diminish the sedative effect of Antihistamines. Risk C: Monitor therapy

Anticholinergics: May enhance the adverse/toxic effect of other Anticholinergics. Exceptions: Paliperidone. Risk C: Monitor therapy

Anticonvulsants (Hydantoin): May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy

Atomoxetine: May enhance the hypertensive effect of Sympathomimetics. Atomoxetine may enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy

Barbiturates: May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy

Betahistine: Antihistamines may diminish the therapeutic effect of Betahistine. Risk C: Monitor therapy

Cannabinoids: May enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy

CarBAMazepine: May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy

Cholestyramine Resin: May decrease the absorption of Acetaminophen. Effect is minimal if cholestyramine is administered 1 hour after acetaminophen. Risk D: Consider therapy modification

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

Codeine: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Risk C: Monitor therapy

CYP2D6 Substrates: CYP2D6 Inhibitors (Moderate) may decrease the metabolism of CYP2D6 Substrates. Exceptions: Tamoxifen. Risk C: Monitor therapy

Fesoterodine: CYP2D6 Inhibitors may increase serum concentrations of the active metabolite(s) of Fesoterodine. Risk C: Monitor therapy

Imatinib: May increase the serum concentration of Acetaminophen. Risk D: Consider therapy modification

Iobenguane I 123: Sympathomimetics may diminish the therapeutic effect of Iobenguane I 123. Risk X: Avoid combination

Isoniazid: May enhance the adverse/toxic effect of Acetaminophen. Risk C: Monitor therapy

MAO Inhibitors: May enhance the hypertensive effect of Alpha1-Agonists. Risk X: Avoid combination

Nebivolol: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Nebivolol. Risk C: Monitor therapy

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy

Pramlintide: May enhance the anticholinergic effect of Anticholinergics. These effects are specific to the GI tract. Risk D: Consider therapy modification

Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Risk C: Monitor therapy

Tamoxifen: CYP2D6 Inhibitors (Moderate) may decrease the metabolism of Tamoxifen. Specifically, CYP2D6 inhibitors may decrease the formation of highly potent active metabolites. Risk D: Consider therapy modification

TraMADol: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of TraMADol. These CYP2D6 inhibitors may prevent the metabolic conversion of tramadol to its active metabolite that accounts for much of its opioid-like effects. Risk C: Monitor therapy

Tricyclic Antidepressants: May enhance the vasopressor effect of Alpha1-Agonists. Risk D: Consider therapy modification

Vitamin K Antagonists (eg, warfarin): Acetaminophen may enhance the anticoagulant effect of Vitamin K Antagonists. Most likely with daily acetaminophen doses >1.3 g for >1 week. Risk C: Monitor therapy

ETHANOL / NUTRITION / HERB INTERACTIONS — See individual agents.

DIETARY CONSIDERATIONS — Theraflu® Nighttime Severe Cold & Cough, Theraflu® Sugar-Free Nighttime Severe Cold & Cough: Powder for oral solution contains: Phenylalanine 13 mg per packet and sodium 23 mg per packet

MECHANISM OF ACTION
Acetaminophen inhibits the synthesis of prostaglandins in the central nervous system and peripherally blocks pain impulse generation.

Diphenhydramine is an H1-receptor antagonist.

Phenylephrine causes vasoconstriction of the arterioles of the nasal mucosa.

PHARMACODYNAMICS / KINETICS — See individual agents.