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Special Alerts
Antiepileptics: Increased Risk of Suicidal Behavior or Ideation - February 2008
The U.S. Food and Drug Administration (FDA) is informing healthcare professionals of an increased risk of suicidality (suicidal behavior or ideation) observed from analysis of clinical studies using various antiepileptic medications compared to placebo. The analysis was performed on 199 placebo-controlled studies involving 43,892 patients (27,863 treated patients versus 16,029 placebo patients) aged ?5 years receiving one of the following 11 drugs: carbamazepine (Carbatrol®, Equetro™, Tegretol®, Tegretol® XR), felbamate (Felbatol®), gabapentin (Neurontin®), lamotrigine (Lamictal®), levetiracetam (Keppra®), oxcarbazepine (Trileptal®), pregabalin (Lyrica®), tiagabine (Gabitril®), topiramate (Topamax®), valproate (Depakote®, Depakote® ER, Depakene®, Depacon®), and zonisamide (Zonegran®). Studies examined medication efficacy in a variety of disorders, including epilepsy, psychiatric disorders (eg, depression, bipolar disorder), and other conditions (eg, migraine, neuropathic pain). According to the FDA, the results revealed a statistically significant increased risk of suicidality in 0.43% treated patients compared to 0.22% placebo patients, or an estimated 2.1 per 1000 (95% CI: 0.7, 4.2) more patients in the treated groups relative to placebo. This increased risk was reported anywhere from 1 week of therapy through 24 weeks. However, most trials were ?24 weeks duration and the risk of suicide extending beyond 24 weeks is currently unknown. The relative risk of suicidal behavior or ideation in the treated patients was higher for patients with epilepsy (RR=3.6) compared to patients treated for psychiatric (RR=1.6) or other conditions (RR=2.3). Overall, the incidence of suicidal behavior or ideation occurred consistently across all demographic subgroups and with each of the drugs studied. Of note, four patients receiving an antiepileptic committed suicide relative to none in the placebo groups.
Forthcoming product labeling changes are likely to extend to all antiepileptic drugs and not limited to the drugs used in the studies, pending discussions scheduled for the upcoming advisory committee meeting. Healthcare professionals and family members/caregivers are encouraged to monitor patients receiving any antiepileptic medication for signs/symptoms of suicidality (eg, anxiety, depression, behavior changes). Patients should not stop taking their antiepileptic therapy unless advised by a healthcare professional.
Additional information can be found at http://www.fda.gov/medwatch/safety/2008/safety08.htm#Antiepileptic
Medication Safety Issues
Sound-alike/look-alike issues:
AcetaZOLAMIDE may be confused with acetoHEXAMIDE
Diamox® Sequels® may be confused with Diabinese®, Dobutrex®, Trimox®
Pronunciation
(a set a ZOLE a mide)
U.S. Brand Names
Generic Available
Yes: Injection, tablet
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
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
Urine alkalinization; respiratory stimulant in COPD; metabolic alkalosis
Pregnancy Risk Factor
C
Pregnancy Considerations
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”)
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.
Adverse Reactions
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
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
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
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
Mefloquine: May diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants. Management: Mefloquine is contraindicated in persons with a history of convulsions. If anticonvulsant is being used for another indication monitor response to treatment closely, as concurrent mefloquine may decrease response to treatment. 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
Methylphenidate: May diminish 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
Storage
Capsules, tablets: Store at controlled room temperature.
Injection: Store vial for injection (prior to reconstitution) at controlled room temperature. Reconstituted solution may be refrigerated (2°C to 8°C) for 1 week, however, use within 12 hours is recommended. Stability of IVPB solution is 5 days at room temperature (25°C) and 44 days at refrigeration (5°C).
Reconstitution
Injection: Reconstitute with at least 5 mL sterile water to provide a solution containing not more than 100 mg/mL. Further dilute in D5W or NS for I.V. infusion.
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.
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)
Dosage
Note: I.M. administration is not recommended because of pain secondary to the alkaline pH
Children:
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: 8-30 mg/kg/day in 1-4 divided doses, not to exceed 1 g/day; extended release capsule is not recommended for treatment of epilepsy
Adults:
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; 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
Elderly: Oral: Initial: 250 mg twice daily; use lowest effective dose
Dosing adjustment in renal impairment:
Clcr 10-50 mL/minute: Administer every 12 hours
Clcr <10 mL/minute: Avoid use (ineffective)
Hemodialysis: Moderately dialyzable (20% to 50%)
Peritoneal dialysis: Supplemental dose is not necessary
Administration: Oral
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.
Administration: I.M.
I.M. administration is painful because of the alkaline pH of the drug; use by this route is not recommended.
Administration: I.V. Detail
pH: 9.2
Monitoring Parameters
Intraocular pressure, potassium, serum bicarbonate; serum electrolytes, periodic CBC with differential; monitor growth in pediatric patients
Test Interactions
May cause false-positive results for urinary protein with Albustix®, Labstix®, Albutest®, Bumintest®; interferes with HPLC theophylline assay and serum uric acid levels
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).
Patient Education
Take as directed; do not chew or crush long-acting capsule (contents may be sprinkled on soft food). May be administered with food to decrease GI upset. You will need periodic ophthalmic examinations while taking this medication. You may experience drowsiness, dizziness, or weakness (use caution when driving or engaging in tasks that require alertness until response to drug is known); or nausea, loss of appetite, or altered taste (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help). Monitor serum glucose closely (may cause altered blood glucose in some patients with diabetes, or unusual response to some forms of glucose testing). You may experience increased sensitivity to sunlight (use sunblock, protective clothing, and avoid exposure to direct sunlight). Report unusual and persistent tiredness; numbness, burning, or tingling of extremities or around mouth, lips, or anus; muscle weakness; black stool; or excessive depression. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Consult prescriber if breast-feeding.
Geriatric Considerations
Malaise and complaints of tiredness and myalgia are signs of excessive dosing and acidosis in older adults. Orthostatic hypotension may occur; assess blood pressure.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Metallic taste (resolves upon discontinuation)
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
Drowsiness is common, may produce depression less commonly
Mental Health: Effects on Psychiatric Treatment
Can rarely cause bone marrow suppression, therefore, use cautiously with clozapine and carbamazepine; may increase the excretion of lithium
Nursing: Physical Assessment/Monitoring
Assess allergy history prior to beginning therapy. Assess effectiveness and interactions of other medications patient may be taking. Monitor for signs of excessive dosing and acidosis (especially in elderly). Measure intraocular pressure at the beginning of therapy and periodically while on this medication. Assess results of laboratory tests, therapeutic effectiveness, and adverse response. Monitor growth in pediatric patients. Monitor blood glucose levels closely if patients have diabetes. Assess knowledge/teach patient appropriate use, possible side effects/appropriate interventions, and adverse symptoms to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, extended release:
Diamox® Sequels®: 500 mg
Injection, powder for reconstitution: 500 mg
Tablet: 125 mg, 250 mg
Pricing: U.S. (www.drugstore.com)
Capsule, 12-hour (Diamox Sequels)
500 mg (60): $249.98
Tablets (AcetaZOLAMIDE)
125 mg (90): $15.00
250 mg (60): $29.99
Extemporaneously Prepared
Tablets may be crushed and suspended in cherry, chocolate, raspberry, or other highly-flavored carbohydrate syrup in concentrations of 25-100 mg/mL; simple suspensions are stable for 7 days. For solutions with longer stability, see references for Parastampuria and Alexander.
Alexander KS, Haribhakti RP, and Parker GA, “Stability of Acetazolamide in Suspension Compounded From Tablets,” Am J Hosp Pharm, 1991, 48(6):1241-4.
McEvoy G, ed, AHFS Drug Information 96, Bethesda, MD: American Society of Health System Pharmacists, 1996.
Parastampuria J and Gupta VD, “Development of Oral Liquid Dosage Forms of Acetazolamide,” J Pharm Sci, 1990, 79:385-6.
References
“American Academy of Pediatrics Committee on Drugs: The Transfer of Drugs and Other Chemicals Into Human Milk,” Pediatrics, 1994, 93(1):137-150.
Chapron DJ, Gomolin IH, and Sweeney KR, “Acetazolamide Blood Concentrations Are Excessive in the Elderly: Propensity for Acidosis and Relationship to Renal Function,” J Clin Pharmacol, 1989, 29(4):348-53.
Chapron DJ, Sweeney KR, Feig PU, et al, “Influence of Advanced Age on the Disposition of Acetazolamide,” Br J Clin Pharmacol, 1985, 19:363-71.
Corbett JT, “Acetazolamide and Purpura,” Br Med J, 1985, 1:1122-3.
Heller I, Halevy J, Cohen S, et al, “Significant Metabolic Acidosis Induced by Acetazolamide,” Arch Intern Med, 1985, 145(10):1815-7.
Marik PE, Kussman BD, Lipman J, et al, "Acetazolamide in the Treatment of Metabolic Alkalosis in Critically Ill Patients," Heart Lung, 1991, 20(5 Pt 1):455-9.
Mazur JE, Devlin JW, Peters MJ, et al, "Single Versus Multiple Doses of Acetazolamide for Metabolic Alkalosis in Critically Ill Medical Patients: A Randomized, Double-Blind Trial," Crit Care Med, 1999, 27(7):1257-61.
Parikh JR, Nolan RL, Bannerjee A, et al, “Acetazolamide-Associated Nephrocalcinosis in a Transplant Kidney,” Transplantation, 1995, 59(12):1742-3.
Reiss WG and Oles KS, “Acetazolamide in the Treatment of Seizures,” Ann Pharmacother, 1996, 30(5):514-9.
Rousseau P and Fuentevilla-Clifton A, “Acetazolamide and Salicylate Interaction in the Elderly: A Case Report,” J Am Geriatr Soc, 1993, 41(8):868-9.
Schwenk MH, St. Peter WL, Meese MG, et al, “Acetazolamide Toxicity and Pharmacokinetics in Patients Receiving Hemodialysis,” Pharmacotherapy, 1995, 15(4):522-7.
Shinnar S, Gammon K, Bergman EW Jr, et al, “Management of Hydrocephalus in Infancy: Use of Acetazolamide and Furosemide to Avoid Cerebrospinal Fluid Shunts,” J Pediatr, 1985, 107(1):31-7.
Vaziri ND, Saiki J, Barton CH, et al, “Hemodialyzability of Acetazolamide,” South Med J, 1980, 73(4):422-3.
Wandstrat TL and Phillips J, “Pseudotumor Cerebri Responsive to Acetazolamide,” Ann Pharmacother, 1995, 29(3):318.
Weiss IS, “Hirsutism After Chronic Administration of Acetazolamide,” Am J Ophthalmol, 1974, 78(2):327-8.
International Brand Names
Lexi-Comp.com
Last full review/revision August 2008
Content last modified August 2008
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