Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Tablet, Oral:
Generic: 250 mg [DSC], 500 mg [DSC]
Pharmacology
Mechanism of Action
Stimulates insulin release from the pancreatic beta cells; reduces glucose output from the liver; insulin sensitivity is increased at peripheral target sites
Pharmacokinetics/Pharmacodynamics
Metabolism
Extensively hepatic to 5 metabolites (activity 0% to 70%)
Excretion
Urine (85%); feces (7%)
Onset of Action
Hypoglycemic effect: 20 minutes; Peak hypoglycemic effect: 4-6 hours
Time to Peak
Serum: 3-4 hours
Duration of Action
10-24 hours
Half-Life Elimination
7 hours
Protein Binding
94%
Use: Labeled Indications
Adjunct to diet for the management of mild-to-moderately severe, stable, type 2 diabetes mellitus
Guideline recommendations: First-generation sulfonylureas (eg, tolazamide) are not recommended treatment options for type 2 diabetes; later-generation sulfonylureas with lower hypoglycemic risks (eg, glipizide) are preferred (ADA 2019).
Contraindications
Hypersensitivity to tolazamide, sulfonylureas, or any component of the formulation; type 1 diabetes mellitus; diabetic ketoacidosis
TOLAZamide Images
Dosage and Administration
Dosing: Adult
Diabetes mellitus, type 2: Oral:
Initial: 100 to 250 mg/day with breakfast or the first main meal of the day
Fasting blood sugar <200 mg/dL: 100 mg/day
Fasting blood sugar >200 mg/dL: 250 mg/day
Patient is malnourished, underweight, or not eating properly: 100 mg/day
Adjustment/titration: Increase in increments of 100 to 250 mg/day at weekly intervals to response; doses >500 mg/day may be given in 2 divided doses; maximum daily dose: 1 g (doses >1 g/day are not likely to improve control)
Conversion from insulin to tolazamide:
<20 units day = 100 mg/day
21 to <40 units/day = 250 mg/day
≥40 units/day = 250 mg/day and 50% of insulin dose
Dosing: Geriatric
Initial: 100 mg once daily; use with caution.
Administration
Oral: Administer with food once a day with breakfast or the first main meal; administer doses >500 mg/day in 2 equally divided doses
Drug Interactions
Ajmaline: Sulfonamides may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased. Monitor therapy
Alcohol (Ethyl): Sulfonylureas may enhance the adverse/toxic effect of Alcohol (Ethyl). A flushing reaction may occur. Monitor therapy
Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy
Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Avoid combination
Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Monitor therapy
Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy
Antidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy
Beta-Blockers: May enhance the hypoglycemic effect of Sulfonylureas. Cardioselective beta-blockers (eg, acebutolol, atenolol, metoprolol, and penbutolol) may be safer than nonselective beta-blockers. All beta-blockers appear to mask tachycardia as an initial symptom of hypoglycemia. Ophthalmic beta-blockers are probably associated with lower risk than systemic agents. Exceptions: Levobunolol; Metipranolol. Monitor therapy
Carbocisteine: Sulfonylureas may enhance the adverse/toxic effect of Carbocisteine. Specifically, sulfonylureas may enhance adverse effects of alcohol that is present in liquid formulations of carbocisteine-containing products. Monitor therapy
Chloramphenicol (Systemic): May decrease the metabolism of Sulfonylureas. Monitor therapy
Cimetidine: May increase the serum concentration of Sulfonylureas. Monitor therapy
Cyclic Antidepressants: May enhance the hypoglycemic effect of Sulfonylureas. Monitor therapy
Dexketoprofen: May enhance the adverse/toxic effect of Sulfonamides. Monitor therapy
Dipeptidyl Peptidase-IV Inhibitors: May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider a decrease in sulfonylurea dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients for hypoglycemia. Consider therapy modification
Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy
Fibric Acid Derivatives: May enhance the hypoglycemic effect of Sulfonylureas. Monitor therapy
Fluconazole: May increase the serum concentration of Sulfonylureas. Management: Seek alternatives when possible. If used together, monitor closely for increased effects of sulfonylureas if fluconazole is initiated/dose increased, or decreased effects if fluconazole is discontinued/dose decreased. Consider therapy modification
Glucagon-Like Peptide-1 Agonists: May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose reductions when used in combination with glucagon-like peptide-1 agonists. Consider therapy modification
Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy
Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy
Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy
Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Monitor therapy
Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy
Maitake: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy
Mecamylamine: Sulfonamides may enhance the adverse/toxic effect of Mecamylamine. Avoid combination
Metreleptin: May enhance the hypoglycemic effect of Sulfonylureas. Management: Sulfonylurea dosage adjustments (including potentially large decreases) may be required to minimize the risk for hypoglycemia with concurrent use of metreleptin. Monitor closely. Consider therapy modification
Miconazole (Oral): May enhance the hypoglycemic effect of Sulfonylureas. Miconazole (Oral) may increase the serum concentration of Sulfonylureas. Monitor therapy
Mitiglinide: May enhance the adverse/toxic effect of Sulfonylureas. Avoid combination
Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy
Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy
Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Monitor therapy
Probenecid: May decrease the protein binding of Sulfonylureas. Probenecid may increase the serum concentration of Sulfonylureas. Monitor therapy
Prothionamide: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy
Quinolones: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolones may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy
RaNITIdine: May increase the serum concentration of Sulfonylureas. Monitor therapy
RifAMPin: May decrease the serum concentration of Sulfonylureas. Management: Seek alternatives to these combinations when possible. Monitor closely for diminished therapeutic effects of sulfonylureas if rifampin is initiated/dose increased, or enhanced effects if rifampin is discontinued/dose decreased. Consider therapy modification
Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy
Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy
Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy
Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors: May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider a decrease in sulfonylurea dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia. Consider therapy modification
Sulfonamide Antibiotics: May enhance the hypoglycemic effect of Sulfonylureas. Monitor therapy
Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy
Thiazolidinediones: May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose adjustments in patients taking thiazolidinediones and monitor for hypoglycemia. Consider therapy modification
Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Monitor therapy
Vitamin K Antagonists (eg, warfarin): Sulfonylureas may enhance the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may enhance the hypoglycemic effect of Sulfonylureas. Monitor therapy
Voriconazole: May increase the serum concentration of Sulfonylureas. Monitor therapy
Adverse Reactions
Frequency not defined.
Central nervous system: Disulfiram-like reaction, dizziness, fatigue, headache, malaise, vertigo
Dermatologic: Maculopapular rash, morbilliform rash, pruritus, skin photosensitivity, skin rash, urticaria
Endocrine & metabolic: Hepatic porphyria, hypoglycemia, hyponatremia, porphyria cutanea tarda, SIADH (syndrome of inappropriate antidiuretic hormone secretion)
Gastrointestinal: Anorexia, constipation, diarrhea, epigastric fullness, heartburn, nausea, vomiting
Genitourinary: Diuretic effect
Hematologic & oncologic: Agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, pancytopenia, thrombocytopenia
Hepatic: Cholestatic jaundice
Neuromuscular & skeletal: Weakness
Warnings/Precautions
Concerns related to adverse effects:
- Cardiovascular mortality: Product labeling states oral hypoglycemic drugs may be associated with an increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. Data to support this association are limited, and several studies, including a large prospective trial (UKPDS), have not supported an association. In patients with established atherosclerotic cardiovascular disease (ASCVD), other agents are preferred (ADA 2019).
- Hypoglycemia: All sulfonylurea drugs are capable of producing severe hypoglycemia. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when ethanol is ingested, or when more than one glucose-lowering drug is used. It is also more likely in elderly patients, malnourished patients and in patients with impaired renal or hepatic function; use with caution.
- Sulfonamide (“sulfa”) allergy: The FDA-approved product labeling for many medications containing a sulfonamide chemical group includes a broad contraindication in patients with a prior allergic reaction to sulfonamides. There is a potential for cross-reactivity between members of a specific class (eg, two antibiotic sulfonamides). However, concerns for cross-reactivity have previously extended to all compounds containing the sulfonamide structure (SO2NH2). An expanded understanding of allergic mechanisms indicates cross-reactivity between antibiotic sulfonamides and nonantibiotic sulfonamides may not occur or at the very least this potential is extremely low (Brackett 2004; Johnson 2005; Slatore 2004; Tornero 2004). In particular, mechanisms of cross-reaction due to antibody production (anaphylaxis) are unlikely to occur with nonantibiotic sulfonamides. T-cell-mediated (type IV) reactions (eg, maculopapular rash) are less well understood and it is not possible to completely exclude this potential based on current insights. In cases where prior reactions were severe (Stevens-Johnson syndrome/TEN), some clinicians choose to avoid exposure to these classes.
Disease-related concerns:
- Bariatric surgery:
– Altered absorption: Use IR formulations after surgery to minimize the potential effects of bypassing stomach and proximal small bowel with gastric bypass or more rapid gastric emptying and proximal small bowel transit with sleeve gastrectomy (Apovian 2015). ER formulations may have altered release and absorption patterns after gastric bypass or sleeve gastrectomy (but not gastric band). Compared to control, Tmax in a gastric bypass cohort administered tolbutamide was significantly shorter (1.4 ± 1.8 vs 5.1 ± 1.7 hours; P < 0.001), while Cmax and AUC0-∞ were not altered (Tandra 2013).
– Hypoglycemia: Use an antidiabetic agent without the potential for hypoglycemia if possible; hypoglycemia may occur after gastric bypass, sleeve gastrectomy, and gastric band (Mechanick 2013). Insulin secretion and sensitivity may be partially or completely restored after these procedures (gastric bypass is most effective, followed by sleeve and finally band) (Korner 2009; Peterli 2012). First-phase insulin secretion and hepatic insulin sensitivity have been shown to be significantly improved in the immediate days after gastric bypass and sleeve gastrectomy. The restorative effects of these procedures on peripheral insulin sensitivity may occur later in the 3- to 12-month period postsurgery (Mingrone 2016).
– Weight gain: Evaluate risk vs benefit and consider alternative therapy after gastric bypass, sleeve gastrectomy, and gastric banding; weight gain may occur (Apovian 2015).
- Glucose-6-phosphate dehydrogenase (G6PD) deficiency: Patients with G6PD deficiency may be at an increased risk of sulfonylurea-induced hemolytic anemia; however, cases have also been described in patients without G6PD deficiency during postmarketing surveillance. Use with caution and consider a nonsulfonylurea alternative in patients with G6PD deficiency.
- Stress-related states: It may be necessary to discontinue therapy and administer insulin if the patient is exposed to stress (fever, trauma, infection, surgery).
Other warnings/precautions:
- Secondary failure: Loss of efficacy may be observed following prolonged use as a result of the progression of type 2 diabetes mellitus which results in continued beta cell destruction. In patients who were previously responding to sulfonylurea therapy, consider additional factors which may be contributing to decreased efficacy (eg, inappropriate dose, nonadherence to diet and exercise regimen). If no contributing factors can be identified, consider discontinuing use of the sulfonylurea due to secondary failure of treatment.
Monitoring Parameters
Signs and symptoms of hypoglycemia (fatigue, sweating, numbness of extremities); blood glucose; hemoglobin A1c (at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; quarterly in patients not meeting treatment goals or with therapy change [ADA 2019])
Pregnancy
Pregnancy Risk Factor
C
Pregnancy Considerations
Severe hypoglycemia lasting 4 to 10 days has been noted in infants born to mothers taking a sulfonylurea at the time of delivery. Additional adverse events have been reported and may be influenced by maternal glycemic control (Piacquadio 1991). The manufacturer recommends if tolazamide is used during pregnancy, it should be discontinued at least 2 weeks before the expected delivery date.
Poorly controlled diabetes during pregnancy can be associated with an increased risk of adverse maternal and fetal outcomes, including diabetic ketoacidosis, preeclampsia, spontaneous abortion, preterm delivery, delivery complications, major birth defects, stillbirth, and macrosomia (ACOG 201 2018). To prevent adverse outcomes, prior to conception and throughout pregnancy, maternal blood glucose and HbA1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ADA 2020; Blumer 2013).
Agents other than tolazamide are currently recommended to treat diabetes mellitus in pregnancy (ADA 2020).
Patient Education
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience nausea, heartburn, or bloating. Have patient report immediately to prescriber yellow skin, dark urine, bruising, bleeding, severe loss of strength and energy, chills, sore throat, or signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, fast heartbeat, confusion, increased hunger, or sweating) (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
