Tolinase

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from light, excess heat, and moisture (not in the bathroom).

Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for more information if you do not have access to a take-back program.

It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. http://www.upandaway.org

Pregnancy Category: C

Lactation: not known if crosses into breast milk, avoid

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

If you take too much Tolinase, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

Take the missed dose as soon as you remember (be sure to take the medicine with food). Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

In the U.S.

• Tolinase

Available Dosage Forms:

• Tablet

Therapeutic Class: Hypoglycemic

Chemical Class: 1st Generation Sulfonylurea

Tolazamide is used to treat high blood sugar levels caused by a type of diabetes mellitus (sugar diabetes) called type 2 diabetes. In type 2 diabetes, your body does not work properly to store excess sugar and the sugar remains in your bloodstream. Chronic high blood sugar can lead to serious health problems in the future .

Proper diet is the first step in managing type 2 diabetes, but often medicines are needed to help your body. Tolazamide belongs to a class of drugs called sulfonylureas. It causes your pancreas to release more insulin into the blood stream .

This medicine is available only with your doctor's prescription .

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Abdominal or stomach pain
• chills
• clay-colored stools
• dark urine
• diarrhea
• difficulty swallowing
• dizziness
• fast heartbeat
• fever
• headache
• hives
• itching
• loss of appetite
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• rash
• shortness of breath
• skin rash
• tightness in chest
• unpleasant breath odor
• unusual tiredness or weakness
• vomiting of blood
• wheezing
• yellow eyes or skin

• Agitation
• back, leg, or stomach pains
• black, tarry stools
• bleeding gums
• blood in urine or stools
• chest pain
• coma
• confusion
• convulsions
• cough or hoarseness
• decreased urine output
• depression
• difficulty breathing
• fast or irregular heartbeat
• fatigue
• fever with or without chills
• fluid-filled skin blisters
• general body swelling
• general feeling of tiredness or weakness
• hostility
• increased thirst
• irritability
• itching of the skin
• lethargy
• light-colored stools
• lower back or side pain
• muscle pain or cramps
• muscle twitching
• nausea or vomiting
• nosebleeds
• painful or difficult urination
• pale skin
• pinpoint red spots on skin
• rapid weight gain
• seizures
• sensitivity to the sun
• skin thinness
• sore throat
• sores, ulcers, or white spots on the lips or in the mouth
• stupor
• swelling of the face, ankles, or hands
• swollen or painful glands
• unusual bleeding or bruising

Get emergency help immediately if any of the following symptoms of overdose occur:

• Anxiety
• cold sweats
• cool, pale skin
• increased hunger
• nervousness
• nightmares
• shakiness
• slurred speech

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Indigestion
• passing of gas

• Feeling of constant movement of self or surroundings
• sensation of spinning

• Redness or other discoloration of skin
• severe sunburn

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Tolinase Tablets contain tolazamide, an oral blood glucose lowering drug of the sulfonylurea class. Tolazamide is a white or creamy-white powder with a melting point of 165° to 173° C. The solubility of tolazamide at pH 6.0 (mean urinary pH) is 27.8 mg per 100 mL.

The chemical names for tolazamide are (1) Benzenesulfonamide, N-[[(hexahydro-1H-azepin-1-yl) amino] carbonyl]-4-methyl-; (2) 1-(Hexahydro-1H-azepin-1-yl)-3-(p-tolylsulfonyl)urea and its molecular weight is 311.40. The structural formula is represented below:

Tolinase Tablets for oral administration are available as scored, white tablets containing 100 mg, 250 mg or 500 mg tolazamide. Inactive ingredients: calcium sulfate, docusate sodium, magnesium stearate, methylcellulose, sodium alginate.

The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with noninsulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups (DIABETES, 19 (supp. 2):747–830, 1970.)

UGDP reported that patients treated for five to eight years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2½ times that of patients with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of Tolinase and of alternative modes of therapy.

Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.

General

All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper patient selection and dosage and instructions are important to avoid hypoglycemic episodes. Renal or hepatic insufficiency may cause elevated blood levels of tolazamide and the latter may also diminish gluconeogenic capacity, both of which increase the risk of serious hypoglycemic reactions. Elderly, debilitated, or malnourished patients and those with adrenal or pituitary insufficiency are particularly susceptible to the hypoglycemic action of glucose lowering drugs. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose-lowering drug is used.

When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, loss of control of blood glucose may occur. At such times it may be necessary to discontinue Tolinase Tablets and administer insulin.

The effectiveness of any hypoglycemic drug, including Tolinase, in lowering blood glucose to a desired level decreases in many patients over a period of time, which may be due to progression of the severity of the diabetes or to diminished responsiveness to the drug. This phenomenon is known as secondary failure to distinguish it from primary failure in which the drug is ineffective in an individual patient when first given. Adequate adjustment of dose and adherence to diet should be assessed before classifying a patient as a secondary failure.

Information for Patients

Patients should be informed of the potential risks and advantages of Tolinase and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of urine and/or blood glucose.

The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. Primary and secondary failure should also be explained.

Laboratory Tests

Blood and urine glucose should be monitored periodically. Measurement of glycosylated hemoglobin may be useful in some patients.

Drug Interactions

The hypoglycemic action of sulfonylureas may be potentiated by certain drugs including nonsteroidal anti-inflammatory agents and other drugs that are highly protein bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, and beta-adrenergic blocking agents. When such drugs are administered to a patient receiving Tolinase, the patient should be closely observed for hypoglycemia. When such drugs are withdrawn from a patient receiving Tolinase, the patient should be observed closely for loss of control.

Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving Tolinase, the patient should be closely observed for loss of control. When such drugs are withdrawn from a patient receiving Tolinase, the patient should be observed closely for hypoglycemia.

A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the intravenous, topical or vaginal preparations of miconazole is not known.

Carcinogenicity

In a bioassay for carcinogenicity, rats and mice of both sexes were treated with tolazamide for 103 weeks at low and high doses. No evidence of carcinogenicity was found.

Pregnancy

Pregnancy Category C

Tolinase, administered to pregnant rats at ten times the human dose, decreased litter size but did not produce teratogenic effects in the offspring. In rats treated at a daily dose of 14 mg/kg no reproductive aberrations or drug related fetal anomalies were noted. At an elevated dose of 100 mg/kg per day there was a reduction in the number of pups born and an increased perinatal mortality. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Tolinase is not recommended for the treatment of the pregnant diabetic patient. Serious consideration should also be given to the possible hazards of the use of Tolinase in women of child bearing age and in those who might become pregnant while using the drug.

Because recent information suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities, many experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible.

Prolonged severe hypoglycemia (four to ten days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. If Tolinase is used during pregnancy, it should be discontinued at least two weeks before the expected delivery date.

Nursing Mothers

Although it is not known whether tolazamide is excreted in human milk, some sulfonylurea drugs are known to be excreted in human milk. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If the drug is discontinued and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

Pediatric Use

Safety and effectiveness in children have not been established.

Geriatric Use

Elderly patients are particularly susceptible to the hypoglycemic action of glucose lowering drugs. Hypoglycemia may be difficult to recognize in the elderly (see PRECAUTIONS). The initial and maintenance dosing should be conservative to avoid hypoglycemic reactions (see DOSAGE AND ADMINISTRATION).

Elderly patients are prone to develop renal insufficiency,which may put them at risk of hypoglycemia. Dose selection should include assessment of renal function.

Applies to tolazamide: oral tablet

General

The most commonly reported adverse reactions have included gastrointestinal disturbances such as nausea, epigastric fullness, and heartburn.[Ref]

Metabolic

Very rare (less than 0.01%): Disulfiram-like reactions
Frequency not reported: Hypoglycemia

Sulfonylureas:
Frequency not reported: Hepatic porphyria[Ref]

Gastrointestinal

Gastrointestinal disturbances such as nausea, epigastric fullness, and heartburn tend to be dose related and may disappear when dosage is reduced.[Ref]

Common (1% to 10%): Nausea, epigastric fullness, heartburn[Ref]

Cardiovascular

In the University Group Diabetes Program (UGDP) study, cardiovascular mortality rate was approximately 2.5 times higher in patients treated for 5 to 8 years with diet plus tolbutamide 1.5 g per day compared with that of patients treated with diet alone. The UGDP study was a long-term prospective clinical trial designed to evaluate the effectiveness of glucose lowering drugs in preventing or delaying vascular complications in patients with type 2 diabetes mellitus (n=823). Tolbutamide was stopped based on the increase in cardiovascular mortality; a significant increase in total mortality was not observed, but stopping the drug may have limited the ability to measure that. In view of the close similarities in mode of action and chemical structure among sulfonylureas, these results may apply to other drug in this class.[Ref]

Sulfonylureas:
Frequency not reported: Increased cardiovascular mortality[Ref]

Hypersensitivity

Frequency not reported: Hypersensitivity reactions[Ref]

Hypersensitivity reactions described as skin reactions, e.g. pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions occurred in 0.4% of patients during clinical trials. These may be transient and may disappear despite continued therapy; however, if skin reactions persist, this drug should be discontinued.[Ref]

Nervous system

Uncommon (0.1% to 1%): Dizziness, headache, weakness[Ref]

Hepatic

Rare (less than 0.1%): Cholestatic jaundice[Ref]

Endocrine

Frequency not reported: Hyponatremia

Sulfonylureas:
Frequency not reported: Syndrome of inappropriate antidiuretic hormone (SIADH) secretion[Ref]

Other

Uncommon (0.1% to 1%): Fatigue, malaise, vertigo[Ref]

Hematologic

Sulfonylureas:
Rare (less than 0.1%): Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia, pancytopenia

Dermatologic

Uncommon (0.1% to 1%): Allergic skin reactions (pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions)

Sulfonylureas:
Frequency not reported: Photosensitivity, porphyria cutanea tarda[Ref]

Some side effects of Tolinase may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.