Rastinon

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Rastinon uses

Rastinon consists of Tolbutamide, Tolbutamide Sodium.

Tolbutamide:


DESCRIPTION

Rastinon (Tolbutamide) is an oral blood-glucose-lowering drug of the sulfonylurea class. Rastinon (Tolbutamide) is a pure, white, crystalline compound which is practically insoluble in water. The chemical name is benzenesulfonamide, N-[(butylamino)-carbonyl]-4-methyl-. Its structure can be represented as follows:

Rastinon (Tolbutamide) is supplied as compressed tablets containing 500 mg of Rastinon (Tolbutamide), USP.

Each tablet for oral administration contains 500 mg of Rastinon (Tolbutamide) and the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate and sodium starch glycolate.

Rastinon (Tolbutamide) Structural Formula

CLINICAL PHARMACOLOGY

Actions

Rastinon appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which Rastinon (Tolbutamide) lowers blood glucose during long-term administration has not been clearly established. With chronic administration in Type II diabetic patients, the blood-glucose-lowering effect persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic effects may be involved in the mechanism of action of oral sulfonylurea hypoglycemic drugs.

Some patients who are initially responsive to oral hypoglycemic drugs, including Rastinon (Tolbutamide), may become unresponsive or poorly responsive over time. Alternatively, Rastinon (Tolbutamide) may be effective in some patients who have become unresponsive to one or more of the other sulfonylurea drugs.

Pharmacokinetics

When administered orally, Rastinon (Tolbutamide) is readily absorbed from the gastrointestinal tract. Absorption is not impaired and glucose lowering and insulin releasing effects are not altered if the drug is taken with food. Detectable levels are present in the plasma within 20 minutes after oral ingestion of a 500 mg Rastinon (Tolbutamide) tablet, with peak levels occurring at 3 to 4 hours and only small amounts detectable at 24 hours. The half-life of Rastinon (Tolbutamide) is 4.5 to 6.5 hours. As Rastinon (Tolbutamide) has no p-amino group, it cannot be acetylated, which is one of the common modes of metabolic degradation for the antibacterial sulfonamides. However, the presence of the p-methyl group renders Rastinon (Tolbutamide) susceptible to oxidation, and this appears to be the principal manner of its metabolic degradation in man. The p-methyl group is oxidized to form a carboxyl group, converting Rastinon (Tolbutamide) into the totally inactive metabolite 1-butyl-3-p-carboxy-phenylsulfonylurea, which can be recovered in the urine within 24 hours in amounts accounting for up to 75% of the administered dose.

The major Rastinon (Tolbutamide) metabolite has been found to have no hypoglycemic or other action when administered orally and IV to both normal and diabetic subjects. This Rastinon (Tolbutamide) metabolite is highly soluble over the critical acid range of urinary pH values, and its solubility increases with increase in pH. Because of the marked solubility of the Rastinon (Tolbutamide) metabolite, crystalluria does not occur. A second metabolite, 1-butyl-3-(p-hydroxymethyl) phenyl sulfonylurea also occurs to a limited extent. It is an inactive metabolite.

The administration of 3 grams of Rastinon (Tolbutamide) to either nondiabetic or tolbutamide-responsive diabetic subjects will, in both instances, occasion a gradual lowering of blood glucose. Increasing the dose to 6 grams does not usually cause a response which is significantly different from that produced by the 3 gram dose. Following the administration of a 3 gram dose of Rastinon (Tolbutamide) solution, non-diabetic fasting adults exhibit a 30% or greater reduction in blood glucose within one hour, following which the blood glucose gradually returns to the fasting level over 6 to 12 hours. Following the administration of a 3 gram dose of Rastinon (Tolbutamide) solution, Rastinon (Tolbutamide) responsive diabetic patients show a gradually progressive blood glucose lowering effect, the maximal response being reached between 5 to 8 hours after ingestion of a single 3 gram dose. The blood glucose then rises gradually and by the 24th hour has usually returned to pretest levels. The magnitude of the reduction, when expressed in terms of percent of the pretest blood glucose, tends to be similar to the response seen in the nondiabetic subject.

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INDICATIONS AND USAGE

Rastinon (Tolbutamide) tablets are indicated as an adjunct to diet to lower the blood glucose in patients with non-insulin-dependent diabetes mellitus (type II) whose hyperglycemia cannot be controlled by diet alone.

In initiating treatment for non-insulin-dependent diabetes, diet should be emphasized as the primary form of treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. Proper dietary management alone may be effective in controlling the blood glucose and symptoms of hyperglycemia. The importance of regular physical activity should also be stressed, and cardiovascular risk factors should be identified and corrective measures taken where possible.

If this treatment program fails to reduce symptoms and/or blood glucose, the use of an oral sulfonylurea or insulin should be considered. Use of Rastinon (Tolbutamide) tablets must be viewed by both the physician and patient as a treatment in addition to diet, and not as a substitute for diet or as a convenient mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control on diet alone may be transient, thus requiring only short-term administration of Rastinon (Tolbutamide) tablets.

During maintenance programs, Rastinon (Tolbutamide) tablets should be discontinued if satisfactory lowering of blood glucose is no longer achieved. Judgments should be based on regular clinical and laboratory evaluations.

In considering the use of Rastinon (Tolbutamide) tablets in asymptomatic patients, it should be recognized that controlling the blood glucose in non-insulin dependent diabetes has not been definitely established to be effective in preventing the long-term cardiovascular or neural complications of diabetes.

CONTRAINDICATIONS

Rastinon (Tolbutamide) tablets are contraindicated in patients with:

  • Known hypersensitivity or allergy to the drug.
  • Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.
  • Type I diabetes, as sole therapy.
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WARNINGS

SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY

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 non-insulin-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 5 to 8 years with diet plus a fixed dose of Rastinon (Tolbutamide) (1.5 grams per day) had a rate of cardiovascular mortality approximately 2½ times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of Rastinon (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 Rastinon (Tolbutamide) 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.

PRECAUTIONS

General

Hypoglycemia

All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Renal or hepatic insufficiency may cause elevated blood levels of Rastinon 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.

Loss of Control of Blood Glucose

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

The effectiveness of any oral hypoglycemic drug, including Rastinon (Tolbutamide), 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 a 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.

Hemolytic Anemia

Treatment of patients with glucose 6-phosphate dehydrogenase deficiency with sulfonylurea agents can lead to hemolytic anemia. Because Rastinon (Tolbutamide) belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered. In post-marketing reports, hemolytic anemia has also been reported in patients who did not have known G6PD deficiency.

Information for Patients

Patients should be informed of the potential risks and advantages of Rastinon (Tolbutamide) 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.

A metabolite of Rastinon in urine may give a false positive reaction for albumin if measured by the acidification-after-boiling test, which causes the metabolite to precipitate. There is no interference with the sulfosalicylic acid test.

Drug Interactions

The hypoglycemia action of sulfonylurea may be potentiated by certain drugs including non-steroidal 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 Rastinon (Tolbutamide), the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving Rastinon (Tolbutamide), 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 Rastinon (Tolbutamide), the patient should be closely observed for loss of control. When such drugs are withdrawn from a patient receiving Rastinon (Tolbutamide), 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 and Mutagenicity

Bioassay for carcinogenicity was performed in both sexes of rats and mice following ingestion of Rastinon for 78 weeks. No evidence of carcinogenicity was found.

Rastinon (Tolbutamide) has also been demonstrated to be nonmutagenic in the Ames salmonella/mammalian microsome mutagenicity test.

Pregnancy

Teratogenic Effects: Pregnancy Category C

Rastinon has been shown to be teratogenic in rats when given in doses 25 to 100 times the human dose. In some studies, pregnant rats given high doses of Rastinon (Tolbutamide) have shown ocular and bony abnormalities and increased mortality in offspring. Repeat studies in other species (rabbits) have not demonstrated a teratogenic effect. There are no adequate and well controlled studies in pregnant women. Rastinon (Tolbutamide) is not recommended for the treatment of pregnant diabetic patients.

Serious consideration should also be given to the possible hazards of the use of Rastinon (Tolbutamide) in women of childbearing 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.

Nonteratogenic Effects

Prolonged severe hypoglycemia (4 to 10 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 Rastinon (Tolbutamide) is used during pregnancy, it should be discontinued at least 2 weeks before the expected delivery date.

Nursing Mothers

Although it is not known whether Rastinon 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.

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ADVERSE REACTIONS

Hypoglycemia

Gastrointestinal Reactions

Cholestatic jaundice may occur rarely; Rastinon should be discontinued if this occurs. Gastrointestinal disturbances, e.g., nausea, epigastric fullness, and heartburn, are the most common reactions and occur in 1.4% of patients treated during clinical trial. They tend to be dose related and may disappear when dosage is reduced.

Dermatologic Reactions

Allergic skin reactions, e.g., pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occur in 1.1% of patients treated during clinical trials. These may be transient and may disappear despite continued use of Rastinon (Tolbutamide); if skin reactions persist, the drug should be discontinued.

Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas.

Hematologic Reactions

Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia, and pancytopenia have been reported with sulfonylureas.

Metabolic Reactions

Hepatic porphyria and disulfiram-like reactions have been reported with sulfonylureas.

Endocrine Reactions

Cases of hyponatremia and the syndrome of inappropriate antidiuretic hormone secretion have been reported with this and other sulfonylureas.

Miscellaneous Reactions

Headache and taste alterations have occasionally been reported with Rastinon (Tolbutamide) administration.

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OVERDOSAGE

Overdosage of sulfonylureas including Rastinon (Tolbutamide) can produce hypoglycemia. Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) dextrose injection. This should be followed by a continuous infusion of a more dilute (10%) dextrose injection at a rate that will maintain the blood glucose at a level above 100 mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours since hypoglycemia may recur after apparent clinical recovery.

DOSAGE AND ADMINISTRATION

There is no fixed dosage regimen for the management of diabetes mellitus with Rastinon tablets or any other hypoglycemic agent. In addition to the usual monitoring of urinary glucose, the patient's blood glucose must also be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of an adequate blood glucose lowering response after an initial period of effectiveness. Glycosylated hemoglobin levels may also be of value in monitoring the patient's response to therapy.

Short-term administration of Rastinon (Tolbutamide) tablets may be sufficient during periods of transient loss of control in patients usually controlled well on diet.

Usual Starting Dose

The usual starting dose is 1 to 2 grams daily. This may be increased or decreased, depending on individual patient response. Failure to follow an appropriate dosage regimen may precipitate hypoglycemia. Patients who do not adhere to their prescribed dietary regimens are more prone to exhibit unsatisfactory response to drug therapy.

Transfer from Other Hypoglycemic Therapy

Patients Receiving Other Antidiabetic Therapy

Transfer of patients from other oral antidiabetes regimens to Rastinon tablets should be done conservatively. When transferring patients from oral hypoglycemic agents other than chlorpropamide to Rastinon (Tolbutamide), no transition period and no initial or priming doses are necessary. When transferring patients from chlorpropamide, however, particular care should be exercised during the first 2 weeks because of the prolonged retention of chlorpropamide, in the body and the possibility that subsequent overlapping drug effects might provoke hypoglycemia.

Patients Receiving Insulin

Patients requiring 20 units or less of insulin daily may be placed directly on Rastinon (Tolbutamide) tablets and insulin abruptly discontinued. Patients whose insulin requirement is between 20 and 40 units daily may be started on therapy with Rastinon (Tolbutamide) tablets with a concurrent 30% to 50% reduction in insulin dose, with further daily reduction of the insulin when response to Rastinon (Tolbutamide) tablets is observed. In patients requiring more than 40 units of insulin daily, therapy with Rastinon (Tolbutamide) tablets may be initiated in conjunction with a 20% reduction in insulin dose the first day, with further careful reduction of insulin as response is observed. Occasionally, conversion to Rastinon (Tolbutamide) tablets in the hospital may be advisable in candidates who require more than 40 units of insulin daily. During this conversion period when both insulin and Rastinon (Tolbutamide) tablets are being used hypoglycemia may rarely occur. During insulin withdrawal, patients should test their urine for glucose and acetone at least 3 times daily and report results to their physician. The appearance of persistent acetonuria with glycosuria indicates that the patient is type I diabetic who requires insulin therapy.

Maximum Dose

Daily doses of greater than 3 grams are not recommended.

Usual Maintenance Dose

The maintenance dose is in the range of 0.25 to 3 grams daily. Maintenance doses above 2 grams are seldom required.

Dosage Interval

The total daily dose may be taken either in the morning or in divided doses through the day. While either schedule is usually effective, the divided dose system is preferred by some clinicians from the standpoint of digestive tolerance.

In elderly patients, debilitated or malnourished patients, and patients with impaired renal or hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions.

HOW SUPPLIED

Rastinon (Tolbutamide) Tablets, USP are available containing 500 mg of Rastinon (Tolbutamide), USP. The tablets are white to off-white round, scored tablets debossed with M to the left of the score and 13 to the right of the score on one side of the tablet and blank on the other side. They are available as follows:

NDC 0378-0215-01

bottles of 100 tablets

NDC 0378-0215-05

bottles of 500 tablets

Store at 20° to 25°C (68° to 77°F).

Protect from light.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505

REVISED FEBRUARY 2009

TOLB:R14

PRINCIPAL DISPLAY PANEL - 500 mg

NDC 0378-0215-01

Rastinon (Tolbutamide)

Tablets, USP

500 mg

Rx only 100 Tablets

Each tablet contains

Rastinon (Tolbutamide), USP 500 mg

Dispense in a tight, light-resistant

container as defined in the USP

using a child-resistant closure.

Keep container tightly closed.

Keep this and all medication

out of the reach of children.

Store at 20° to 25°C (68° to 77°F).

[See USP Controlled Room

Temperature.]

Protect from light.

Usual

Dosage: See accompanying

prescribing information.

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505 U.S.A.

Mylan.com

RM0215A12

Tolbutamide Sodium:


DESCRIPTION

Rastinon (Tolbutamide Sodium) is an oral blood-glucose-lowering drug of the sulfonylurea class. Rastinon (Tolbutamide Sodium) is a pure, white, crystalline compound which is practically insoluble in water. The chemical name is benzenesulfonamide, N-[(butylamino)-carbonyl]-4-methyl-. Its structure can be represented as follows:

Rastinon (Tolbutamide Sodium) is supplied as compressed tablets containing 500 mg of Rastinon (Tolbutamide Sodium), USP.

Each tablet for oral administration contains 500 mg of Rastinon (Tolbutamide Sodium) and the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate and sodium starch glycolate.

Rastinon (Tolbutamide Sodium) Structural Formula

CLINICAL PHARMACOLOGY

Actions

Rastinon appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which Rastinon (Tolbutamide Sodium) lowers blood glucose during long-term administration has not been clearly established. With chronic administration in Type II diabetic patients, the blood-glucose-lowering effect persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic effects may be involved in the mechanism of action of oral sulfonylurea hypoglycemic drugs.

Some patients who are initially responsive to oral hypoglycemic drugs, including Rastinon (Tolbutamide Sodium), may become unresponsive or poorly responsive over time. Alternatively, Rastinon (Tolbutamide Sodium) may be effective in some patients who have become unresponsive to one or more of the other sulfonylurea drugs.

Pharmacokinetics

When administered orally, Rastinon (Tolbutamide Sodium) is readily absorbed from the gastrointestinal tract. Absorption is not impaired and glucose lowering and insulin releasing effects are not altered if the drug is taken with food. Detectable levels are present in the plasma within 20 minutes after oral ingestion of a 500 mg Rastinon (Tolbutamide Sodium) tablet, with peak levels occurring at 3 to 4 hours and only small amounts detectable at 24 hours. The half-life of Rastinon (Tolbutamide Sodium) is 4.5 to 6.5 hours. As Rastinon (Tolbutamide Sodium) has no p-amino group, it cannot be acetylated, which is one of the common modes of metabolic degradation for the antibacterial sulfonamides. However, the presence of the p-methyl group renders Rastinon (Tolbutamide Sodium) susceptible to oxidation, and this appears to be the principal manner of its metabolic degradation in man. The p-methyl group is oxidized to form a carboxyl group, converting Rastinon (Tolbutamide Sodium) into the totally inactive metabolite 1-butyl-3-p-carboxy-phenylsulfonylurea, which can be recovered in the urine within 24 hours in amounts accounting for up to 75% of the administered dose.

The major Rastinon (Tolbutamide Sodium) metabolite has been found to have no hypoglycemic or other action when administered orally and IV to both normal and diabetic subjects. This Rastinon (Tolbutamide Sodium) metabolite is highly soluble over the critical acid range of urinary pH values, and its solubility increases with increase in pH. Because of the marked solubility of the Rastinon (Tolbutamide Sodium) metabolite, crystalluria does not occur. A second metabolite, 1-butyl-3-(p-hydroxymethyl) phenyl sulfonylurea also occurs to a limited extent. It is an inactive metabolite.

The administration of 3 grams of Rastinon (Tolbutamide Sodium) to either nondiabetic or tolbutamide-responsive diabetic subjects will, in both instances, occasion a gradual lowering of blood glucose. Increasing the dose to 6 grams does not usually cause a response which is significantly different from that produced by the 3 gram dose. Following the administration of a 3 gram dose of Rastinon (Tolbutamide Sodium) solution, non-diabetic fasting adults exhibit a 30% or greater reduction in blood glucose within one hour, following which the blood glucose gradually returns to the fasting level over 6 to 12 hours. Following the administration of a 3 gram dose of Rastinon (Tolbutamide Sodium) solution, Rastinon (Tolbutamide Sodium) responsive diabetic patients show a gradually progressive blood glucose lowering effect, the maximal response being reached between 5 to 8 hours after ingestion of a single 3 gram dose. The blood glucose then rises gradually and by the 24th hour has usually returned to pretest levels. The magnitude of the reduction, when expressed in terms of percent of the pretest blood glucose, tends to be similar to the response seen in the nondiabetic subject.

INDICATIONS AND USAGE

Rastinon (Tolbutamide Sodium) tablets are indicated as an adjunct to diet to lower the blood glucose in patients with non-insulin-dependent diabetes mellitus (type II) whose hyperglycemia cannot be controlled by diet alone.

In initiating treatment for non-insulin-dependent diabetes, diet should be emphasized as the primary form of treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. Proper dietary management alone may be effective in controlling the blood glucose and symptoms of hyperglycemia. The importance of regular physical activity should also be stressed, and cardiovascular risk factors should be identified and corrective measures taken where possible.

If this treatment program fails to reduce symptoms and/or blood glucose, the use of an oral sulfonylurea or insulin should be considered. Use of Rastinon (Tolbutamide Sodium) tablets must be viewed by both the physician and patient as a treatment in addition to diet, and not as a substitute for diet or as a convenient mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control on diet alone may be transient, thus requiring only short-term administration of Rastinon (Tolbutamide Sodium) tablets.

During maintenance programs, Rastinon (Tolbutamide Sodium) tablets should be discontinued if satisfactory lowering of blood glucose is no longer achieved. Judgments should be based on regular clinical and laboratory evaluations.

In considering the use of Rastinon (Tolbutamide Sodium) tablets in asymptomatic patients, it should be recognized that controlling the blood glucose in non-insulin dependent diabetes has not been definitely established to be effective in preventing the long-term cardiovascular or neural complications of diabetes.

CONTRAINDICATIONS

Rastinon (Tolbutamide Sodium) tablets are contraindicated in patients with:

  • Known hypersensitivity or allergy to the drug.
  • Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.
  • Type I diabetes, as sole therapy.

WARNINGS

SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY

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 non-insulin-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 5 to 8 years with diet plus a fixed dose of Rastinon (Tolbutamide Sodium) (1.5 grams per day) had a rate of cardiovascular mortality approximately 2½ times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of Rastinon (Tolbutamide Sodium) 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 Rastinon (Tolbutamide Sodium) 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.

PRECAUTIONS

General

Hypoglycemia

All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Renal or hepatic insufficiency may cause elevated blood levels of Rastinon 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.

Loss of Control of Blood Glucose

When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a loss of control may occur. At such times, it may be necessary to discontinue Rastinon (Tolbutamide Sodium) and administer insulin.

The effectiveness of any oral hypoglycemic drug, including Rastinon (Tolbutamide Sodium), 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 a 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.

Hemolytic Anemia

Treatment of patients with glucose 6-phosphate dehydrogenase deficiency with sulfonylurea agents can lead to hemolytic anemia. Because Rastinon (Tolbutamide Sodium) belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered. In post-marketing reports, hemolytic anemia has also been reported in patients who did not have known G6PD deficiency.

Information for Patients

Patients should be informed of the potential risks and advantages of Rastinon (Tolbutamide Sodium) 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.

A metabolite of Rastinon in urine may give a false positive reaction for albumin if measured by the acidification-after-boiling test, which causes the metabolite to precipitate. There is no interference with the sulfosalicylic acid test.

Drug Interactions

The hypoglycemia action of sulfonylurea may be potentiated by certain drugs including non-steroidal 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 Rastinon (Tolbutamide Sodium), the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving Rastinon (Tolbutamide Sodium), 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 Rastinon (Tolbutamide Sodium), the patient should be closely observed for loss of control. When such drugs are withdrawn from a patient receiving Rastinon (Tolbutamide Sodium), 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 and Mutagenicity

Bioassay for carcinogenicity was performed in both sexes of rats and mice following ingestion of Rastinon for 78 weeks. No evidence of carcinogenicity was found.

Rastinon (Tolbutamide Sodium) has also been demonstrated to be nonmutagenic in the Ames salmonella/mammalian microsome mutagenicity test.

Pregnancy

Teratogenic Effects: Pregnancy Category C

Rastinon has been shown to be teratogenic in rats when given in doses 25 to 100 times the human dose. In some studies, pregnant rats given high doses of Rastinon (Tolbutamide Sodium) have shown ocular and bony abnormalities and increased mortality in offspring. Repeat studies in other species (rabbits) have not demonstrated a teratogenic effect. There are no adequate and well controlled studies in pregnant women. Rastinon (Tolbutamide Sodium) is not recommended for the treatment of pregnant diabetic patients.

Serious consideration should also be given to the possible hazards of the use of Rastinon (Tolbutamide Sodium) in women of childbearing 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.

Nonteratogenic Effects

Prolonged severe hypoglycemia (4 to 10 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 Rastinon (Tolbutamide Sodium) is used during pregnancy, it should be discontinued at least 2 weeks before the expected delivery date.

Nursing Mothers

Although it is not known whether Rastinon 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.

ADVERSE REACTIONS

Hypoglycemia

Gastrointestinal Reactions

Cholestatic jaundice may occur rarely; Rastinon should be discontinued if this occurs. Gastrointestinal disturbances, e.g., nausea, epigastric fullness, and heartburn, are the most common reactions and occur in 1.4% of patients treated during clinical trial. They tend to be dose related and may disappear when dosage is reduced.

Dermatologic Reactions

Allergic skin reactions, e.g., pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occur in 1.1% of patients treated during clinical trials. These may be transient and may disappear despite continued use of Rastinon (Tolbutamide Sodium); if skin reactions persist, the drug should be discontinued.

Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas.

Hematologic Reactions

Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia, and pancytopenia have been reported with sulfonylureas.

Metabolic Reactions

Hepatic porphyria and disulfiram-like reactions have been reported with sulfonylureas.

Endocrine Reactions

Cases of hyponatremia and the syndrome of inappropriate antidiuretic hormone secretion have been reported with this and other sulfonylureas.

Miscellaneous Reactions

Headache and taste alterations have occasionally been reported with Rastinon (Tolbutamide Sodium) administration.

OVERDOSAGE

Overdosage of sulfonylureas including Rastinon (Tolbutamide Sodium) can produce hypoglycemia. Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) dextrose injection. This should be followed by a continuous infusion of a more dilute (10%) dextrose injection at a rate that will maintain the blood glucose at a level above 100 mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours since hypoglycemia may recur after apparent clinical recovery.

DOSAGE AND ADMINISTRATION

There is no fixed dosage regimen for the management of diabetes mellitus with Rastinon tablets or any other hypoglycemic agent. In addition to the usual monitoring of urinary glucose, the patient's blood glucose must also be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of an adequate blood glucose lowering response after an initial period of effectiveness. Glycosylated hemoglobin levels may also be of value in monitoring the patient's response to therapy.

Short-term administration of Rastinon (Tolbutamide Sodium) tablets may be sufficient during periods of transient loss of control in patients usually controlled well on diet.

Usual Starting Dose

The usual starting dose is 1 to 2 grams daily. This may be increased or decreased, depending on individual patient response. Failure to follow an appropriate dosage regimen may precipitate hypoglycemia. Patients who do not adhere to their prescribed dietary regimens are more prone to exhibit unsatisfactory response to drug therapy.

Transfer from Other Hypoglycemic Therapy

Patients Receiving Other Antidiabetic Therapy

Transfer of patients from other oral antidiabetes regimens to Rastinon tablets should be done conservatively. When transferring patients from oral hypoglycemic agents other than chlorpropamide to Rastinon (Tolbutamide Sodium), no transition period and no initial or priming doses are necessary. When transferring patients from chlorpropamide, however, particular care should be exercised during the first 2 weeks because of the prolonged retention of chlorpropamide, in the body and the possibility that subsequent overlapping drug effects might provoke hypoglycemia.

Patients Receiving Insulin

Patients requiring 20 units or less of insulin daily may be placed directly on Rastinon (Tolbutamide Sodium) tablets and insulin abruptly discontinued. Patients whose insulin requirement is between 20 and 40 units daily may be started on therapy with Rastinon (Tolbutamide Sodium) tablets with a concurrent 30% to 50% reduction in insulin dose, with further daily reduction of the insulin when response to Rastinon (Tolbutamide Sodium) tablets is observed. In patients requiring more than 40 units of insulin daily, therapy with Rastinon (Tolbutamide Sodium) tablets may be initiated in conjunction with a 20% reduction in insulin dose the first day, with further careful reduction of insulin as response is observed. Occasionally, conversion to Rastinon (Tolbutamide Sodium) tablets in the hospital may be advisable in candidates who require more than 40 units of insulin daily. During this conversion period when both insulin and Rastinon (Tolbutamide Sodium) tablets are being used hypoglycemia may rarely occur. During insulin withdrawal, patients should test their urine for glucose and acetone at least 3 times daily and report results to their physician. The appearance of persistent acetonuria with glycosuria indicates that the patient is type I diabetic who requires insulin therapy.

Maximum Dose

Daily doses of greater than 3 grams are not recommended.

Usual Maintenance Dose

The maintenance dose is in the range of 0.25 to 3 grams daily. Maintenance doses above 2 grams are seldom required.

Dosage Interval

The total daily dose may be taken either in the morning or in divided doses through the day. While either schedule is usually effective, the divided dose system is preferred by some clinicians from the standpoint of digestive tolerance.

In elderly patients, debilitated or malnourished patients, and patients with impaired renal or hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions.

HOW SUPPLIED

Rastinon (Tolbutamide Sodium) Tablets, USP are available containing 500 mg of Rastinon (Tolbutamide Sodium), USP. The tablets are white to off-white round, scored tablets debossed with M to the left of the score and 13 to the right of the score on one side of the tablet and blank on the other side. They are available as follows:

NDC 0378-0215-01

bottles of 100 tablets

NDC 0378-0215-05

bottles of 500 tablets

Store at 20° to 25°C (68° to 77°F).

Protect from light.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505

REVISED FEBRUARY 2009

TOLB:R14

PRINCIPAL DISPLAY PANEL - 500 mg

NDC 0378-0215-01

Rastinon (Tolbutamide Sodium)

Tablets, USP

500 mg

Rx only 100 Tablets

Each tablet contains

Rastinon (Tolbutamide Sodium), USP 500 mg

Dispense in a tight, light-resistant

container as defined in the USP

using a child-resistant closure.

Keep container tightly closed.

Keep this and all medication

out of the reach of children.

Store at 20° to 25°C (68° to 77°F).

[See USP Controlled Room

Temperature.]

Protect from light.

Usual

Dosage: See accompanying

prescribing information.

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505 U.S.A.

Mylan.com

RM0215A12

Rastinon pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Rastinon available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Rastinon destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Rastinon Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Rastinon pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."TOLBUTAMIDE TABLET [MYLAN PHARMACEUTICALS INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."TOLBUTAMIDE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "tolbutamide". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Rastinon?

Depending on the reaction of the Rastinon after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Rastinon not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Rastinon addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Rastinon, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Rastinon consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Arunabha Ray, MD Pharmacology

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