Chlorpropamide

DIABINESE (chlorpropamide) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Overdosage of sulfonylureas including DIABINESE (chlorpropamide) 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%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution 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.

DIABINESE (chlorpropamide) 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 DIABINESE (chlorpropamide) lowers blood glucose during long-term administration has not been clearly established. Extra-pancreatic effects may play a part in the mechanism of action of oral sulfonylurea hypoglycemic drugs. While chlorpropamide is a sulfonamide derivative, it is devoid of antibacterial activity.

DIABINESE (chlorpropamide) may also prove effective in controlling certain patients who have experienced primary or secondary failure to other sulfonylurea agents.

A method developed which permits easy measurement of the drug in blood is available on request.

Chlorpropamide does not interfere with the usual tests to detect albumin in the urine.

DIABINESE (chlorpropamide) is absorbed rapidly from the gastrointestinal tract. Within one hour after a single oral dose, it is readily detectable in the blood, and the level reaches a maximum within two to four hours. It undergoes metabolism in humans and it is excreted in the urine as unchanged drug and as hydroxylated or hydrolyzed metabolites. The biological half-life of chlorpropamide averages about 36 hours. Within 96 hours, 80-90% of a single oral dose is excreted in the urine. However, long-term administration of therapeutic doses does not result in undue accumulation in the blood, since absorption and excretion rates become stabilized in about 5 to 7 days after the initiation of therapy.

DIABINESE (chlorpropamide) exerts a hypoglycemic effect in healthy subjects within one hour, becoming maximal at 3 to 6 hours and persisting for at least 24 hours. The potency of chlorpropamide is approximately six times that of tolbutamide. Some experimental results suggest that its increased duration of action may be the result of slower excretion and absence of significant deactivation.

Serious side effects have been reported with chlorpropamide. See the “Drug Precautions” section.

Common side effects of chlorpropamide include the following:

• nausea
• diarrhea
• vomiting
• anorexia
• hunger

This is not a complete list of chlorpropamide side effects. Ask your doctor or pharmacist for more information.

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

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Chlorpropamide falls into category C. No studies have been done in animals, and no well-controlled studies have been done in pregnant women. Chlorpropamide should be given to a pregnant woman only if clearly needed.

Take chlorpropamide exactly as prescribed.

This medication comes in tablet form and is taken once a day in the morning with breakfast or the first meal of the day.

If you miss a dose, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of chlorpropamide at the same time.

Do not use this medication if you are allergic to chlorpropamide, or if you are in a state of diabetic ketoacidosis. Call your doctor for treatment with insulin.

Before taking chlorpropamide, tell your doctor if you have kidney or liver disease, a disorder of your pituitary or adrenal glands, a history of heart disease, or if you are malnourished.

Certain oral diabetes medications may increase your risk of serious heart problems. However, not treating your diabetes can damage your heart and other organs. Talk to your doctor about the risks and benefits of treating your diabetes with chlorpropamide.

Low blood sugar (hypoglycemia) can occur if you skip a meal, exercise too long, drink alcohol, or are under stress. Symptoms include headache, hunger, weakness, sweating, tremors, irritability, or trouble concentrating. Carry hard candy or glucose tablets with you in case you have low blood sugar. Other sugar sources include orange juice and milk. Be sure your family and close friends know how to help you in an emergency.

Signs of blood sugar that is too high (hyperglycemia) may include increased thirst, increased urination, hunger, dry mouth, fruity breath odor, drowsiness, dry skin, blurred vision, and weight loss. Your blood sugar will need to be checked often, and you may need to adjust your chlorpropamide dose.

Chlorpropamide is only part of a complete program of treatment that may also include diet, exercise, weight control, foot care, eye care, and testing your blood sugar. Follow your diet, medication, and exercise routines very closely. Changing any of these factors can affect your blood sugar levels.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. A chlorpropamide overdose can cause life-threatening hypoglycemia.

Symptoms of severe hypoglycemia include extreme weakness, confusion, tremors, sweating, fast heart rate, trouble speaking, nausea, vomiting, rapid breathing, fainting, and seizure (convulsions).

Avoid drinking alcohol. It lowers blood sugar and may interfere with your diabetes treatment.

Avoid exposure to sunlight or tanning beds. Chlorpropamide can make you sunburn more easily. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors.

Usual Adult Dose for Diabetes Type 2:

Initial dose: 100 mg to 250 mg orally once a day
-Adjust dose in increments of 50 to 125 mg no more often than every 3 to 5 days
Maintenance dose: 100 mg to 500 mg per day
Maximum dose: 750 mg per day

Comments:
-Therapy for the management of type 2 diabetes mellitus should be individualized; lower initial doses should be considered for patients at greater risk of hypoglycemia.
-Patients who do not respond completely to 500 mg/day will usually not respond to higher doses.
-Total daily dose may be taken as a single dose each morning with breakfast; gastrointestinal intolerance may be relieved by dividing the daily dose.
-Transferring patients from other antidiabetic regimens should be done conservatively: see dose adjustments.

Use: As an adjunct to diet and exercise improve glycemic control in patients with type 2 diabetes.

Usual Geriatric Dose for Diabetes Type 2:

Initial dose: 100 mg to 125 mg orally once a day

You may be more likely to have hypoglycemia (low blood sugar) if you take chlorpropamide with other drugs that can lower blood sugar, such as:

• exenatide (Byetta);

• probenecid (Benemid);

• aspirin or other salicylates (including Pepto Bismol);

• a blood thinner (warfarin, Coumadin, Jantoven);

• sulfa drugs (Bactrim, SMZ-TMP, and others);

• a monoamine oxidase inhibitor (MAOI); or

• insulin or other oral diabetes medications.

This list is not complete, and many other medicines can increase or decrease the effects of chlorpropamide on lowering your blood sugar. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Tell your doctor about all medicines you use, and those you start or stop using during your treatment with chlorpropamide. Not all possible interactions are listed in this medication guide.

Absorption

Bioavailability

Rapidly absorbed following oral administration; peak plasma concentrations attained within 2–4 hours.189 a b

Onset

In healthy individuals, hypoglycemic action begins ≤1 hour; maximal at 3–6 hours.189

Duration

In healthy individuals, hypoglycemic action persists for ≥24 hours;189 longest duration of action of the sulfonylureas.a d

Food

Food does not appear to affect absorption or bioavailability; decreases peak serum concentrations of drug.b

Special Populations

Following administration of a single dose in healthy elderly and young adult individuals, age did not affect pharmacokinetics of chlorpropamide.b

Distribution

Extent

Sulfonylureas are distributed into extracellular fluids.a

Chlorpropamide crosses the placenta and is distributed into milk.189 (See Pregnancy under Cautions.)

Plasma Protein Binding

Highly bound to plasma proteins.a

Elimination

Metabolism

Extensively metabolized, mainly by CYP2C9.c

Elimination Route

Excreted in urine (80–90%) mainly as metabolites.189 a c

Increased or decreased rate of elimination in alkaline or acidic urine, respectively.a c

Half-life

36 hours (range: 25–60 hours).189 a b c d

Special Populations

Renal or hepatic insufficiency may affect pharmacokinetics and increase the risk of serious hypoglycemic reactions.189

Metabolism influenced by CYP2C9 polymorphism; genetic differences in drug metabolism affect drug response.c

Storage

Oral

<30°C.189

• Stimulates secretion of postprandial endogenous insulin from beta cells of pancreas.189 a d

• Ineffective in absence of functioning beta cells.189 a

• During prolonged administration, extrapancreatic effects (e.g., enhanced peripheral sensitivity to insulin, reduction of basal hepatic glucose production) contribute to hypoglycemic action.189 a

• Inform patients of potential risks and advantages of chlorpropamide therapy and alternative forms of treatment.189

• Importance of regular testing of blood glucose concentrations and HbA1c values.189

• During insulin withdrawal, importance of testing blood glucose concentrations ≥3 times daily.189 Importance of patients immediately informing clinicians of abnormal results for appropriate adjustments in therapy, if necessary.189

• Importance of adhering to diet and exercise regimen.101 102 107 110 189

• Importance of hygiene and avoidance of infection.a

• Advise patients about nature of diabetes mellitus, prevention and detection of complications, and importance of glycemic control.a

• Importance of understanding primary and secondary failure to therapy.189

• Risks of hypoglycemia.189 Importance of patients and responsible family members understanding symptoms and treatment of hypoglycemic reactions and identifying conditions that predispose to development of such reactions.189

• Risk of alcohol intolerance (e.g., facial flushing).a

• Advise patients to use caution while driving and operating machinery.189

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.189

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.189

• Importance of informing patients of other important precautionary information.189 (See Cautions.)

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

In the U.S.

• Diabinese

Available Dosage Forms:

• Tablet

Therapeutic Class: Hypoglycemic

Chemical Class: 1st Generation Sulfonylurea

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For chlorpropamide, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to chlorpropamide or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of chlorpropamide in the pediatric population. Safety and efficacy have not been established.

Geriatric

Although appropriate studies on the relationship of age to the effects of chlorpropamide have not been performed in the geriatric population, geriatric-specific problems are not expected to limit the usefulness of chlorpropamide in the elderly. However, elderly patients are more likely to have age-related liver or kidney problems, which may require an adjustment in the dose for patients receiving chlorpropamide.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking chlorpropamide, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using chlorpropamide with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acarbose
• Aspirin
• Balofloxacin
• Besifloxacin
• Ciprofloxacin
• Disopyramide
• Dulaglutide
• Enoxacin
• Fleroxacin
• Flumequine
• Gatifloxacin
• Gemifloxacin
• Lanreotide
• Levofloxacin
• Lixisenatide
• Lomefloxacin
• Metreleptin
• Moxifloxacin
• Nadifloxacin
• Norfloxacin
• Octreotide
• Ofloxacin
• Pasireotide
• Pazufloxacin
• Pefloxacin
• Pioglitazone
• Prulifloxacin
• Rufloxacin
• Sparfloxacin
• Thioctic Acid
• Tosufloxacin

Using chlorpropamide with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acebutolol
• Aminolevulinic Acid
• Atenolol
• Betaxolol
• Bisoprolol
• Bitter Melon
• Carteolol
• Carvedilol
• Celiprolol
• Chloramphenicol
• Clofibrate
• Esmolol
• Fenugreek
• Furazolidone
• Garlic
• Glucomannan
• Guar Gum
• Iproniazid
• Isocarboxazid
• Labetalol
• Levobunolol
• Linezolid
• Methylene Blue
• Metipranolol
• Metoprolol
• Moclobemide
• Nadolol
• Nebivolol
• Nialamide
• Oxprenolol
• Penbutolol
• Phenelzine
• Pindolol
• Practolol
• Procarbazine
• Propranolol
• Psyllium
• Rasagiline
• Rifampin
• Rifapentine
• Safinamide
• Saxagliptin
• Selegiline
• Sotalol
• Timolol
• Tranylcypromine

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using chlorpropamide with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use chlorpropamide, or give you special instructions about the use of food, alcohol, or tobacco.

• Ethanol

Other Medical Problems

The presence of other medical problems may affect the use of chlorpropamide. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcohol intoxication or
• Underactive adrenal glands or
• Underactive pituitary gland or
• Undernourished condition or
• Weakened physical condition—May cause side effects to become worse.

• Diabetic ketoacidosis (ketones in the blood) or
• Type I diabetes—Should not be used in patients with these conditions.

• Glucose 6-phosphate dehydrogenase (G6PD) deficiency (an enzyme problem)—Use with caution. May cause hemolytic anemia (blood disorder) in patients with this condition.

• Heart or blood vessel disease—Use with caution. May make this condition worse.

• Kidney disease or
• Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take chlorpropamide at the same time of day.
• Take with the first meal of the day, if taking once a day.
• To gain the most benefit, do not miss doses.
• Keep taking this medicine as you have been told by your doctor or other health care provider, even if you feel well.
• Be sure you know what to do if you do not eat as much as normal or if you skip a meal.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it, with a meal.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

• Store at room temperature.
• Protect from light.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

(klor PROE pa mide)

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

Tablet, Oral:

Generic: 100 mg, 250 mg

Administer once daily with breakfast. Daily dose may be divided to reduce GI upset. Patients that are NPO or require decreased caloric intake may need doses held to avoid hypoglycemia.

Animal reproduction studies have not been conducted. Chlorpropamide crosses the placenta and measurable serum concentrations can be found in infants exposed in utero. Severe hypoglycemia lasting 4 to 10 days has been noted in infants born to mothers taking a sulfonylurea (including chlorpropamide) at the time of delivery; additional adverse events have also been reported and may be influenced by maternal glycemic control (Jackson 1962; Kemball 1970; Uhrig 1983; Zucker 1968).

In women with diabetes, maternal hyperglycemia can be associated with congenital malformations as well as adverse effects in the fetus, neonate, and the mother (ACOG 2005; ADA 2017c; Kitzmiller 2008; Metzger 2007). 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 (ACOG 2013; ADA 2017c; Blumer 2013; Kitzmiller 2008). Agents other than chlorpropamide are currently recommended to treat diabetes in pregnant women (ADA 2017c). The manufacturer recommends if chlorpropamide is used during pregnancy, it should be discontinued at least 1 month before the expected delivery date.

Applies to chlorpropamide: oral tablet

General

The most commonly reported adverse reactions have included gastrointestinal disturbances such as nausea, diarrhea, vomiting, anorexia, and hunger.[Ref]

Metabolic

Rare (less than 0.1%): Disulfiram-like reactions
Frequency not reported: Hypoglycemia

Sulfonylureas:
Frequency not reported: Hepatic porphyria[Ref]

Gastrointestinal

Common (1% to 10%): Nausea, diarrhea, vomiting, anorexia, hunger
Frequency not reported: Proctocolitis[Ref]

Dermatologic

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

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

Hypersensitivity

Frequency not reported: Allergic skin reactions

Hepatic

Rare (less than 0.1%): Cholestatic jaundice, hepatitis
Frequency not reported: Hepatic porphyria[Ref]

Hematologic

Sulfonylureas:
Frequency not reported: Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia, pancytopenia, eosinophilia[Ref]

Cardiovascular

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

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]

Nervous system

Frequency not reported: Dizziness, headache[Ref]

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