Orabet

Orabet is a biguanide antihyperglycemic agent used for treating non-insulin-dependent diabetes mellitus (NIDDM). It improves glycemic control by decreasing hepatic glucose production, decreasing glucose absorption and increasing insulin-mediated glucose uptake. Orabet may induce weight loss and is the drug of choice for obese NIDDM patients. Use of Orabet is associated with modest weight loss. When used alone, Orabet does not cause hypoglycemia; however, it may potentiate the hypoglycemic effects of sulfonylureas and insulin. Its main side effects are dyspepsia, nausea and diarrhea. Dose titration and/or use of smaller divided doses may decrease side effects. Orabet should be avoided in those with severely compromised renal function (creatinine clearance < 30 ml/min), acute/decompensated heart failure, severe liver disease and for 48 hours after the use of iodinated contrast dyes due to the risk of lactic acidosis. Lower doses should be used in the elderly and those with decreased renal function. Orabet decreases fasting plasma glucose, postprandial blood glucose and glycosolated hemoglobin (HbA1c) levels, which are reflective of the last 8-10 weeks of glucose control. Orabet may also have a positive effect on lipid levels. In 2012, a combination tablet of linagliptin plus Orabet hydrochloride was marketed under the name Jentadueto for use in patients when treatment with both linagliptin and Orabet is appropriate.

In maturity onset (non-insulin-dependent) obese diabetics and juvenile diabetics in whom diet alone has failed as monotherapy or in combination with insulin, glitazones or sulfonylureas. Also as an adjunct to diet and exercise to improve glycemic control in patients with type-2 diabetes.

Glitazones are used in combination with Orabet HCl when glycemic control is poor on Orabet HCl monotherapy and maximum tolerated dose (preferable) of Orabet HCl has been tried. The combination of glitazone plus Orabet HCl is preferred to glitazone plus sufonylurea, particularly for obese patients.

Orabet is used to treat high blood sugar levels that are caused by a type of diabetes mellitus or sugar diabetes called type 2 diabetes. With this type of diabetes, insulin produced by the pancreas is not able to get sugar into the cells of the body where it can work properly. Using Orabet alone, with a type of oral antidiabetic medicine called a sulfonylurea, or with insulin, will help to lower blood sugar when it is too high and help restore the way you use food to make energy.

Many people can control type 2 diabetes with diet and exercise. Following a specially planned diet and exercise will always be important when you have diabetes, even when you are taking medicines. To work properly, the amount of Orabet you take must be balanced against the amount and type of food you eat and the amount of exercise you do. If you change your diet or exercise, you will want to test your blood sugar to find out if it is too low. Your doctor will teach you what to do if this happens.

Orabet does not help patients does not help patients who have insulin-dependent or type 1 diabetes because they cannot produce insulin from their pancreas gland. Their blood glucose is best controlled by insulin injections.

Orabet is available only with your doctor's prescription.

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although this use is not included in product labeling, Orabet is used in certain patients with the following medical conditions:

• Polycystic ovary syndrome.

There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with Orabet or Orabet XR or any other pharmacologic agent. Dosage of Orabet or Orabet XR must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily doses. The maximum recommended daily dose of Orabet is 2550 mg in adults and 2000 mg in pediatric patients (10-16 years of age); the maximum recommended daily dose of Orabet XR in adults is 2000 mg.

Orabet should be given in divided doses with meals while Orabet XR should generally be given once daily with the evening meal. Orabet or Orabet XR should be started at a low dose, with gradual dose escalation, both to reduce gastrointestinal side effects and to permit identification of the minimum dose required for adequate glycemic control of the patient.

During treatment initiation and dose titration, fasting plasma glucose should be used to determine the therapeutic response to Orabet or Orabet XR and identify the minimum effective dose for the patient. Thereafter, glycosylated hemoglobin should be measured at intervals of approximately 3 months. The therapeutic goal should be to decrease both fasting plasma glucose and glycosylated hemoglobin levels to normal or near normal by using the lowest effective dose of Orabet or Orabet XR, either when used as monotherapy or in combination with sulfonylurea or insulin.

Monitoring of blood glucose and glycosylated hemoglobin will also permit detection of primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication, and secondary failure, i.e., loss of an adequate blood glucose lowering response after an initial period of effectiveness.

Short-term administration of Orabet or Orabet XR may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone.

Orabet XR tablets must be swallowed whole and never crushed or chewed. Occasionally, the inactive ingredients of Orabet XR will be eliminated in the feces as a soft, hydrated mass.

Recommended Dosing Schedule

In general, clinically significant responses are not seen at doses below 1500 mg per day. However, a lower recommended starting dose and gradually increased dosage is advised to minimize gastrointestinal symptoms.

The usual starting dose of Orabet Tablets is 500 mg twice a day or 850 mg once a day, given with meals. Dosage increases should be made in increments of 500 mg weekly or 850 mg every 2 weeks, up to a total of 2000 mg per day, given in divided doses. Patients can also be titrated from 500 mg twice a day to 850 mg twice a day after 2 weeks. For those patients requiring additional glycemic control, Orabet may be given to a maximum daily dose of 2550 mg per day. Doses above 2000 mg may be better tolerated given 3 times a day with meals.

The usual starting dose of Orabet XR (Orabet hydrochloride) Extended-Release Tablets is 500 mg once daily with the evening meal. Dosage increases should be made in increments of 500 mg weekly, up to a maximum of 2000 mg once daily with the evening meal. If glycemic control is not achieved on Orabet XR 2000 mg once daily, a trial of Orabet XR 1000 mg twice daily should be considered. If higher doses of Orabet are required, Orabet should be used at total daily doses up to 2550 mg administered in divided daily doses, as described above.

In a randomized trial, patients currently treated with Orabet were switched to Orabet XR. Results of this trial suggest that patients receiving Orabet treatment may be safely switched to Orabet XR once daily at the same total daily dose, up to 2000 mg once daily. Following a switch from Orabet to Orabet XR, glycemic control should be closely monitored and dosage adjustments made accordingly.

Pediatrics

The usual starting dose of Orabet is 500 mg twice a day, given with meals. Dosage increases should be made in increments of 500 mg weekly up to a maximum of 2000 mg per day, given in divided doses. Safety and effectiveness of Orabet XR in pediatric patients have not been established.

Transfer From Other Antidiabetic Therapy

When transferring patients from standard oral hypoglycemic agents other than chlorpropamide to Orabet or Orabet XR, no transition period generally is necessary. When transferring patients from chlorpropamide, care should be exercised during the first 2 weeks because of the prolonged retention of chlorpropamide in the body, leading to overlapping drug effects and possible hypoglycemia.

Concomitant Orabet or Orabet XR and

Oral Sulfonylurea Therapy in Adult Patients

If patients have not responded to 4 weeks of the maximum dose of Orabet or Orabet XR monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing Orabet or Orabet XR at the maximum dose, even if prior primary or secondary failure to a sulfonylurea has occurred. Clinical and pharmacokinetic drug-drug interaction data are currently available only for Orabet plus glyburide (glibenclamide).

With concomitant Orabet or Orabet XR and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. In a clinical trial of patients with type 2 diabetes and prior failure on glyburide, patients started on Orabet 500 mg and glyburide 20 mg were titrated to 1000/20 mg, 1500/20 mg, 2000/20 mg, or 2500/20 mg of Orabet and glyburide, respectively, to reach the goal of glycemic control as measured by FPG, HbA1c, and plasma glucose response. However, attempts should be made to identify the minimum effective dose of each drug to achieve this goal. With concomitant Orabet or Orabet XR and sulfonylurea therapy, the risk of hypoglycemia associated with sulfonylurea therapy continues and may be increased. Appropriate precautions should be taken.

If patients have not satisfactorily responded to 1 to 3 months of concomitant therapy with the maximum dose of Orabet or Orabet XR and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without Orabet or Orabet XR.

Concomitant Orabet or Orabet XR and Insulin Therapy in Adult Patients

The current insulin dose should be continued upon initiation of Orabet or Orabet XR therapy. Orabet or Orabet XR therapy should be initiated at 500 mg once daily in patients on insulin therapy. For patients not responding adequately, the dose of Orabet or Orabet XR should be increased by 500 mg after approximately 1 week and by 500 mg every week thereafter until adequate glycemic control is achieved. The maximum recommended daily dose is 2500 mg for Orabet and 2000 mg for Orabet XR. It is recommended that the insulin dose be decreased by 10% to 25% when fasting plasma glucose concentrations decrease to less than 120 mg/dL in patients receiving concomitant insulin and Orabet or Orabet XR. Further adjustment should be individualized based on glucose-lowering response.

Specific Patient Populations

Orabet or Orabet XR are not recommended for use in pregnancy. Orabet is not recommended in patients below the age of 10 years. Orabet XR is not recommended in pediatric patients (below the age of 17 years).

The initial and maintenance dosing of Orabet or Orabet XR should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dosage adjustment should be based on a careful assessment of renal function. Generally, elderly, debilitated, and malnourished patients should not be titrated to the maximum dose of Orabet or Orabet XR.

Monitoring of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly.

See also:
What is the most important information I should know about Orabet?

Orabet® is contraindicated in patients with:

1. Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females] or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia.
2. Known hypersensitivity to Orabet.
3. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.

Orabet® should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function.

WARNINGS

Lactic Acidosis:

Lactic acidosis is a rare, but serious, metabolic complication that can occur due to Orabet accumulation during treatment with Orabet® (Orabet hydrochloride) Extended-Release Tablets; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/ L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When Orabet is implicated as the cause of lactic acidosis, Orabet plasma levels >5 μg/mL are generally found.

The reported incidence of lactic acidosis in patients receiving Orabet hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/ surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking Orabet® (Orabet hydrochloride) Extended-Release Tablets and by use of the minimum effective dose of Orabet®. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Orabet® treatment should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, Orabet® should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, Orabet® should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking Orabet®, since alcohol potentiates the effects of Orabet hydrochloride on lactate metabolism. In addition, Orabet® should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure.

The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur. Orabet® should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose and, if indicated, blood pH, lactate levels, and even blood Orabet levels may be useful. Once a patient is stabilized on any dose level of Orabet®, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking Orabet® do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling.

Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).

Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking Orabet®, the drug should be discontinued immediately and general supportive measures promptly instituted. Because Orabet hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated Orabet. Such management often results in prompt reversal of symptoms and recovery.

Use Orabet extended-release tablets as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Orabet extended-release tablets. Talk to your pharmacist if you have questions about this information.
• Take Orabet extended-release tablets by mouth with the evening meal unless your doctor tells you otherwise.
• Swallow Orabet extended-release tablets whole. Do not break, crush, or chew before swallowing.
• Take Orabet extended-release tablets on a regular schedule to get the most benefit from it. Taking Orabet extended-release tablets at the same time each day will help you remember to take it.
• Continue to take Orabet extended-release tablets even if you feel well. Do not miss any doses.
• If you miss a dose of Orabet extended-release tablets, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Orabet extended-release tablets.

Use: Labeled Indications

Diabetes mellitus, type 2: Management of type 2 diabetes mellitus when hyperglycemia cannot be managed with diet and exercise alone.

Note: If not contraindicated and if tolerated, Orabet is the preferred initial pharmacologic agent for type 2 diabetes management (ADA 2020).

Off Label Uses

Antipsychotic-induced weight gain

Data from multiple meta-analyses of randomized controlled trials with varying degrees of heterogeneity (primarily in patients with schizophrenia and schizoaffective disorder) support the use of Orabet in promoting modest weight loss and preventing weight gain associated with second-generation antipsychotics in adult patients

See also:
What other drugs will affect Orabet?

Drug Interactions (Clinical Evaluation Of Drug Interactions Conducted With Immediate-Release Orabet)

Glyburide

In a single-dose interaction study in type 2 diabetes patients, co-administration of Orabet and glyburide did not result in any changes in either Orabet pharmacokinetics or pharmacodynamics. Decreases in glyburide AUC and Cmax were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects, makes the clinical significance of this interaction uncertain.

Furosemide

A single-dose, Orabet-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by co-administration. Furosemide increased the Orabet plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in Orabet renal clearance. When administered with Orabet, the Cmax and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of Orabet and furosemide when co-administered chronically.

Nifedipine

A single-dose, Orabet-nifedipine drug interaction study in normal healthy volunteers demonstrated that co-administration of nifedipine increased plasma Orabet Cmax and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. Tmax and half-life were unaffected. Nifedipine appears to enhance the absorption of Orabet. Orabet had minimal effects on nifedipine.

Cationic Drugs

Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with Orabet by competing for common renal tubular transport systems. Such interaction between Orabet and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, Orabet-cimetidine drug interaction studies, with a 60% increase in peak Orabet plasma and whole blood concentrations and a 40% increase in plasma and whole blood Orabet AUC. There was no change in elimination half-life in the single-dose study. Orabet had no effect on cimetidine pharmacokinetics. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of Orabet® and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.

Other

Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic 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 Orabet®, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving Orabet®, the patient should be observed closely for hypoglycemia.

In healthy volunteers, the pharmacokinetics of Orabet and propranolol, and Orabet and ibuprofen were not affected when coadministered in single-dose interaction studies.

Orabet is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins.

See also:
What are the possible side effects of Orabet?

During treatment initiation, the most common adverse reactions are nausea, vomiting, diarrhoea, abdominal pain and loss of appetite which resolve spontaneously in most cases.

In a US double-blind clinical study of Orabet in patients with type 2 diabetes, a total of 141 patients received Orabet therapy (up to 2550 mg/day) and 145 patients received placebo. Adverse reactions reported in >5% of the Orabet patients, and that was more common in Orabet than placebo-treated patients, are listed in Table 2.

Diarrhea led to discontinuation of study medication in 6% of patients treated with Orabet. Additionally, the following adverse reactions were reported in >1% to <5% of Orabet patients and were more commonly reported with Orabet than placebo: Abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, increased sweating, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation.

In worldwide clinical trials, over 900 patients with type 2 diabetes have been treated with Orabet extended-release tablet in placebo- and active-controlled studies. In placebo-controlled trials, 781 patients were administered Orabet extended-release tablet and 195 patients received placebo. Adverse reactions reported in >5% of the Orabet extended-release tablet patients and that were more common in Orabet extended-release tablet than placebo treated patients, are listed in Table 3.

Diarrhea led to discontinuation of study medication in 0.6% of patients treated with Orabet extended-release tablet. Additionally, the following adverse reactions were reported in >1% to <5% of Orabet extended-release tablet patients and were more commonly reported with Orabet extended-release tablet than placebo: Abdominal pain, constipation, abdomen distention, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance.

In clinical trials with Orabet in pediatric patients with type 2 diabetes, the profile of adverse reactions was similar to that observed in adults.

Other reported adverse events with use of Orabet are: Skin reactions eg, erythema, pruritus and urticaria; isolated reports of liver function tests abnormalities or hepatitis resolving upon Orabet discontinuation; lactic acidosis; decrease of vitamin B12 absorption with decrease of serum levels during long-term use of Orabet, consideration of such etiology is recommended if a patient presents with megaloplastic anaemia.