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HIGHLIGHTS OF PRESCRIBING INFORMATION
——— DOSAGE AND ADMINISTRATION ———
• The repaglinide component can cause hypoglycemia. Initiate These highlights do not include all the information needed
• The dosage of PrandiMet® should be individualized. (2) PrandiMet® at the lowest available dose in patients naive to to use PrandiMet® safely and effectively. See full
• Start with 1 mg/500 mg twice daily unless the patient is prescribing information for PrandiMet®.
already taking higher co-administered doses of repaglinide • Metformin can cause vitamin B12 deficiency. Measure PrandiMet® (repaglinide and metformin HCl) Tablets
Initial U.S. Approval: 2008
• Do not exceed 10 mg repaglinide/2500 mg metformin HCl daily • May need to discontinue PrandiMet® and temporarily use or 4 mg repaglinide/1000 mg metformin HCl per meal. (2) insulin if glycemic control deteriorates during periods of stress WARNING: LACTIC ACIDOSIS
or if there is decreased intake of fluids and food (e.g., • Give in divided doses within 15 minutes prior to meals. (2) See full prescribing information for
• Patients who skip a meal should skip the PrandiMet® dose for complete boxed warning
• There have been no clinical studies establishing conclusive • Lactic acidosis can occur due to metformin
evidence of macrovascular risk reduction with PrandiMet® or accumulation. The risk increases with conditions
——— DOSAGE FORMS AND STRENGTHS ———
any other oral anti-diabetic drug. (5.15) such as sepsis, dehydration, excess alcohol intake,
——— ADVERSE REACTIONS ———
hepatic impairment, renal impairment, and acute
• 1 mg repaglinide/500 mg metformin HCl (3) congestive heart failure. (5.1)
• Hypoglycemia and headache were the most common adverse • 2 mg repaglinide/500 mg metformin HCl (3) reactions (≥10%) reported among patients treated with • Symptoms include malaise, myalgias, respiratory
repaglinide in combination with metformin HCl, occurring distress, increasing somnolence, and nonspecific
——— CONTRAINDICATIONS ———
more frequently than among patients treated with repaglinide abdominal distress. Laboratory abnormalities
include low pH, increased anion gap and elevated
blood lactate. (5.1)
• Gastrointestinal reactions (e.g., diarrhea, nausea and vomiting) • with metabolic acidosis, including diabetic ketoacidosis. (4, 5.1) are the most common adverse reactions with metformin HCl • If acidosis is suspected, discontinue PrandiMet® and
• receiving gemfibrozil. (4, 5.7, 7.2, 12.3) treatment and are more frequent at higher metformin HCl hospitalize the patient immediately.
——— WARNINGS AND PRECAUTIONS ———
To report SUSPECTED ADVERSE REACTIONS, contact Novo
——— RECENT MAJOR CHANGES ———
• Metformin HCl is contraindicated in renal impairment. Assess Nordisk at 1-800-727-6500 or FDA at 1-800-FDA-1088 or
renal function before initiating PrandiMet® and at least • Warnings and Precautions, Drug Interactions (5.7) www.fda.gov/medwatch.
annually thereafter, and verify as normal. (4, 5.2) ——— INDICATIONS AND USAGE ———
• Temporarily discontinue PrandiMet® in patients receiving ——— DRUG INTERACTIONS ———
• PrandiMet® is a meglitinide and biguanide combination iodinated contrast for radiological studies. (5.3) • Cationic drugs eliminated by renal tubular secretion may product indicated as an adjunct to diet and exercise to • Hepatic impairment is associated with lactic acidosis.
interfere with metformin elimination: use with caution. (7.1) improve glycemic control in adults with type 2 diabetes Recommend not using in patients with hepatic impairment.
• Repaglinide is partly metabolized by CYP2C8 and CYP3A4.
mellitus who are already treated with a meglitinide and Use caution in patients taking inhibitors and/or inducers of metformin HCl or who have inadequate glycemic control on a • Alcohol potentiates the effect of metformin on lactate meglitinide alone or metformin HCl alone. (1) metabolism. Warn patients against excess alcohol intake. (5.5) See 17 for PATIENT COUNSELING INFORMATION
• PrandiMet® should not be used in combination with NPH Revised: 4/2012
• Do not use to treat type 1 diabetes or diabetic ketoacidosis. (1) • Gemfibrozil substantially increases repaglinide exposure.
Coadministration of gemfibrozil and PrandiMet® is notrecommended. (4, 5.7, 7.2, 12.3) FULL PRESCRIBING INFORMATION: CONTENTS*
HOW SUPPLIED/STORAGE AND HANDLING
WARNING: LACTIC ACIDOSIS
ADVERSE REACTIONS
PATIENT COUNSELING INFORMATION
INDICATIONS AND USAGE
6.1 Most Frequently Observed Adverse Reactions DOSAGE AND ADMINISTRATION
*Sections or subsections omit ed from the ful prescribing information are not listed DOSAGE FORMS AND STRENGTHS
CONTRAINDICATIONS
DRUG INTERACTIONS
WARNINGS AND PRECAUTIONS
7.2 CYP2C8 and CYP3A4 Inhibitors/Inducers USE IN SPECIFIC POPULATIONS
5.3 Radiologic Studies with Intravascular Iodinated Contrast Materials OVERDOSAGE
DESCRIPTION
CLINICAL PHARMACOLOGY
5.12 Use of Concomitant Medications Af ecting Renal Function or Metformin NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 5.14 Change in Clinical Status of Patients with Previously Control ed Type 2 CLINICAL STUDIES
14.1 Patients with Inadequate Glycemic Control on Metformin HCl Monotherapy FULL PRESCRIBING INFORMATION
fatal cases/1,000 patient-years of exposure). In more than 20,000 patient-years exposure dif icult to recognize in the elderly and in people who are taking ß-adrenergic blocking to metformin HCl in clinical trials, there were no reports of lactic acidosis. Reported cases drugs [see Adverse Reactions (6.1)].
have occurred primarily in diabetic patients with significant renal impairment, including WARNING: LACTIC ACIDOSIS
Vitamin B
both intrinsic renal disease and renal hypoperfusion, often in the set ing of multiple 12 Levels
Lactic acidosis is a rare but serious complication that can occur due to
concomitant medical/surgical problems and multiple concomitant medications. Patients In control ed clinical trials of metformin HCl of 29 weeks’ duration, a decrease to subnormal metformin accumulation. The risk increases with conditions such as
with congestive heart failure requiring pharmacologic management, in particular those with levels of previously normal serum vitamin B12 levels, without clinical manifestations, was sepsis, dehydration, excess alcohol intake, hepatic impairment, renal
unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, observed in approximately 7% of patients. This finding, possibly due to interference with impairment, and acute congestive heart failure.
are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree B12 absorption from the B12-intrinsic factor complex, is rarely associated with anemia and The onset of lactic acidosis often is subtle, and accompanied only by
of renal impairment and the patient's age. The risk of lactic acidosis may, therefore, be appears to be rapidly reversible with discontinuation of metformin HCl or vitamin B12 nonspecific symptoms such as malaise, myalgias, respiratory distress,
significantly decreased by regular monitoring of renal function in patients taking supplementation. Measurement of hematologic parameters on an annual basis is advised increasing somnolence, and nonspecific abdominal distress.
PrandiMet® and by use of the minimum ef ective dose of PrandiMet®. In particular, in patients on PrandiMet® and any apparent abnormalities should be appropriately inves- Laboratory abnormalities include low pH, increased anion gap and
treatment of the elderly should be accompanied by careful monitoring of renal function.
elevated blood lactate.
Treatment with PrandiMet® should not be initiated in patients ≥80 years of age unless Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) measurement of creatinine clearance demonstrates that renal function is not reduced, as If acidosis is suspected, PrandiMet® should be discontinued and the
appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, these patients are more susceptible to developing lactic acidosis. In addition, PrandiMet® patient hospitalized immediately [see Warnings and Precautions (5.1)].
routine serum vitamin B12 measurements at 2- to 3-year intervals may be useful.
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 5.10 Surgical Procedures
INDICATIONS AND USAGE
to clear lactate, PrandiMet® should general y be avoided in patients with clinical or Use of PrandiMet® should be temporarily suspended for any surgical procedure (except PrandiMet® is indicated as an adjunct to diet and exercise to improve glycemic control in laboratory evidence of hepatic disease. Patients should be cautioned against excessive minor procedures not associated with restricted intake of food and fluids) and should not adults with type 2 diabetes mel itus who are already treated with a meglitinide and alcohol intake, either acute or chronic, when taking PrandiMet®, since alcohol potentiates be restarted until the patient's oral intake has resumed and renal function has been metformin HCl or who have inadequate glycemic control on a meglitinide alone or the ef ects of metformin HCl on lactate metabolism. In addition, PrandiMet® should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical 5.11 Loss of Control of Blood Glucose
procedure [see Warnings and Precautions (5.3), (5.5), and (5.10)].
When a patient stabilized on any diabetic regimen is exposed to stress such as fever, PrandiMet® should not be used in patients with type 1 diabetes or for the treatment of The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such diabetic ketoacidosis, as it would not be ef ective in these set ings.
such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific times, it may be necessary to withhold PrandiMet® and temporarily administer insulin.
abdominal distress. There may be associated hypothermia, hypotension, and resistant PrandiMet® may be reinstituted after the acute episode is resolved.
DOSAGE AND ADMINISTRATION
bradyarrhythmias with more marked acidosis. The patient and the patient's physician must 5.12 Use of Concomitant Medications Affecting Renal Function or Metformin
be aware of the possible importance of such symptoms and the patient should be Disposition
The dosage of PrandiMet® should be individualized on the basis of the patient’s current instructed to notify the physician immediately if they occur (see also Warnings and regimen, ef ectiveness and tolerability. PrandiMet® can be administered 2 to 3 times a day Precautions). PrandiMet® should be withdrawn until the situation is clarified. Serum elec- Concomitant medication(s) that may affect renal function or result in significant up to a maximum daily dose of 10 mg repaglinide/2500 mg metformin HCl. No more than trolytes, ketones, blood glucose and, if indicated, blood pH, lactate levels, and even blood hemodynamic change or may interfere with the disposition of metformin, such as cationic 4 mg repaglinide/1000 mg metformin HCl should be taken per meal. Initiation and metformin levels may be useful. Once a patient is stabilized on any dose level of drugs that are eliminated by renal tubular secretion [see Drug Interactions (7.1)] should be maintenance of combination therapy with PrandiMet® should be individualized to the PrandiMet®, gastrointestinal symptoms, which are common during initiation of therapy, are patient, and at the discretion of the health care provider. Blood glucose monitoring should unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to 5.13 Hypoxic States
be performed to determine the therapeutic response to PrandiMet®.
lactic acidosis or other serious disease.
Cardiovascular col apse (shock) from whatever cause, acute congestive heart failure, acute PrandiMet® doses should usual y be taken within 15 minutes prior to the meal but the Levels of fasting venous plasma lactate above the upper limit of normal but less than5 mmol/L in patients taking PrandiMet® do not necessarily indicate impending lactic myocardial infarction, and other conditions characterized by hypoxemia have been timing can vary from immediately preceding the meal up to 30 minutes before the meal.
acidosis and may be explainable by other mechanisms, such as poorly control ed diabetes associated with lactic acidosis and may also cause prerenal azotemia. When such events Patients who skip a meal should be instructed to skip the PrandiMet® dose for that meal.
or obesity, vigorous physical activity or technical problems in sample handling [see occur in patients receiving PrandiMet®, the drug should be promptly discontinued.
Patients Inadequately Control ed with Metformin HCl Monotherapy Warnings and Precautions (5.11), (5.14)].
5.14 Change in Clinical Status of Patients with Previously Control ed Type 2
If therapy with a combination tablet containing repaglinide and metformin HCl is considered Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking Diabetes
appropriate for a patient with type 2 diabetes mel itus inadequately control ed with evidence of ketoacidosis (ketonuria and ketonemia).
metformin HCl alone, the recommended starting dose of PrandiMet® is 1 mg A patient with type 2 diabetes previously wel -control ed on PrandiMet® who develops repaglinide/500 mg metformin HCl administered twice daily with meals, with gradual dose Lactic acidosis is a medical emergency that must be treated in a hospital set ing. In a laboratory abnormalities or clinical il ness (especial y vague and poorly defined il ness) escalation (based on glycemic response) to reduce the risk of hypoglycemia with patient with lactic acidosis who is taking PrandiMet®, the drug should be discontinued should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation immediately and general supportive measures promptly instituted. Because metformin HCl should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), lactate, pyruvate, and metformin levels. If acidosis of either form occurs, PrandiMet® must Patients Inadequately Control ed with Meglitinide Monotherapy prompt hemodialysis is recommended to correct the acidosis and remove the accumulated be stopped immediately and other appropriate corrective measures initiated.
If therapy with a combination tablet containing repaglinide and metformin HCl is considered metformin. Such management often results in prompt reversal of symptoms and recovery appropriate for a patient with type 2 diabetes mel itus inadequately control ed with 5.15 Macrovascular Outcomes
repaglinide alone, the recommended starting dose of the metformin HCl component of There have been no clinical studies establishing conclusive evidence of macrovascular risk PrandiMet® should be 500 mg metformin HCl twice a day, with gradual dose escalation Impaired Renal Function
reduction with PrandiMet® or any other oral anti-diabetic drug.
(based on glycemic response) to reduce gastrointestinal side ef ects associated with Patients with renal impairment should not receive PrandiMet® [see Warnings and Precautions (5.1), Contraindications (4)].
ADVERSE REACTIONS
Patients Currently Using Repaglinide and Metformin HCl Concomitantly As metformin is substantial y excreted by the kidney, before initiation of therapy with Most Frequently Observed Adverse Reactions
For patients switching from repaglinide co-administered with metformin HCl, PrandiMet® PrandiMet® and at least annual y thereafter, renal function should be assessed and verified can be initiated at the dose of repaglinide and metformin HCl similar to (but not exceeding) as normal. In patients in whom development of renal impairment is anticipated, renal In clinical trials of repaglinide, hypoglycemia is the most common adverse reaction (> 5%) the patient’s current doses, then may be titrated to the maximum daily dose as necessary function should be assessed more frequently and PrandiMet® discontinued if evidence of leading to withdrawal of patients treated with repaglinide.
to achieve targeted glycemic control.
renal impairment is present [see Clinical Pharmacology (12.3)].
No studies have been performed examining the safety and ef icacy of PrandiMet® in Radiologic Studies with Intravascular Iodinated Contrast Materials
Gastrointestinal reactions (e.g., diarrhea, nausea, vomiting) are the most common adverse patients previously treated with other oral antihyperglycemic agents and switched to Intravascular contrast studies with iodinated materials can lead to acute alteration of renal reactions (> 5%) with metformin HCl treatment and are more frequent at higher metformin PrandiMet®. Any change in therapy should be undertaken with care and with appropriate function and have been associated with lactic acidosis in patients receiving metformin HCl monitoring as changes in glycemic control can occur.
[see Contraindications (4)]. Therefore, in patients in whom any such study is planned, Clinical Trial Experience
DOSAGE FORMS AND STRENGTHS
PrandiMet® should be temporarily discontinued at the time of or prior to the procedure,and withheld for 48 hours subsequent to the procedure and reinstituted only after renal Because clinical trials are conducted under varying conditions, adverse reaction rates • 1 mg repaglinide /500mg metformin HCl tablets are yel ow, biconvex, debossed with function has been re-evaluated and found to be normal.
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical Novo Nordisk (Apis) bul symbol on one side, and strength indicated on the other side trials of another drug and may not reflect the rates observed in practice.
Impaired Hepatic Function
• 2 mg repaglinide /500mg metformin HCl tablets are pink, biconvex, debossed with Patients with Inadequate Glycemic Control on Metformin HCl Monotherapy Novo Nordisk (Apis) bul symbol on one side, and strength indicated on the other side Hepatic impairment has been associated with some cases of lactic acidosis. Therefore, Table 1 summarizes the most common adverse reactions occurring in a 6-month PrandiMet® should general y be avoided in patients with hepatic impairment [see Clinical randomized study of repaglinide added to metformin HCl in patients with type 2 diabetes CONTRAINDICATIONS
inadequately control ed on metformin HCl alone.
Alcohol Intake
Table 1: Repaglinide added to metformin HCl in patients with type 2 diabetes
• Renal impairment (e.g., serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL Alcohol potentiates the ef ect of metformin on lactate metabolism. Patients should be inadequately control ed on metformin HCl alone.
[females], or abnormal creatinine clearance) [see Warnings and Precautions (5.2)].
warned against excessive alcohol intake while receiving PrandiMet®.
Adverse reaction reported (regardless of Investigator Assessment of Causality)
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoaci- Combination with NPH-insulin
in 10% of patients receiving combination therapy*
dosis should be treated with insulin [see Warnings and Precautions (5.1)].
• Patients receiving gemfibrozil [see Warnings and Precautions (5.7), Drug Interactions Repaglinide is not indicated for use in combination with NPH-insulin.
(7.2), Clinical Pharmacology (12.3)].
Across seven control ed clinical trials, there were six serious adverse events (1.4%) of • Patients with known hypersensitivity to repaglinide, metformin HCl or any inactive myocardial ischemia with repaglinide in combination with NPH-insulin compared to one event (0.3%) in patients using insulin alone [see Adverse Reactions (6.2)]. WARNINGS AND PRECAUTIONS
Drug Interactions
Lactic Acidosis
Repaglinide is partly metabolized by CYP2C8 and CYP3A4 and appears to be a substrate for active hepatic uptake transporter (organic anion transporting protein OATP1B1). Drugs that inhibit CYP2C8, CYP3A4, or OATP1B1 (e.g., cyclosporine) may increase plasma Lactic acidosis is a rare, but serious, metabolic complication that can occur due to concentrations of repaglinide. Dose reduction of repaglinide may be needed [see Drug metformin accumulation during treatment with PrandiMet®; when it occurs, it is fatal in Interactions (7.2) and Clinical Pharmacology (12.3)].
approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mel itus, and whenever there is Gemfibrozil significantly increased repaglinide exposure. Therefore, patients should not take significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by PrandiMet® with gemfibrozil [see Contraindications (4) and Clinical Pharmacology (12.3)].
elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances Hypoglycemia
**There were no cases of severe hypoglycemia (hypoglycemia requiring the assistance of another with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is Most blood glucose-lowering drugs, including repaglinide, can cause hypoglycemia.
implicated as the cause of lactic acidosis, metformin plasma levels >5 µg/mL are general y Patients who have not previously been treated with a meglitinide should be started on the Cardiovascular Events in repaglinide monotherapy trials lowest available repaglinide component of PrandiMet® to reduce the risk of hypoglycemia.
In one-year trials comparing repaglinide to sulfonylurea drugs, the incidence of angina was The reported incidence of lactic acidosis in patients receiving metformin HCl is very low Elderly, debilitated or malnourished patients and those with adrenal or pituitary insuf iciency 1.8% for both treatments, with an incidence of chest pain of 1.8% for repaglinide and (approximately 0.03 cases/1,000 patient-years of exposure, with approximately 0.015 or alcohol intoxication are particularly susceptible to hypoglycemia. Hypoglycemia may be 1.0% for sulfonylureas. The incidence of other selected cardiovascular events (hyperten- sion, abnormal electrocardiogram, myocardial infarction, arrhythmias, and palpitations) was Geriatric Use
Repaglinide lowers blood glucose levels by stimulating the release of insulin from the ≤1% and not dif erent between repaglinide and the comparator drugs.
Healthy volunteers treated with repaglinide 2 mg before each of 3 meals, showed no pancreas. This action is dependent upon functioning beta (ß) cel s in the pancreatic islets.
The incidence of total serious cardiovascular adverse events, including ischemia, was significant dif erences in repaglinide pharmacokinetics between the group of patients <65 Repaglinide closes ATP-dependent potassium channels in the ß-cel membrane by binding higher for repaglinide (51/1228 or 4%) than for sulfonylurea drugs (13/498 or 3%) in years of age and those ≥65 years of age.
at characterizable sites. This potassium channel blockade depolarizes the ß-cel , which control ed clinical trials. In 1-year control ed trials, repaglinide treatment was not associated In patients with advanced age, PrandiMet® should be careful y titrated to establish the leads to an opening of calcium channels. The resulting increased calcium influx induces with excess mortality when compared to the rates observed with other oral hypoglycemic minimum dose for adequate glycemic ef ect, because aging is associated with reduced insulin secretion. The ion channel mechanism is highly tissue selective with low af inity for agent therapies such as glyburide and glipizide.
renal function. In elderly patients, particularly those ≥80 years of age, dose adjustment of Seven control ed clinical trials included repaglinide combination therapy with NPH-insulin PrandiMet® should be based on a careful assessment of renal function [see Warnings Metformin is an anti-hyperglycemic agent, which improves glucose tolerance in patients (n=431), insulin formulations alone (n=388) or other combinations (sulfonylurea plus NPH- and Precautions (5.1 and 5.2), Contraindications (4), Clinical Pharmacology (12.3)].
with type 2 diabetes by lowering both the basal and postprandial plasma glucose.
insulin or repaglinide plus metformin HCl) (n=120). There were six serious adverse events OVERDOSAGE
Metformin decreases hepatic glucose production, decreases intestinal absorption of of myocardial ischemia in patients treated with repaglinide plus NPH-insulin (1.4%) from glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and two studies, and one event in patients using insulin formulations alone from another study utilization. With metformin therapy, insulin secretion remains unchanged while fasting (0.3%) [see Warnings and Precautions (5.6)].
No data are available with regard to overdose of PrandiMet®. Findings related to the insulin levels and day-long plasma insulin response may actual y decrease.
individual active substances are listed below.
Postmarketing Experience
12.3 Pharmacokinetics
In a clinical trial, dizziness, headache, and diarrhea were reported in subjects receiving The fol owing additional adverse reactions have been identified during postapproval use of increasing doses of repaglinide up to 80 mg a day for 14 days. Hypoglycemia did not occur The results of a bioequivalence study in healthy subjects (Table 2) demonstrated that repaglinide. Because these reactions are reported voluntarily from a population of uncertain when meals were given with these high doses.
PrandiMet® (repaglinide/metformin HCl) 1 mg/500 mg and 2 mg/500 mg combination size, it is general y not possible to reliably estimate their frequency or a causal relationship tablets are bioequivalent to co-administration of corresponding doses of repaglinide and Hypoglycemic symptoms without loss of consciousness or neurologic findings should betreated aggressively with oral glucose and adjustments in drug dosage and/or meal metformin HCl as individual tablets. Repaglinide dose proportionality was demonstrated for Postmarketing experience with repaglinide includes infrequent reports of the fol owing pat erns. Close monitoring should continue until the physician is assured that the patient is PrandiMet® (2 mg/500 mg) and PrandiMet® (1 mg/500 mg).
adverse events; alopecia, hemolytic anemia, pancreatitis, Stevens-Johnson Syndrome, and out of danger. Patients should be closely monitored for a minimum of 24 to 48 hours, since severe hepatic dysfunction including jaundice and hepatitis.
Table 2. Mean (SD) Pharmacokinetic Parameters for Repaglinide and Metformin
hypoglycemia may recur after apparent clinical recovery. There is no evidence that Pharmacokinetic Parameter
DRUG INTERACTIONS
repaglinide is dialyzable using hemodialysis. Severe hypoglycemic reactions with coma,seizure, or other neurological impairment occur infrequently, but constitute medical Treatment
AUC (ng·h/mL)
Cationic Drugs
max (ng/mL)
emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or Repaglinide
Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, suspected, the patient should be given a rapid intravenous injection of concentrated (50%) ranitidine, triamterene, trimethoprim, and vancomycin) that are eliminated by renal tubular glucose solution. This should be fol owed by a continuous infusion of more dilute (10%) secretion theoretical y have the potential for interaction with metformin by competing for glucose solution at a rate that wil maintain the blood glucose at a level above 100 mg/dL.
common renal tubular transport systems. Careful patient monitoring and dose adjustment of PrandiMet® and/or the interfering drug is recommended in patients who are taking Overdose of metformin HCl has occurred, including ingestion of amounts greater than 50 cationic medications that are excreted via the proximal renal tubular secretory system [see Metformin
grams. Hypoglycemia was reported in approximately 10% of cases, but no causal Clinical Pharmacology (12.3)].
association with metformin HCl has been established. Lactic acidosis has been reported in CYP2C8 and CYP3A4 Inhibitors/Inducers
approximately 32% of metformin HCl overdose cases [see Warnings and Precautions (5.1)]. Metformin is dialyzable with a clearance of up to 170 mL/min under good Repaglinide is metabolized by CYP2C8 and to a lesser extent by CYP3A4. Drugs that inhibit hemodynamic conditions. Therefore, hemodialysis may be useful for removal of 2C8 (gemfibrozil, trimethoprim, deferasirox), inhibit 3A4 (itraconazole, ketaconazole), or accumulated drug from patients in whom metformin HCl overdosage is suspected.
induce CYP2C8/3A4 (rifampin) may alter the pharmacokinetics and pharmacodynamics of repaglinide. In vivo data from a study that evaluated the co-administration of gemfibrozil DESCRIPTION
B = 2 mg repaglinide tablet + 500 mg metformin HCl tablet and repaglinide in healthy subjects showed a significant increase in repaglinide blood PrandiMet® (repaglinide and metformin HCl) tablets contain two oral antihyperglycemic levels. Administration of PrandiMet® and gemfibrozil to the same patient is not drugs used in the management of type 2 diabetes: repaglinide and metformin HCl. The recommended [see Warnings and Precautions (5.7) and Clinical Pharmacology (12.3)].
concomitant use of repaglinide and metformin HCl has been previously approved based on Repaglinide: After single and multiple oral doses in healthy subjects or in patients with type Repaglinide exposures are increased more than 20-fold in patients taking both gemfibrozil clinical trials in patients with type 2 diabetes inadequately control ed on exercise, diet, and 2 diabetes, peak plasma drug levels (Cmax) occur within 1 hour (Tmax). Repaglinide is and itraconazole [see Contraindications (4) and Clinical Pharmacology (12.3)].
eliminated from the blood stream with a half-life of approximately 1 hour. The mean USE IN SPECIFIC POPULATIONS
Repaglinide, S(+)2-ethoxy-4(2( 3-methyl-1-(2-(1-piperidinyl) phenyl)-butyl) amino)-2- absolute bioavailability is 56%. When repaglinide was given with food, the mean Tmax was oxoethyl) benzoic acid, is chemical y unrelated to the oral sulfonylurea insulin secreta- not changed, but the mean Cmax and AUC (area under the time/plasma concentration Pregnancy
gogues. Repaglinide is a white to of -white powder with molecular formula C27 H36 N2 O4 curve) were decreased 20% and 12.4%, respectively.
and a molecular weight of 452.6 with the structural formula as shown below. Repaglinide Metformin HCl: The absolute bioavailability of a 500 mg metformin HCl tablet given under There are no adequate and wel -control ed studies in pregnant women with PrandiMet® or is freely soluble in methanol and ethanol. The pKa of repaglinide in acid is 3.9, and the pKa fasting conditions is approximately 50% to 60%. Studies using single oral doses of its individual components. Because animal reproduction studies are not always predictive metformin HCl tablets of 500 mg to 1,500 mg, and 850 mg to 2,550 mg, indicate that of human response, PrandiMet® like other antidiabetic medications, should be used during Structural formula of Repaglinide
there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Food decreases the extent of and slightly No animal studies have been conducted with the combined products in PrandiMet®. The delays the absorption of metformin, as shown by approximately a 40% lower peak concen- fol owing data are based on findings in studies performed with repaglinide or metformin tration (Cmax), a 25% lower area under plasma concentration (AUC) and a 35-minute prolongation of time to peak plasma concentration (Tmax) fol owing administration of a single 850 mg tablet of metformin HCl with food, compared to the same tablet strength Repaglinide was not teratogenic in rats at doses 40 times, and rabbits approximately 0.8 administered fasting. The clinical relevance of these decreases is unknown.
times the clinical exposure (on a mg/m2 basis) throughout pregnancy. Of spring of rat dams exposed to repaglinide at 15 times clinical exposure on a mg/m2 basis during days 17 to Repaglinide: After intravenous (IV) dosing in healthy subjects, the volume of distribution at 22 of gestation and during lactation developed nonteratogenic skeletal deformities steady state (Vss) was 31 L, and the total body clearance (CL) was 38 L/h. Protein binding consisting of shortening, thickening, and bending of the humerus during the postnatal and binding to human serum albumin was greater than 98%.
period. This ef ect was not seen at doses up to 2.5 times clinical exposure (on a mg/m2basis) on days 1 to 22 of pregnancy or at higher doses given during days 1 to 16 of Metformin HCl: The apparent volume of distribution (V/F) of metformin fol owing single oral pregnancy. Relevant human exposure has not occurred to date and therefore the safety of dose of 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins.
repaglinide administration throughout pregnancy or lactation cannot be established.
Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical Metformin HCl (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemical y doses and dosing schedules of metformin HCl, steady state plasma concentrations of or pharmacological y related to any other classes of oral antihyperglycemic agents.
Metformin HCl alone was not teratogenic in rats or rabbits at doses up to 600 mg/kg/day.
metformin are reached within 24-48 hours and are general y <1 µg/mL. During control ed Metformin HCl is a white to of -white crystal ine compound with a molecular formula of This represents an exposure of approximately two and six times the near-maximal clinical trials, maximum metformin plasma levels did not exceed 5 µg/mL, even at C4H11N5•HCl and a molecular weight of 165.63. Metformin HCl is freely soluble in water ef icacious human daily dose of 2000 mg of the metformin HCl component of PrandiMet® and is practical y insoluble in acetone, ether, and chloroform. The pKa of metformin HCl is based on body surface area comparisons for rats and rabbits, respectively. Determination 12.4. The pH of a 1% aqueous solution of metformin HCl is 6.68. The structural formula of of fetal concentrations demonstrated a partial placental barrier to metformin.
Repaglinide: Repaglinide is completely metabolized by oxidative biotransformation and Nursing Mothers
Structural formula of Metformin HCl
direct conjugation with glucuronic acid after either an intravenous or oral dose. The major No studies in lactating animals have been conducted with the PrandiMet® fixed dose metabolites are an oxidized dicarboxylic acid (M2), the aromatic amine (M1), and the acyl combination. In studies performed with individual components, both repaglinide and glucuronide (M7). The cytochrome P-450 enzyme system, specifical y 2C8 and 3A4, have metformin are excreted into milk of lactating rats.
been shown to be involved in the N-dealkylation of repaglinide to M2 and the furtheroxidation to M1. Metabolites do not contribute to the glucose-lowering ef ect of repaglinide.
Within 96 hours after dosing with 14C-repaglinide as a single, oral dose, approximately In rat reproduction studies, measurable levels of repaglinide were detected in the breast 90% of the radiolabel was recovered in the feces and approximately 8% in the urine. Only milk of the dams and lowered blood glucose levels were observed in the pups. Cross 0.1% of the dose is cleared in the urine as parent compound. The major metabolite (M2) fostering studies indicated that skeletal changes could be induced in control pups nursedby treated dams, although this occurred to a lesser degree than those pups treated in PrandiMet® is available as a tablet for oral administration containing 1 mg repaglinide with accounted for 60% of the administered dose. Less than 2% of parent drug was recovered 500 mg metformin HCl (1 mg/500 mg) or 2 mg repaglinide with 500 mg metformin HCl in feces. Repaglinide appears to be a substrate for active hepatic uptake transporter(organic anion transporting protein OATP1B1).
(2 mg/500 mg) formulated with the fol owing inactive ingredients: poloxamer 188, micro- Studies in lactating rats with metformin HCl show that it is excreted into milk and reaches crystal ine cel ulose, polacril in potassium, magnesium stearate, hypromel ose 3cp or 6cp, Metformin HCl: Intravenous single-dose studies in normal subjects demonstrate that levels comparable to those in plasma.
povidone, meglumine, sorbitol, talc, titanium dioxide, red or yel ow iron oxide, and polyeth- metformin is excreted unchanged in the urine and does not undergo hepatic metabolism ylene glycol. Propylene glycol is present in the 2 mg/500 mg PrandiMet® tablets.
(no metabolites have been identified in humans) or biliary excretion. Renal clearance is It is not known whether repaglinide or metformin are excreted in human milk. PrandiMet® approximately 3.5 times greater than creatinine clearance, which indicates that tubular is not recommended in nursing mothers because it may potential y cause hypoglycemia in CLINICAL PHARMACOLOGY
secretion is the major route of metformin elimination. Fol owing oral administration, approx- 12.1 Mechanism of Action
imately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, Pediatric Use
with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half- Safety and ef ectiveness of PrandiMet® in pediatric patients have not been established.
PrandiMet® combines two anti-hyperglycemic agents with dif erent mechanisms of action life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a PrandiMet® is not recommended for use in children.
to improve glycemic control in patients with type 2 diabetes.
Table 5: Effect of Metformin or Repaglinide on AUC and Cmax of Other Drugs
HOW SUPPLIED/STORAGE AND HANDLING
Renal Impairment
Other Drugs
PrandiMet® tablets are supplied as biconvex tablets available in 1 mg/500 mg (yel ow) and Furosemide1
2 mg/500 mg (pink) strengths. Tablets are debossed with the Novo Nordisk (Apis) bul Because PrandiMet® contains metformin HCl, it should not be used in patients with renal symbol on one side and tablet strength on the other side.The tablets are colored to indicate Ethinyl Estradiol2
impairment [see Contraindications (4); Warnings and Precautions (5.2)].
Fenofibrate
1 mg repaglinide/500 mg metformin HCl tablets Bot les of 20 Single-dose and steady-state pharmacokinetics of repaglinide were compared between patients with type 2 diabetes and normal renal function (CrCl >80 mL/min), mild to 2 Co-administration of a combination tablet (0.15 mg levonorgestrel/0.03 mg ethinyl estradiol) once 2 mg repaglinide/500 mg metformin HCl tablets Bot les of 20 moderate renal function impairment (CrCl = 40-80 mL/min), and severe renal function daily for 21 days with 2 mg repaglinide administered TID (days 1-4) and a single dose on day 5.
impairment (CrCl = 20-40 mL/min). Both AUC and Cmax of repaglinide were similar in patients with normal and mild to moderately impaired renal function (mean values 56.7 Protect from moisture. Keep bot les tightly closed.
ng/mL*hr vs 57.2 ng/mL*hr and 37.5 ng/mL vs 37.7 ng/mL, respectively). Patients withseverely reduced renal function had elevated mean AUC and C Dispense in tight containers with safety closures.
NONCLINICAL TOXICOLOGY
and 50.7 ng/mL, respectively), but this study showed only a weak correlation between 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
PATIENT COUNSELING INFORMATION
repaglinide levels and creatinine clearance.
17.1 Physician Instructions
No animal studies have been conducted with the combined products in PrandiMet® to In patients with decreased renal function (based on measured creatinine clearance), the Patients should be informed of the potential risks and advantages of PrandiMet® and of evaluate carcinogenesis, mutagenesis and impairment of fertility. The fol owing data are plasma and blood half-life of metformin is prolonged and the renal clearance is decreased alternative modes of therapy. They should also be informed about the importance of based on findings in studies performed with the individual components.
in proportion to the decrease in creatinine clearance.
adherence to dietary instructions, of a regular exercise program, and of regular testing of Hepatic Impairment
blood glucose, HbA1c, renal function, and hematologic parameters. The risks of hypo- In a 104-week carcinogenicity study in rats at doses up to 120 mg/kg/day, the incidences glycemia, its symptoms and treatment, and conditions that predispose to its development of benign adenomas of the thyroid and liver were increased in male rats. The higher and concomitant administration of other glucose-lowering drugs should be explained to PrandiMet® should be avoided in patients with hepatic impairment [see Warnings and incidences of thyroid and liver tumors in male rats were not seen at lower dose of patients and family members. Medication requirements may change during periods of 30 mg/kg/day and 60 mg/kg/day respectively (which are over 15 and 30 times, respec- stress such as fever, trauma, infection, or surgery, due to loss of glycemic control. Patients tively, clinical exposures on a mg/m2 basis).
should be advised to seek medical advice promptly.
A single-dose, open-label study was conducted in 12 healthy subjects and 12 patients with In a 104-week carcinogenicity study in mice at doses up to 500 mg/kg/day, no evidence The risks of lactic acidosis, its symptoms, and conditions that predispose to its chronic liver disease (CLD) classified by Child-Pugh scale and caf eine clearance. Patients of carcinogenicity was found in mice (which is approximately 125 times clinical exposure development, as noted in the Warnings and Precautions (5.1), should be explained to with moderate to severe impairment of liver function had higher and more prolonged serum patients. Patients should be advised to discontinue PrandiMet® immediately and to concentrations of both total and unbound repaglinide than healthy subjects (AUChealthy: promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, 91.6 ng/mL*hr; AUCCLD patients: 368.9 ng/mL*hr; Cmax, healthy: 46.7 ng/mL; Cmax, CLD Repaglinide was non-genotoxic in a bat ery of in vivo and in vitro studies: Bacterial unusual somnolence, or other nonspecific symptoms occur. Once a patient is stabilized on patients: 105.4 ng/mL). AUC was statistical y correlated with caf eine clearance. No mutagenesis (Ames test), in vitro forward cel mutation assay in V79 cel s (HGPRT), in vitro any dose level of PrandiMet®, gastrointestinal symptoms, which are common during dif erence in glucose profiles was observed across patient groups. Patients with impaired chromosomal aberration assay in human lymphocytes, unscheduled and replicating DNA initiation of metformin HCl therapy, are unlikely to be drug related. Later occurrence of liver function may be exposed to higher concentrations of repaglinide and its associated synthesis in rat liver, and in vivo mouse and rat micronucleus tests.
gastrointestinal symptoms could be due to lactic acidosis or other serious disease.
metabolites than would patients with normal liver function receiving usual doses.Therefore, In a rat fertility study, repaglinide was administered to male and female rats at doses up to repaglinide should general y be avoided in patients with impaired liver function.
Patients should be instructed to take PrandiMet® with meals. Doses are usual y taken 300 and 80 mg/kg/day, respectively. No adverse ef ects on fertility were observed (which within 15 minutes prior to the meal but the timing can vary from immediately preceding are over 40 times clinical exposure on a mg/m2 basis).
the meal up to 30 minutes before the meal. Patients who skip a meal should be instructed No pharmacokinetics studies with metformin HCl have been conducted in patients with to skip the PrandiMet® dose for that meal.
In a 104-week carcinogenicity study in rats at doses up to 900 mg/kg/day, the incidences Patients should be counseled against excessive alcohol intake, either acute or chronic, Geriatric Patients
of benign stromal uterine polyps were increased in female rats at 900 mg/kg/day (which Healthy volunteers treated with repaglinide 2 mg before each of 3 meals, showed no is approximately four times the maximal recommended human daily dose of 2000 mg of significant dif erences in repaglinide pharmacokinetics between the group of patients <65 metformin HCl component of PrandiMet® on a mg/m2 basis).
17.2 Laboratory Tests
years of age and those ≥65 years of age.
In a 91-week carcinogenicity study in mice at doses up to 1500 mg/kg/day, no evidence Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and Limited data from control ed pharmacokinetic studies of metformin HCl in healthy elderly of carcinogenicity was found in mice (which is approximately four times the maximal red blood cel indices) and renal function (serum creatinine) should be performed, at least subjects suggest that total plasma clearance is decreased, the half-life is prolonged, and recommended human daily dose of 2000 mg of metformin HCl component of PrandiMet® 12 deficiency should be excluded if megaloblastic anemia is Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by achange in renal function [see Warnings and Precautions (5.2)].
There was no evidence of a mutagenic potential of metformin HCl alone in the fol owingin vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cel s), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronu- Table 3: Effect of Other Drugs on AUC and Cmax of Metformin
Study Drug*
Metformin AUC
Metformin Cmax
In a rat fertility study, metformin HCl was administered to male and female rats at doses Cimetidine
up to 600 mg/kg/day. No adverse ef ects on fertility were observed (which is approximatelythree times the maximal recommended human daily dose of 2000 mg of metformin HCl Furosemide
component of PrandiMet® on a mg/m2 basis).
Nifedipine
Propranolol-metformin
CLINICAL STUDIES
Ibuprofen-metformin
14.1 Patients with Inadequate Glycemic Control on Metformin HCl
Monotherapy
Unless indicated al drug interactions were observed with single dose co-administration*single and multiple dose co-administration In a double-blind, clinical trial, 83 patients with type 2 diabetes and inadequate glycemic control on metformin HCl monotherapy were randomized to add-on repaglinide, repaglinide monotherapy, or continued treatment with metformin HCl monotherapy. The repaglinidedosage was titrated for 4 to 8 weeks, fol owed by a 3-month dose maintenance period.
Table 4: Effect of Other Drugs on AUC and Cmax of Repaglinide
Repaglinide add-on to metformin HCl resulted in a statistical y significant improvement in Duration
Repaglinide
Study Drug
HbA1c and fasting plasma glucose compared to the monotherapy arms (Table 6). In this Other Drug
Other Drug
study where metformin HCl dosage was kept constant, repaglinide add-on to metformin Clarithromycin*
HCl resulted in a greater reduction in HbA1c and fasting plasma glucose at a lower daily Cyclosporine
repaglinide dosage than in the repaglinide monotherapy group (dose sparing with respect Deferasirox
to repaglinide). However, the repaglinide add-on to metformin HCl group had a higher incidence of hypoglycemia than the repaglinide monotherapy group [see Adverse Reactions Fenofibrate
(6.2)]. The 2 repaglinide treatment arms experienced weight gain, whereas the metformin Gemfibrozil*1
HCl monotherapy arm had weight loss.
Itraconazole*
Table 6. Repaglinide as Add-on to Metformin HCl: Mean Changes from Baseline
Gemfibrozil+Itraconazole Gem: 600 mg BID;
in Glycemic Parameters and Body Weight After 4 to 5 Months of Treatment1
Ketoconazole2
Levonorgestrel/ethinyl
Estradiol3
Nifedipine*3
Version: 5
Rifampin*4
PrandiMet ® is a registered trademark of Novo Nordisk A/S. Simvastatin3
Trimethoprim*
Unless indicated al drug interactions were observed with single dose of 0.25 mg repaglinide 1 Coadministration of gemfibrozil with PrandiMet® is not recommended [see Warnings and Precautions (5.7) and Drug Interactions (7.2)] 2 Single dose of 2 mg repaglinide was administered 3 2 mg repaglinide was administered TID for 4 days 4 Single dose of 4 mg repaglinide was administered 5 Two doses, twelve hours apart, healthy volunteers 6 Single dose of 0.5 mg repaglinide was administered *: p< 0.05, for pairwise comparisons with repaglinide and metformin HCl monotherapy.
* Indicates data are from published literature #: p< 0.05, for pairwise comparison with metformin HCl monotherapy.

Source: http://www.novo-pi.com/prandimet.pdf

El uso de terapia de reemplazo hormonal en la menopausia y el cáncer

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