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There are no adequate and well-controlled studies in pregnant women with GLUCOPHAGE or GLUCOPHAGE XR. Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/ kg/ day. This represents an exposure of about two and six times the maximum recom-mended human daily dose of 2000 mg based on body surface area comparisons for rats and rab-bits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin. Nursing Mothers Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted in nursing mothers. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to dis-continue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If GLUCOPHAGE or GLUCOPHAGE XR is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered. Text Continues Below
Pediatric Use The safety and effectiveness of GLUCOPHAGE for the treatment of type 2 diabetes have been established in pediatric patients ages 10 to 16 years (studies have not been conducted in pediatric patients below the age of 10 years). Use of GLUCOPHAGE in this age group is supported by evi-dence from adequate and well-controlled studies of GLUCOPHAGE in adults with additional data from a controlled clinical study in pediatric patiens ages 10-16 years with type 2 diabetes, which demonstrated a similar response in glycemic control to that seen in adults. (See CLINICAL PHAR-MACOLOGY: Pediatric Clinical Studies.) In this study, adverse effects were similar to those described in adults. (See ADVERSE REACTIONS: Pediatric Patients.) A maximum daily dose of 2000 mg is recommended. (See DOSAGE AND ADMINISTRATION: Recommended Dosing Schedule: Pediatrics.) Safety and effectiveness of GLUCOPHAGE XR in pediatric patients have not been established. Geriatric Use Controlled clinical studies of GLUCOPHAGE and GLUCOPHAGE XR did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and younger patients. Metformin is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, GLUCOPHAGE and GLUCOPHAGE XR should only be used in patients with normal renal function (see CONTRAINDICATIONS, WARNINGS, and CLINICAL PHARMACOLOGY: Pharmacokinetics). Because aging is associated with reduced renal function, GLUCOPHAGE (metformin hydrochloride tablets) or GLUCOPHAGE XR (metformin hydrochloride extended-release tablets) should be used with caution as age increases. Care should be taken in dose selec-tion and should be based on careful and regular monitoring of renal function. Generally, elderly patients should not be titrated to the maximum dose of GLUCOPHAGE or GLUCOPHAGE XR (see also WARNINGS and DOSAGE AND ADMINISTRATION).
Drug Interactions
(clinical evaluation of drug interactions done with GLUCOPHAGE) Glyburide In a single-dose interaction study in type 2 diabetes patients, co-administration of metformin and glyburide did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Decreases in glyburide AUC and C max were observed, but were highly vari-able. The single-dose nature of this study and the lack of correlation between glyburide blood lev-els and pharmacodynamic effects, makes the clinical significance of this interaction uncertain (see ADVERSE REACTIONS In a U. S. double-blind clinical study of GLUCOPHAGE in patients with type 2 diabetes, a total of 141 patients received GLUCOPHAGE therapy (up to 2550 mg per day) and 145 patients received place-bo. Adverse reactions reported in greater than 5% of the GLUCOPHAGE patients, and that were more common in GLUCOPHAGE-than placebo-treated patients, are listed in Table 11. * Reactions that were more common in GLUCOPHAGE-than placebo-treated patients.
Diarrhea led to discontinuation of study medication in 6% of patients treated with GLUCOPHAGE.
Additionally, the following adverse reactions were reported in 1.0- 5.0% of GLUCOPHAGE patients and were more commonly reported with GLUCOPHAGE than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disor-der, chest discomfort, chills, flu syndrome, flushing, palpitation. In worldwide clinical trials over 900 patients with type 2 diabetes have been treated with GLUCOPHAGE XR in placebo-and active-controlled studies. In placebo-controlled trials, 781 patients were administered GLUCOPHAGE XR and 195 patients received placebo. Adverse reac-tions reported in greater than 5% of the GLUCOPHAGE XR patients, and that were more common in GLUCOPHAGE XR-than placebo-treated patients, are listed in Table 12. * Reactions that were more common in GLUCOPHAGE XR-than placebo-treated patients Diarrhea led to discontinuation of study medication in 0.6% of patients treated with GLUCOPHAGE XR. Additionally, the following adverse reactions were reported in 1.0%- 5.0% of GLUCOPHAGE XR patients and were more commonly reported with GLUCOPHAGE XR than placebo: abdominal
pain, constipation, distention abdomen, dyspepsia/ heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance. Pediatric Patients In clinical trials with GLUCOPHAGE in pediatric patients with type 2 diabetes, the profile of adverse reactions was similar to that observed in adults.
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