Doi:10.1016/s1558-0164(07)70586-2

N o v e m b e r 2 0 0 7 • w w w. c l i n i c a l e n d o c r i n o l o g y n e w s . c o m Osteoporosis & Bone Metabolism
FDA Eyes Atrial Fib Data in Bisphosphonate Users B Y D E N I S E P E T E R S O N
physicians alter their prescribing choices or two studies describing increased rates of serious atrial fibrillation in older women treated with zoledronic acid or alendronate ports of atrial fibrillation in association The Food and Drug Administration proved primarily to treat osteoporosis, for osteoporosis (N. Engl. J. Med. with both oral and intravenous bisphos- slow bone turnover in Paget’s disease, and 2007;356:1809-33 and N. Engl. J. Med.
phonates, the agency did not find a “pop- treat bone metastases in cancer patients— specifically alendronate (Fosamax and Fos- searchers found that more women who creased risk” for the atrial fibrillation. And received a bisphosphonate developed seri- since atrial fibrillation is a common disor- Actonel with Calcium), ibandronate (Boni- ous atrial fibrillation versus those receiving va), zoledronic acid (Reclast and Zometa), rates of atrial fibrillation were not statisti- cally different between the studies’ active cles—the FDA cautioned that it is “unclearhow these data . should be interpreted.” ADVERSE REACTIONS
volunteers demonstrated that coadministration of nifedipine increased plasma metformin months, according to the FDA. This is the Clinical Trials Experience. The overall incidence of side effects reported in patients
max and AUC by 20% and 9%, respectively, and increased the amount excreted in the agency’s second “early communication” of receiving sitagliptin and metformin was similar to that reported with patients receiving max and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.
a drug safety review, part of the FDA’s ef- The Use of Metformin with Other Drugs. Certain drugs tend to produce hyperglycemia and
In a 24-week placebo-controlled trial of sitagliptin 100 mg administered once daily added forts to be more transparent in oversight of may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, to a twice-daily metformin regimen, there were no adverse reactions reported regardless corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, postmarketing drug safety. The first com- of investigator assessment of causality in ≥5% of patients and more commonly than in nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When patients given placebo. Discontinuation of therapy due to clinical adverse reactions was such drugs are administered to a patient receiving JANUMET the patient should be closely similar to the placebo treatment group (sitagliptin and metformin, 1.9%; placebo and observed to maintain adequate glycemic control.
In healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin The overall incidence of adverse reactions of hypoglycemia in patients treated with and ibuprofen were not affected when coadministered in single-dose interaction studies.
sitagliptin and metformin was similar to patients treated with placebo and metformin This newspaper and “The Pink Sheet” are (100 mg sitagliptin and metformin, 1.3%; placebo and metformin, 2.1%). Adverse Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact reactions of hypoglycemia were based on all reports of hypoglycemia; a concurrent glucose with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and measurement was not required. The incidence of selected gastrointestinal adverse probenecid, as compared to the sulfonylureas, which are extensively bound to serum reactions in patients treated with sitagliptin and metformin was also similar to placebo and metformin: nausea (sitagliptin and metformin, 1.3%; placebo and metformin, 0.8%), USE IN SPECIFIC POPULATIONS
vomiting (1.1%, 0.8%), abdominal pain (2.2%, 3.8%), and diarrhea (2.4%, 2.5%).
Pregnancy
No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed with the combination of sitagliptin and metformin.
JANUMET. There are no adequate and well-controlled studies in pregnant women with The most common adverse experience in sitagliptin monotherapy reported regardless JANUMET or its individual components; therefore, the safety of JANUMET in pregnant of investigator assessment of causality in ≥5% of patients and more commonly than women is not known. JANUMET should be used during pregnancy only if clearly needed.
in patients given placebo was nasopharyngitis.
Merck & Co., Inc. maintains a registry to monitor the pregnancy outcomes of women The most common (>5%) established adverse reactions due to initiation of metformin exposed to JANUMET while pregnant. Health care providers are encouraged to report any therapy are diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, prenatal exposure to JANUMET by calling the Pregnancy Registry at (800) 986-8999.
No animal studies have been conducted with the combined products in JANUMET to M O N T R E A L — Osteoporosis secondary evaluate effects on reproduction. The following data are based on findings in studies Sitagliptin. The incidence of laboratory adverse reactions was similar in patients treated performed with sitagliptin or metformin individually.
with sitagliptin and metformin (7.6%) compared to patients treated with placebo and Sitagliptin. Reproduction studies have been performed in rats and rabbits. Doses of vorably and early to curative adrenalecto- metformin (8.7%). In most but not all studies, a small increase in white blood cell count sitagliptin up to 125 mg/kg (approximately 12 times the human exposure at the maximum (approximately 200 cells/microL difference in WBC vs placebo; mean baseline WBC recommended human dose) did not impair fertility or harm the fetus. There are, however, approximately 6600 cells/microL) was observed due to a small increase in neutrophils.
no adequate and well-controlled studies with sitagliptin in pregnant women. This change in laboratory parameters is not considered to be clinically relevant.
Sitagliptin administered to pregnant female rats and rabbits from gestation day 6 to 20 Metformin hydrochloride. In controlled clinical trials of metformin of 29 weeks duration, (organogenesis) was not teratogenic at oral doses up to 250 mg/kg (rats) and 125 mg/kg a decrease to subnormal levels of previously normal serum Vitamin B (rabbits), or approximately 30 and 20 times human exposure at the maximum recommended clinical manifestations, was observed in approximately 7% of patients. Such decrease, human dose (MRHD) of 100 mg/day based on AUC comparisons. Higher doses increased the possibly due to interference with B12 absorption from the B12-intrinsic factor complex, incidence of rib malformations in offspring at 1000 mg/kg, or approximately 100 times is, however, very rarely associated with anemia and appears to be rapidly reversible months post surgery and was sustained for with discontinuation of metformin or Vitamin B12 supplementation [see Warnings Sitagliptin administered to female rats from gestation day 6 to lactation day 21 decreasedbody weight in male and female offspring at 1000 mg/kg. No functional or behavioral Postmarketing Experience. The following additional adverse reactions have been
toxicity was observed in offspring of rats.
identified during postapproval use of sitagliptin, one of the components of JANUMET.
Because these reactions are reported voluntarily from a population of uncertain size, Placental transfer of sitagliptin administered to pregnant rats was approximately 45% at it is generally not possible to reliably estimate their frequency or establish a causal 2 hours and 80% at 24 hours postdose. Placental transfer of sitagliptin administered to age was 42 years. Of the 17, 7 had osteo- pregnant rabbits was approximately 66% at 2 hours and 30% at 24 hours.
Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria.
Metformin hydrochloride. Metformin was not teratogenic in rats and rabbits at doses upto 600 mg/kg/day. This represents an exposure of about 2 and 6 times the maximum to Cushing’s syndrome from adrenal ade- DRUG INTERACTIONS
recommended human daily dose of 2000 mg based on body surface area comparisons noma. All patients underwent curative la- Cationic Drugs. Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine,
for rats and rabbits, respectively. Determination of fetal concentrations demonstrated quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal a partial placental barrier to metformin. tubular secretion theoretically have the potential for interaction with metformin by competing Nursing Mothers. No studies in lactating animals have been conducted with the
for common renal tubular transport systems. Such interaction between metformin and oral combined components of JANUMET. In studies performed with the individual components, cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose sured preoperatively as well as 3, 6, 12, 18, both sitagliptin and metformin are secreted in the milk of lactating rats. It is not known metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin whether sitagliptin is excreted in human milk. Because many drugs are excreted in human plasma and whole blood concentrations and a 40% increase in plasma and whole blood milk, caution should be exercised when JANUMET is administered to a nursing woman.
metformin AUC. There was no change in elimination half-life in the single-dose study.
Metformin had no effect on cimetidine pharmacokinetics. Although such interactions Pediatric Use. Safety and effectiveness of JANUMET in pediatric patients under 18 years
significantly reduced, compared with that remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of JANUMET and/or the interfering drug is recommended in patients who are taking cationic of the femoral neck (T scores were –3.53 Geriatric Use. JANUMET. Because sitagliptin and metformin are substantially excreted
medications that are excreted via the proximal renal tubular secretory system.
by the kidney and because aging can be associated with reduced renal function, vs. –1.88, respectively), and postsurgical re- Digoxin. There was a slight increase in the area under the curve (AUC, 11%) and mean
JANUMET should be used with caution as age increases. Care should be taken in dose peak drug concentration (Cmax, 18%) of digoxin with the coadministration of 100 mg selection and should be based on careful and regular monitoring of renal function [see sitagliptin for 10 days. These increases are not considered likely to be clinically meaningful. Digoxin, as a cationic drug, has the potential to compete with metformin for Sitagliptin. Of the total number of subjects (N=3884) in Phase II and III clinical studies of common renal tubular transport systems, thus affecting the serum concentrations of either sitagliptin, 725 patients were 65 years and over, while 61 patients were 75 years and over.
digoxin, metformin or both. Patients receiving digoxin should be monitored appropriately.
No overall differences in safety or effectiveness were observed between subjects 65 years No dosage adjustment of digoxin or JANUMET is recommended. and over and younger subjects. While this and other reported clinical experience have not Glyburide. In a single-dose interaction study in type 2 diabetes patients,
identified differences in responses between the elderly and younger patients, greater coadministration of metformin and glyburide did not result in any changes in either sensitivity of some older individuals cannot be ruled out.
metformin pharmacokinetics or pharmacodynamics. Decreases in glyburide AUC and Metformin hydrochloride. Controlled clinical studies of metformin did not include Cmax were observed, but were highly variable. The single-dose nature of this study and sufficient numbers of elderly patients to determine whether they respond differently from spine, and by the end of the study period, the lack of correlation between glyburide blood levels and pharmacodynamic effects younger patients, although other reported clinical experience has not identified differences make the clinical significance of this interaction uncertain.
in responses between the elderly and young patients. Metformin should only be used in Furosemide. A single-dose, metformin-furosemide drug interaction study in healthy
patients with normal renal function. The initial and maintenance dosing of metformin subjects demonstrated that pharmacokinetic parameters of both compounds were affected should be conservative in patients with advanced age, due to the potential for decreased by coadministration. Furosemide increased the metformin plasma and blood Cmax by 22% renal function in this population. Any dose adjustment should be based on a careful and blood AUC by 15%, without any significant change in metformin renal clearance.
assessment of renal function [see Contraindications; Warnings and Precautions].
When administered with metformin, the Cmax and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life wasdecreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide JANUMET is a trademark of Merck & Co., Inc. Copyright 2007 Merck & Co., Inc.
Nifedipine. A single-dose, metformin-nifedipine drug interaction study in normal healthy
Whitehouse Station, NJ 08889, USA All rights reserved. 20704475(1)(103)-JMT BMD did not differ significantly betweenthese two groups, she said. —Kate Johnson

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