Sitagliptin. The incidence of laboratory adverse reactions was similar in patients treated
with sitagliptin and metformin immediate-release (7.6%) compared to patients treated with
placebo and metformin (8.7%). In most but not all studies, a small increase in white blood
cell count (approximately 200 cells/microL difference in WBC vs. placebo; mean baseline
WBC approximately 6600 cells/microL) was observed due to a small increase in neutrophils.
This change in laboratory parameters is not considered to be clinically relevant.
Metformin hydrochloride. In controlled clinical trials of metformin of 29 weeks duration, a
decrease to subnormal levels of previously normal serum Vitamin B12 levels, without clinical
manifestations, was observed in approximately 7% of patients. Such decrease, possibly due
to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very
rarely associated with anemia and appears to be rapidly reversible with discontinuation of
metformin or Vitamin B12 supplementation. [See Warnings and Precautions.]
Postmarketing Experience. Additional adverse reactions have been identified during
postapproval use of sitagliptin with or without metformin, and/or in combination with
other antidiabetic medications. Because these reactions are reported voluntarily from a
population of uncertain size, it is generally not possible to reliably estimate their frequency
or establish a causal relationship to drug exposure.
Hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, cutaneous
vasculitis, and exfoliative skin conditions including Stevens-Johnson syndrome [see
Warnings and Precautions]; upper respiratory tract infection; hepatic enzyme elevations;
acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing
pancreatitis [see Indications and Usage; Warnings and Precautions] ; worsening renal
function, including acute renal failure (sometimes requiring dialysis) [see Warnings and
Precautions]; constipation; vomiting; headache.
Carbonic Anhydrase Inhibitors. Topiramate or other carbonic anhydrase inhibitors (e.g.,
zonisamide, acetazolamide or dichlorphenamide) frequently decrease serum bicarbonate
and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these
drugs may induce metabolic acidosis. Use these drugs with caution in patients treated
with JANUME T® XR (sitagliptin and metformin HCI extended-release) tablets, as the risk
of lactic acidosis may increase.
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
metformin by competing for common renal tubular transport systems. Although such
interactions remain theoretical (except for cimetidine), careful patient monitoring and
dose adjustment of JANUMET XR and/or the interfering drug is recommended in patients
who are taking cationic medications that are excreted via the proximal renal tubular
The Use of Metformin with Other Drugs. 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 JANUMET XR the
patient should be closely observed to maintain adequate glycemic control.
USE IN SPECIFIC POPULATIONS
Pregnancy. Pregnancy Category B.
JANUMET XR. There are no adequate and well-controlled studies in pregnant women
with JANUME T XR or its individual components; therefore, the safety of JANUMET XR
in pregnant women is not known. JANUME T XR should be used during pregnancy only
if clearly needed.
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., maintains a registry
to monitor the pregnancy outcomes of women exposed to JANUMET XR while pregnant.
Health care providers are encouraged to report any prenatal exposure to JANUMET XR
by calling the Pregnancy Registry at 1-800-986-8999.
No animal studies have been conducted with the combined products in JANUMET XR to
evaluate effects on reproduction. The following data are based on findings in studies
performed with sitagliptin or metformin individually.
Sitagliptin. Reproduction studies have been performed in rats and rabbits. Doses of
sitagliptin up to 125 mg/kg (approximately 12 times the human exposure at the maximum
recommended human dose) did not impair fertility or harm the fetus. There are, however,
no adequate and well-controlled studies with sitagliptin in pregnant women.
Sitagliptin administered to pregnant female rats and rabbits from gestation
day 6 to 20 (organogenesis) was not teratogenic at oral doses up to 250 mg/kg (rats)
and 125 mg/kg (rabbits), or approximately 30 and 20 times human exposure at the
maximum recommended human dose (MRHD) of 100 mg/day based on AUC comparisons.
Higher doses increased the incidence of rib malformations in offspring at 1000 mg/kg,
or approximately 100 times human exposure at the MRHD.
Sitagliptin administered to female rats from gestation day 6 to lactation day 21 decreased
body weight in male and female offspring at 1000 mg/kg. No functional or behavioral
toxicity was observed in offspring of rats.
Placental transfer of sitagliptin administered to pregnant rats was approximately 45% at
2 hours and 80% at 24 hours postdose. Placental transfer of sitagliptin administered to
pregnant rabbits was approximately 66% at 2 hours and 30% at 24 hours.
Metformin hydrochloride. Metformin was not teratogenic in rats and rabbits at doses
up to 600 mg/kg/day, which represent 3 and 6 times the maximum recommended human
daily dose of 2000 mg based on body surface area comparison for rats and rabbits,
respectively. However, because animal reproduction studies are not always predictive of
human response, metformin hydrochloride should not be used during pregnancy unless
Nursing Mothers. No studies in lactating animals have been conducted with the
combined components of JANUMET XR. In studies performed with the individual
components, both sitagliptin and metformin are secreted in the milk of lactating rats. It
is not known whether sitagliptin or metformin are excreted in human milk. Because many
drugs are excreted in human milk, caution should be exercised when JANUMET XR is
administered to a nursing woman.
Pediatric Use. Safety and effectiveness of JANUMET XR in pediatric patients under
18 years have not been established.
Geriatric Use. JANUMET XR. Because sitagliptin and metformin are substantially
excreted by the kidney and because aging can be associated with reduced renal function,
JANUME T XR should be used with caution as age increases. Care should be taken in dose
selection and should be based on careful and regular monitoring of renal function. [See
Warnings and Precautions; Clinical Pharmacology.]
Sitagliptin. Of the total number of subjects (N=3884) in premarketing Phase II and III
clinical studies of sitagliptin, 725 patients were 65 years and over, while 61 patients
were 75 years and over. No overall differences in safety or effectiveness were observed
between subjects 65 years and over and younger subjects. While this and other reported
clinical experience have not identified differences in responses between the elderly and
younger patients, greater sensitivity of some older individuals cannot be ruled out.
Metformin hydrochloride. Controlled clinical studies of metformin 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 young patients. Metformin should only
be used in patients with normal renal function. The initial and maintenance dosing of
metformin should be conservative in patients with advanced age, due to the potential for
decreased renal function in this population. Any dose adjustment should be based on a
careful assessment of renal function. [See Contraindications; Warnings and Precautions;
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