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Rx
SIGLIP
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COMPOSITION:
Each Film coated tablet
contains:
Sitagliptin25/50/100mg.
DESCRIPTION:
Sitagliptin is a new oral hypoglycemic
(anti-diabetic drug) approved by the FDA in October 2006 as an adjunct to diet
and exercise to improve glycemic control in patients with type 2 diabetes.
Sitagliptin belongs to a new novel class of antihyperglycemic medications,
dipeptidyl peptidase-4 (DPP-4) inhibitors, or incretin enhancers, and is the first such drug approved for the
treatment of type 2 diabetes in the U.S.. This enzyme-inhibiting drug is to be
used either alone or in combination with metformin or a thiazolidinedione for
control of type 2 diabetes mellitus. The drug works to competitively inhibit a
protein/enzyme, dipeptidyl peptidase 4 (DPP-4), that
results in an increased amount of active incretins (GLP-1
and GIP), reduced amount of release of glucagon
(diminishes its release) and increased release of insulin.
PHARMACOLOGY:
Its mechanism of action involves
selective inhibition of the enzyme DPP-4 that rapidly inactivates incretin
hormones in the GI tract. The predominant incretin hormones are glucagon-like
peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Both
hormones are involved in the regulation of glucose homeostasis and are
responsible for stimulation of insulin secretion. GLP-1 is also responsible for
the slowing of gastric emptying, reduction of food intake, and suppression of
glucagon secretion, which leads to reduced hepatic glucose production.
Inhibition of DPP-4 by sitagliptin causes GLP-1 and GIP levels to rise,
increasing insulin secretion from pancreatic beta cells and decreasing glucagon
secretion from pancreatic alpha cells in a glucose-dependent manner.
PHARMACOKINETIC:
Absorption
Sitagliptin is rapidly absorbed, with a 100 mg dose reaching
a C max of 950 nM in 1 to 4 h; AUC was 8.52 mcM. The bioavailability
is approximately 87%.
Distribution
Vd is approximately 198 L. Plasma protein binding is 38%.
Metabolism
Metabolism by CYP3A4 and, to a lesser degree, CYP2C8.
Elimination
Terminal half-life is approximately 12.4 h and renal Cl is
approximately 350 mL/min. Approximately13% is excreted in the feces and 87% in
the urine via active tubular secretion (79% as unchanged drug).
Special Populations
Renal Function Impairment
Plasma AUC levels of sitagliptin were increased
approximately 2- and 4-fold in patients with moderate and severe renal
impairment, including patients with ESRD on hemodialysis, respectively. Dosage
adjustment is required.
Hepatic Function Impairment
Mean AUC and C max of sitagliptin increased
approximately 21% and 13%, respectively, in patients with moderate hepatic
impairment. There is no clinical experience in patients with severe hepatic
impairment.
Elderly
Elderly patients had an approximate 19% higher plasma
concentration; no dosage adjustment is required.
Children
Studies characterizing the pharmacokinetics of sitagliptin
in children have not been performed.
Gender/Race/BMI
No clinically meaningful effects on the pharmacokinetics of
sitagliptin were observed.
PRECAUTION & WARNING:
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Monitor
Periodically monitor blood
glucose and HbA 1c . Assess renal function prior to initiation of
therapy and periodically thereafter. Observe patients carefully for signs and
symptoms of pancreatitis.
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Pregnancy
Category B .
Lactation
Undetermined.
Children
Safety and efficacy not
established.
Elderly
Use with caution.
Hypersensitivity
Use with caution in patients
with a history of angioedema. Serious hypersensitivity reactions, including
anaphylaxis, angioedema, and exfoliative skin conditions, including
Stevens-Johnson syndrome, have occurred.
Renal Function
Use caution to ensure the
correct dose of sitagliptin is prescribed for patients with moderate to severe
renal impairment and in patients with ESRD requiring hemodialysis or peritoneal
dialysis.
Pancreatitis
Acute pancreatitis, both fatal
and nonfatal hemorrhagic or necrotizing pancreatitis, has been reported.
Type 1 diabetes/diabetic ketoacidosis
Do not use sitagliptin in these
settings.
DRUG INTERACTION:
Cyclosporine
Sitagliptin plasma
concentrations may be increased modestly (approximately 68%), which is not
expected to be clinically important.
Digoxin
Digoxin plasma concentrations
may be increased slightly (approximately 18%); no dosage adjustment is
recommended.
Insulin, sulfonylureas (eg;
tolbutamide)
A lower dose of the insulin or
sulfonylurea may be needed to reduce the risk of hypoglycemia.
CONTRAINDICATION;
History of a serious
hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema.
ADVERSE REACTIONS:
In clinical trials for both
monotherapy and combination therapy, the overall incidence of adverse events
was similar to placebo.
Adverse reactions reported in 5%
of patients included nasopharyngitis, upper respiratory infection, and
headache.
Abdominal pain (2.3%), nausea
(1.4%), and diarrhea (3.0%) were GI adverse events.
The overall occurrence of hypoglycemia was
similar in patients treated with sitagliptin to those on placebo (1.2% vs.
0.9%). Hypoglycemia has not been studied in patients receiving sitagliptin and
other drugs that cause hypoglycemia (e.g., insulin, sulfonylureas,
meglitinides, and alpha-glucose inhibitors); thus, the risk of hypoglycemia
cannot be ruled out with these medications. Sitagliptin is considered weight-
and lipid-neutral.
DOSAGE AND ADMINISTRATION:
Adults
PO 100 mg once daily.
Renal Function Impairment
Adults
Moderate renal impairment (CrCl 30 to less than 50 mL/min or approximate
serum creatinine levels of more than 1.7 up to 3 mg/dL in men and more than 1.5
up to 2.5 mg/dL in women)
PO 50 mg once daily.
Severe renal impairment (CrCl less than 30 mL/min or
approximate serum creatinine levels of more than 3 mg/dL in men and more than
2.5 mg/dL in women)
PO 25 mg once daily.
ESRD requiring hemodialysis or peritoneal dialysis
PO 25 mg once daily. Administer without regard to the timing
of hemodialysis.
General Advice
Instruct patients to take with or without food.
Instruct patients to swallow the tablet whole and not to
split, crush, or chew before swallowing.
When used in combination with an insulin secretagogue (eg,
sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or
insulin may be required to reduce the risk of hypoglycemia.
OVERDOSAGE:
Single dosage up to 800 mg was
found tolerable in clinical controlled trials. There is no evidence above
800mcg in clinical studies. In the events of an overdose, usual supportive
measures should be instituted. Like removing unabsorbed material from the
gastrointestinal tract, employing clinical monitoring (including obtaining an
electrocardiogram) and provision of supportive therapy is required. Prolonged
hemodialysis may be considered if clinically appropriate. It is not known if
sitagliptin is dialyzable by peritoneal dialysis.
PRESENTATION:
SIGLIP is available as 5×10'S
packing.
