- Empagliflozin - Metformin HCL
Composition: Each film coated tablet contains:
Empagliflozin 5 mg, Metformin HCL 500 mg.
Empagliflozin 5 mg, Metformin HCL 1000 mg.
Empagliflozin 12.5 mg, Metformin HCL 500 mg.
Empagliflozin 12.5 mg, Metformin HCL 1000 mg.
Excipients: copovidone, magnesium stearate, colloidal silicon dioxide, corn
starch, hypromellose, titanium dioxide, talc, polyethylene glycol 400, and yellow
ferric oxide (5 mg/500 mg, 5 mg/1000 mg) or red ferric oxide and black
ferrosoferric oxide (12.5 mg/500 mg, 12.5 mg/1000 mg).
Mechanism of Action:
Floziphage combines 2 antihyperglycemic agents with complementary
mechanisms of action to improve glycemic control in patients with type 2 diabetes:
empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, and
metformin, a member of the biguanide class.
Sodium-glucose co-transporter 2 (SGLT2) is the predominant transporter
responsible for reabsorption of glucose from the glomerular filtrate back into
the circulation. Empagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2,
empagliflozin reduces renal reabsorption of filtered glucose and lowers the
renal threshold for glucose, and thereby increases urinary glucose excretion.
Metformin is an antihyperglycemic agent which improves glucose tolerance in
patients with type 2 diabetes mellitus, lowering both basal and postprandial
Metformin decreases hepatic glucose production, decreases intestinal
absorption of glucose, and improves insulin sensitivity by increasing peripheral
glucose uptake and utilization.
Administration of Floziphage with food resulted in no change in overall exposure
of empagliflozin. For metformin hydrochloride extended-release high-fat meals
increased systemic exposure to metformin [AUC] by approximately 70% relative
to fasting, while Cmax is not affected.
Absorption: After oral administration, peak plasma concentrations of empagliflozin
were reached at 1.5 hours post-dose.
Distribution: The apparent steady-state volume of distribution was estimated
to be 73.8 L based on a population pharmacokinetic analysis.
Metabolism: No major metabolites of empagliflozin were detected in human
plasma and the most abundant metabolites were three glucuronide conjugates.
Elimination: The apparent terminal elimination half-life of empagliflozin
was estimated to be 12.4 h. Following administration of empagliflozin,
approximately 95.6% of the drug was eliminated in feces (41.2%) or urine
(54.4%). The majority of drug recovered in feces was unchanged parent drug
and approximately half of drug-related radioactivity excreted in urine was
unchanged parent drug.
Absorption: Following a single oral dose of 1000 mg (2 x 500 mg tablets)
metformin hydrochloride extended-release after a meal, the time to reach
maximum plasma metformin concentration (Tmax) is achieved at
approximately 7 to 8 hours.
Distribution: Metformin is negligibly bound to plasma proteins, in contrast to
SUs, which are more than 90% protein bound. Metformin partitions into
erythrocytes, most likely as a function of time.
Metabolism: Intravenous single-dose studies in normal subjects demonstrate
that metformin is excreted unchanged in the urine and does not undergo
hepatic metabolism (no metabolites have been identified in humans) nor
Elimination: Renal clearance is approximately 3.5 times greater than
creatinine clearance, which indicates that tubular secretion is the major route
of metformin elimination. Following oral administration, approximately 90% of
the absorbed drug is eliminated via the renal route within the first 24 hours,
with a plasma elimination half-life of approximately 6.2 hours. In blood, the
elimination half-life is approximately 17.6 hours.
Floziphage is a combination of empagliflozin and metformin hydrochloride
indicated as an adjunct to diet and exercise to improve glycemic control in
adults with type 2 diabetes mellitus when treatment with both empagliflozin
and metformin hydrochloride is appropriate.
Empagliflozin is indicated to reduce the risk of cardiovascular death in adults
with type 2 diabetes mellitus and established cardiovascular disease.
However, the effectiveness of Floziphage on reducing the risk of cardiovascular
death in adults with type 2 diabetes mellitus and cardiovascular disease has not
Limitations of Use: Floziphage is not recommended for patients with type
1 diabetes or for the treatment of diabetic ketoacidosis.
Floziphage is contraindicated in patients with:
• Moderate to severe renal impairment (eGFR less than 45 mL/min/1.73 m2),
end stage renal disease, or dialysis .
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic
ketoacidosis should be treated with insulin .
• History of serious hypersensitivity reaction to empagliflozin or metformin.
DOSAGE AND ADMINISTRATION:
• In patients with volume depletion not previously treated with empagliflozin,
correct this condition before initiating Floziphage.
• Individualize the starting dose of Floziphage based on the patient’s current
− In patients on metformin hydrochloride, switch to Floziphage containing
a similar total daily dose of metformin hydrochloride and a total daily dose
of empagliflozin 10 mg;
− In patients on empagliflozin, switch to Floziphage containing the same total
daily dose of empagliflozin and a total daily dose of metformin hydrochloride
extended-release 1000 mg;
− In patients already treated with empagliflozin and metformin hydrochloride,
switch to Floziphage containing the same total daily doses of empagliflozin
and a similar total daily dose of metformin hydrochloride.
Take Floziphage twice daily with meals; with gradual dose escalation to reduce
the gastrointestinal side effects due to metformin.
• Adjust dosing based on effectiveness and tolerability while not exceeding
the maximum recommended daily dose of metformin hydrochloride 2000 mg
and empagliflozin 25 mg).
• The dose of metformin hydrochloride should be gradually escalated to
reduce the gastrointestinal side effects due to metformin hydrochloride.
• Take Floziphage orally once daily with a meal in the morning
• Swallow the product tablets whole. Do not split, crush, dissolve, or chew
before swallowing. There have been reports of incompletely dissolved
tablets being eliminated in the feces for other tablets containing metformin
hydrochloride extended-release. If a patient reports seeing tablets in feces,
the healthcare provider should assess adequacy of glycemic control.
• Floziphage10 mg/1000 mg and 25 mg/1000 mg tablets should be taken as
a single tablet once daily. Floziphage 5 mg/1000 mg and 12.5 mg/1000 mg
tablets should be taken as two tablets together once daily.
Recommended Dosage in Patients with Renal Impairment:
• Assess renal function prior to initiation of Floziphage and periodically, thereafter.
• Floziphage is contraindicated in patients with an eGFR less than
45 mL/min/1.73 m2
Discontinuation for Iodinated Contrast Imaging Procedures:
Discontinue Floziphage at the time of, or prior to, an iodinated contrast imaging
procedure in patients with an eGFR between 45 and 60 mL/min/1.73 m2; in
patients with a history of liver disease, alcoholism or heart failure; or in
patients who will be administered intra-arterial iodinated contrast. Re-evaluate
eGFR 48 hours after the imaging procedure; restart Floziphage if renal
function is stable.
WARNINGS AND PRECAUTIONS:
There have been postmarketing cases of metformin-associated lactic acidosis,
including fatal cases. These cases had a subtle onset and were accompanied
by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory
distress, or increased somnolence; however, hypothermia, hypotension, and
resistant bradyarrhythmias have occurred with severe acidosis. Metforminassociated
lactic acidosis was characterized by elevated blood lactate
concentrations (> 5 mmol/Liter), anion gap acidosis (without evidence of
ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin
plasma levels generally > 5 mcg/mL. Metformin decreases liver uptake of
lactate increasing lactate blood levels which may increase the risk of lactic
acidosis, especially in patients at risk.
If metformin-associated lactic acidosis is suspected, general supportive
measures should be instituted promptly in a hospital setting, along with immediate
discontinuation of Floziphage. In Floziphage -treated patients with a diagnosis
or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to
correct the acidosis and remove accumulated metformin (metformin is
dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic
conditions). Hemodialysis has often resulted in reversal of symptoms and
Renal Impairment: The postmarketing metformin-associated lactic acidosis
cases primarily occurred in patients with significant renal impairment. The risk
of metformin accumulation and metformin-associated lactic acidosis increases
with the severity of renal impairment because metformin is substantially
excreted by the kidney .
• Before initiating Floziphage, obtain an estimated glomerular filtration rate
• Floziphage is contraindicated in patients with an eGFR below
45 mL/min/1.73 m2.
• Obtain an eGFR at least annually in all patients taking Floziphage. In
patients at increased risk for the development of renal impairment (e.g., the
elderly), renal function should be assessed more frequently.
The concomitant use of Floziphage with specific drugs may increase the risk
of metformin-associated lactic acidosis those that impair renal function, result
in significant hemodynamic change, interfere with acid-base balance or
increase metformin accumulation. Therefore, consider more frequent
monitoring of patients.
Age 65 or Greater: The risk of metformin-associated lactic acidosis increases
with the patient’s age because elderly patients have a greater likelihood of
having hepatic, renal, or cardiac impairment than younger patients. Assess
renal function more frequently in elderly patients .
Radiological Studies with Contrast: Administration of intravascular iodinated
contrast agents in metformin treated patients has led to an acute decrease in
renal function and the occurrence of lactic acidosis. Stop Floziphage at the
time of, or prior to, an iodinated contrast imaging procedure in patients with
an eGFR between 45 and 60 mL/min/1.73 m2; in patients with a history of
hepatic impairment, alcoholism, or heart failure; or in patients who will be
administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours
after the imaging procedure, and restart Floziphage if renal function is stable.
Surgery and Other Procedures:
Withholding of food and fluids during surgical or other procedures may
increase the risk for volume depletion, hypotension and renal impairment.
Floziphage should be temporarily discontinued while patients have restricted
food and fluid intake.
Several of the postmarketing cases of metformin-associated lactic acidosis
occurred in the setting of acute congestive heart failure (particularly when
accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse
(shock), acute myocardial infarction, sepsis, and other conditions associated
with hypoxemia have been associated with lactic acidosis and may also cause
prerenal azotemia. When such events occur, discontinue Floziphage.
Excessive Alcohol Intake:
Alcohol potentiates the effect of metformin on lactate metabolism and this
may increase the risk of metformin-associated lactic acidosis. Warn patients
against excessive alcohol intake while receiving Floziphage .
Patients with hepatic impairment have developed cases of metformin-associated
lactic acidosis. This may be due to impaired lactate clearance resulting in
higher lactate blood levels. Therefore, avoid use of Floziphage in patients with
clinical or laboratory evidence of hepatic disease.
Empagliflozin causes intravascular volume contraction. Symptomatic
hypotension may occur after initiating empagliflozin particularly in patients
with renal impairment, the elderly, in patients with low systolic blood pressure,
and in patients on diuretics. Before initiating Floziphage, assess for volume
contraction and correct volume status if indicated. Monitor for signs and
symptoms of hypotension after initiating therapy and increase monitoring in
clinical situations where volume contraction is expected
Reports of ketoacidosis, a serious life-threatening condition requiring urgent
hospitalization have been identified in postmarketing surveillance in patients
with type 1 and type 2 diabetes mellitus receiving sodium glucose
co-transporter-2 (SGLT2) inhibitors, including empagliflozin. Fatal cases of
ketoacidosis have been reported in patients taking empagliflozin.
Floziphage is not indicated for the treatment of patients with type 1 diabetes
Patients treated with Floziphage who present with signs and symptoms
consistent with severe metabolic acidosis should be assessed for ketoacidosis
regardless of presenting blood glucose levels, as ketoacidosis associated
with Floziphage may be present even if blood glucose levels are less than
250 mg/dL. If ketoacidosis is suspected, Floziphage should be discontinued,
patient should be evaluated, and prompt treatment should be instituted.
Treatment of ketoacidosis may require insulin, fluid and carbohydrate
Before initiating Floziphage, consider factors in the patient history that may
predispose to ketoacidosis including pancreatic insulin deficiency from any
cause, caloric restriction, and alcohol abuse. In patients treated with
Floziphage consider monitoring for ketoacidosis and temporarily discontinuing
Floziphage in clinical situations known to predispose to ketoacidosis.
Acute Kidney Injury and Impairment in Renal Function:
Empagliflozin causes intravascular volume contraction and can cause renal
impairment .There have been postmarketing reports of acute kidney injury,
some requiring hospitalization and dialysis, in patients receiving SGLT2
inhibitors, including empagliflozin; some reports involved patients younger
than 65 years of age.
Before initiating Floziphage, consider factors that may predispose patients to
acute kidney injury including hypovolemia, chronic renal insufficiency,
congestive heart failure and concomitant medications (diuretics, ACE
inhibitors, ARBs, NSAIDs). Consider temporarily discontinuing Floziphage in
any setting of reduced oral intake (such as acute illness or fasting) or fluid
losses (such as gastrointestinal illness or excessive heat exposure); monitor
patients for signs and symptoms of acute kidney injury. If acute kidney injury
occurs, discontinue Floziphage promptly and institute treatment.
Empagliflozin increases serum creatinine and decreases eGFR. Patients with
hypovolemia may be more susceptible to these changes. Renal function
abnormalities can occur after initiating Floziphage. Renal function should be
evaluated prior to initiation of Floziphage and monitored periodically
thereafter. More frequent renal function monitoring is recommended in
patients with an eGFR below 60 mL/min/1.73 m2. Use of Floziphage is
contraindicated in patients with an eGFR less than 45 mL/min/1.73 m2.
Urosepsis and Pyelonephritis:
There have been postmarketing reports of serious urinary tract infections
including urosepsis and pyelonephritis requiring hospitalization in patients
receiving SGLT2 inhibitors, including empagliflozin. Treatment with SGLT2
inhibitors increases the risk for urinary tract infections. Evaluate patients for
signs and symptoms of urinary tract infections and treat promptly, if indicated.
Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues:
Insulin and insulin secretagogues are known to cause hypoglycemia. The risk
of hypoglycemia is increased when empagliflozin is used in combination with
insulin secretagogues (e.g., sulfonylurea) or insulin. Therefore, a lower dose
of the insulin secretagogue or insulin may be required to reduce the risk of
hypoglycemia when used in combination with Floziphage.
Hypoglycemia does not occur in patients receiving metformin alone under
usual circumstances of use, but could occur when caloric intake is deficient,
when strenuous exercise is not compensated by caloric supplementation, or
during concomitant use with other glucose-lowering agents (such as SUs and
insulin) or ethanol. Elderly, debilitated, or malnourished patients, and those
with adrenal or pituitary insufficiency or alcohol intoxication are particularly
susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize
in the elderly, and in people who are taking β-adrenergic blocking drugs.
Monitor for a need to lower the dose of Floziphage to minimize the risk of
hypoglycemia in these patients.
Genital Mycotic Infections:
Empagliflozin increases the risk for genital mycotic infections. Patients with a
history of chronic or recurrent genital mycotic infections were more likely to
develop mycotic genital infections. Monitor and treat as appropriate.
Vitamin B12 Levels:
A decrease to subnormal levels of previously normal serum vitamin B12
levels, without clinical manifestations, was observed in approximately 7% of
metformin-treated patients. Such decrease, possibly due to interference with
B12 absorption from the B12-intrinsic factor complex, is, however, very rarely
associated with anemia or neurologic manifestations due to the short duration
(<1 year) of the clinical trials.
The decrease in vitamin B12 levels appears to be rapidly reversible with
discontinuation of metformin or vitamin B12 supplementation.
Increased Low-Density Lipoprotein Cholesterol (LDL-C):
Increases in LDL-C can occur with empagliflozin. Monitor and treat as
• Lactic Acidosis.
• Ketoacidosis .
• Acute Kidney Injury and Impairment in Renal Function .
• Urosepsis and Pyelonephritis.
• Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues.
• Genital Mycotic Infections .
• Vitamin B12 Deficiency
• Increased Low-Density Lipoprotein Cholesterol (LDL-C).
• Nasopharyngitis .
• Upper respiratory tract infection .
• Increased urinationc .
• Arthralgia .
• Nausea .
• Volume Depletion .
- Drug Interactions with Empagliflozin :
Coadministration of empagliflozin with diuretics resulted in increased urine
volume and frequency of voids, which might enhance the potential for volume
Insulin or Insulin Secretagogues:
Coadministration of empagliflozin with insulin or insulin secretagogues
increases the risk for hypoglycemia.
Positive Urine Glucose Test:
Monitoring glycemic control with urine glucose tests is not recommended in
patients taking SGLT2 inhibitors as SGLT2 inhibitors increase urinary glucose
excretion and will lead to positive urine glucose tests. Use alternative
methods to monitor glycemic control.
Interference with 1,5-anhydroglucitol (1,5-AG) Assay:
Monitoring glycemic control with 1,5-AG assay is not recommended as
measurements of 1,5-AG are unreliable in assessing glycemic control in
patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic
- Drug Interactions with Metformin Hydrochloride :
Drugs that Reduce Metformin Clearance:
Concomitant use of drugs that interfere with common renal tubular transport
systems involved in the renal elimination of metformin (e.g., organic cationic
transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors such as
ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic
exposure to metformin and may increase the risk for lactic acidosis . Consider
the benefits and risks of concomitant use.
Carbonic Anhydrase Inhibitors :
Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide,
acetazolamide or dichlorphenamide) frequently causes a decrease in serum
bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis.
Concomitant use of these drugs with Floziphage may increase the risk of
lactic acidosis. Consider more frequent monitoring of these patients.
Drugs Affecting Glycemic Control :
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
Floziphage, the patient should be closely observed to maintain adequate
glycemic control .When such drugs are withdrawn from a patient receiving
Floziphage, the patient should be observed closely for hypoglycemia.
Alcohol is known to potentiate the effect of metformin on lactate metabolism.
Warn patients against excessive alcohol intake while receiving
Floziphage is not recommended during the second and third trimesters of
Because of the potential for serious adverse reactions in a breastfed infant,
advise women that use of Floziphageis not recommended while breastfeeding.
Safety and effectiveness of Floziphage in pediatric patients under 18 years of
age have not been established.
Because renal function abnormalities can occur after initiating empagliflozin,
metformin is substantially excreted by the kidney, and aging can be associated
with reduced renal function, renal function should be assessed more
frequently in elderly patients .
Renal Impairment :
Floziphage is contraindicated in patients with moderate to severe renal
impairment (eGFR less than 45 mL/min/1.73 m2).
Hepatic Impairment :
Floziphage should generally be avoided in patients with clinical or laboratory
evidence of hepatic disease .
In the event of an overdose with Floziphage, contact the Poison Control
Center. Employ the usual supportive measures (e.g., remove unabsorbed
material from the gastrointestinal tract, employ clinical monitoring, and institute
supportive treatment) as dictated by the patient’s clinical status. Removal of
empagliflozin by hemodialysis has not been studied. However, metformin is
dialyzable with a clearance of up to 170 mL/min under good hemodynamic
conditions. Therefore, hemodialysis may be useful partly for removal of
accumulated metformin from patients in whom Floziphage overdosage is
Overdose of metformin hydrochloride has occurred, including ingestion of
amounts greater than 50 grams. Hypoglycemia was reported in approximately
10% of cases, but no causal association with metformin has been established.
Lactic acidosis has been reported in approximately 32% of metformin
Store in dry place at room temperature (15-30 °C), Protected from light and
out of the reach of children.
floziphage 5/500 : box contains: 30, 60 film – coated tablets.
floziphage 5/1000 : box contains: 30, 60 film – coated tablets.
floziphage 12.5/500 : box contains: 30, 60 film – coated tablets.
floziphage 12.5/1000: box contains: 30, 60 film – coated tablets.