Farxiga

Oral tablets: 5 and 10 mg

Tablets may be stored at room temperature, between 20 C to 25 C (68 F to 77 F).

Common Side Effects of Farxiga

Farxiga may cause changes in blood sugar, frequent urination, urinary tract infections, and increased thirst.

You should tell your doctor if these symptoms become severe or do not go away.

Severe Side Effects of Farxiga

You should tell your doctor immediately or get emergency medical help if you experience any of the following serious side effects:

• Cloudy, red, pink, or brown urine
• Strong smelling urine
• Frequent, urgent, burning, or painful urination
• Pain in the pelvis or rectum
• Vaginal odor; a white or yellowish vaginal discharge; or vaginal itching
• Redness; itching or swelling of the penis; rash on the penis, foul-smelling discharge coming from the penis; or pain in the skin around the penis
• Weakness
• Rash, hives, or itching
• Difficulty breathing or swallowing
• Hoarseness
• Swelling of the face, throat, tongue, lips, eyes, hands, or feet

You should tell your doctor about all prescription, non-prescription, illegal, recreational, herbal, nutritional, or dietary drugs you are taking, especially insulin or other diabetes medications.

If taken with Farxiga, beta blocker drugs may prevent the pounding heartbeat you might usually feel when your blood sugar levels fall too low.

Examples of beta-blockers include:

• Metoprolol (Toprol)
• Propranolol (Inderal)
• Timolol (Blocadren)

These drugs may also affect other symptoms of low blood sugar such as dizziness, hunger, or sweating.

Farxiga and Alcohol

Alcohol may cause a change in blood sugar.

You should talk to your doctor before consuming alcohol while taking Farxiga.

Farxiga and Other Interactions

Do not drive, operate machinery, or perform any other activity that requires alertness while taking Farxiga until you know how the drug affects you.

>10%

Renal impairment

• Overall (1.8-6.7%; placebo 1.7-4.2%)
• Age ≥65 yr (3.1-14%; placebo 2.1-7.9%)
• eGFR 30-60 mL/min (8-28.3%; placebo 6.5-16.1%)
• Age ≥65 yr and eGFR 30-60 mL/min (7-35.1%; placebo 4.9-19.1%)

1-10%

Female genital mycotic infections (6.9-8.4%)

Urinary tract infection (4.3-5.7%)

Increased urination (2.9-3.8%)

Male genital mycotic infections (2.7-2.8%)

Dyslipidemia (2.1-2.5%)

Constipation (1.9-2.2%)

Discomfort with urination (2.6-2.1%)

Extremity pain (1.7-2%)

Volume depletion

• Overall (0.6-1.1%; placebo 0.4-0.7%)
• Patients on loop diuretics (0-9.7%; 1.8-2.5%)
• Patients with moderate renal impairment, GFR 30-60 mL/min (0.9-1.9%; placebo 1.5-1.9%)
• Age ≥65 yr (0.5-1.7%; placebo 0.4-0.8%)

<1%

Hypersensitivity (0.3%)

Postmarketing Reports

Rash

Farxiga is a prescription medication used to control blood sugar levels in people with type 2 diabetes. Farxiga is part of a new class of drugs that work in the kidney to block a protein called SGLT2. By blocking this protein, the drug can remove excess glucose (sugar) through the urine, which helps lower blood sugar levels.

This medication comes in tablet form and is usually taken once daily. Farxiga tablets should be swallowed whole and can be taken with or without food.

Common side effects of Farxiga include low blood sugar (hypoglycemia), yeast infections of the penis or vagina, and backache.

Before taking Farxiga tell your doctor about all of your medical conditions including if you:

• have type 1 diabetes
• have increased levels of “ketone bodies” in your urine or blood, seen in tests
• have a kidney problem 
• have a liver problem
• have a history of serious heart disease or if you have had a stroke
• are are on medicines to lower your blood pressure (anti-hypertensives) and have a history of low blood pressure (hypotension) 
• have very high levels of glucose in your blood which may make you dehydrated
• have or develop nausea (feeling sick), vomiting or fever or if you are not able to eat or drink. These conditions can cause dehydration.
• often get infections of the urinary tract
• are 75 years old or older
• are taking another medicine for diabetes that contains “pioglitazone”
• have an increase in the amount of red blood cells in your blood, seen in tests
• are pregnant or breastfeeding

Tell your doctor about all of the medicines you take including prescription and non-prescription medicines, vitamins and herbal supplements.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• little or no urination;

• ketoacidosis (too much acid in the blood)--nausea, vomiting, stomach pain, confusion, unusual drowsiness, or trouble breathing;

• dehydration symptoms--dizziness, weakness, feeling light-headed (like you might pass out);

• signs of a bladder infection--pain or burning when you urinate, increased urination, blood in your urine, fever, pain in your pelvis or back; or

• signs of a genital infection (penis or vagina)--pain, burning, itching, rash, redness, odor, or discharge.

Some people taking this medicine have had bladder cancer, but it is not clear if dapagliflozin was the actual cause.

Side effects may be more likely to occur in older adults.

Common side effects may include:

• urinating more than usual; or

• sore throat and runny or stuffy nose.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

• It is used to lower blood sugar in patients with high blood sugar (diabetes).

• If you have an allergy to dapagliflozin or any other part of Farxiga (dapagliflozin).
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have any of these health problems: Acidic blood problem, bladder cancer, or type 1 diabetes.
• If you have kidney disease.
• If you are breast-feeding or plan to breast-feed.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take Farxiga with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

The following important adverse reactions are described below and elsewhere in the labeling:

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The data in Table 1 is derived from 12 placebo-controlled studies ranging from 12 to 24 weeks. In 4 studies Farxiga was used as monotherapy, and in 8 studies Farxiga was used as add-on to background antidiabetic therapy or as combination therapy with metformin [see Clinical Studies (14)].

These data reflect exposure of 2338 patients to Farxiga with a mean exposure duration of 21 weeks. Patients received placebo (N=1393), Farxiga 5 mg (N=1145), or Farxiga 10 mg (N=1193) once daily. The mean age of the population was 55 years and 2% were older than 75 years of age. Fifty percent (50%) of the population were male; 81% were White, 14% were Asian, and 3% were Black or African American. At baseline, the population had diabetes for an average of 6 years, had a mean hemoglobin A1c (HbA1c) of 8.3%, and 21% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired in 92% of patients and moderately impaired in 8% of patients (mean eGFR 86 mL/min/1.73 m2).

Table 1 shows common adverse reactions associated with the use of Farxiga. These adverse reactions were not present at baseline, occurred more commonly on Farxiga than on placebo, and occurred in at least 2% of patients treated with either Farxiga 5 mg or Farxiga 10 mg.

The safety and tolerability of Farxiga 10 mg was also evaluated in a larger placebo-controlled study pool. This pool combined 13 placebo-controlled studies, including 3 monotherapy studies, 9 add-on to background antidiabetic therapy studies, and an initial combination with metformin study. Across these 13 studies, 2360 patients were treated once daily with Farxiga 10 mg for a mean duration of exposure of 22 weeks. The mean age of the population was 59 years and 4% were older than 75 years. Fifty-eight percent (58%) of the population were male; 84% were White, 9% were Asian, and 3% were Black or African American. At baseline, the population had diabetes for an average of 9 years, had a mean HbA1c of 8.2%, and 30% had established microvascular disease. Baseline renal function was normal or mildly impaired in 88% of patients and moderately impaired in 11% of patients (mean eGFR 82 mL/min/1.73 m2).

Farxiga causes an osmotic diuresis, which may lead to reductions in intravascular volume. Adverse reactions related to volume depletion (including reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension) are shown in Table 2 for the 12-study and 13-study, short-term, placebo-controlled pools [see Warnings and Precautions (5.1)].

Use of Farxiga was associated with increases in serum creatinine and decreases in eGFR (see Table 3). In patients with normal or mildly impaired renal function at baseline, serum creatinine and eGFR returned to baseline values at Week 24. Renal-related adverse reactions, including renal failure and blood creatinine increase, were more frequent in patients treated with Farxiga (see Table 4). Elderly patients and patients with impaired renal function were more susceptible to these adverse reactions (see Table 4). Sustained decreases in eGFR were seen in patients with moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m2).

The safety of Farxiga was evaluated in a study of patients with moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m2) [see Clinical Studies (14)]. In this study 13 patients experienced bone fractures for treatment durations up to 104 weeks. No fractures occurred in the placebo group, 5 occurred in the Farxiga 5 mg group, and 8 occurred in the Farxiga 10 mg group. Eight of these 13 fractures were in patients who had a baseline eGFR of 30 to 45 mL/min/1.73 m2. Eleven of the 13 fractures were reported within the first 52 weeks. There was no apparent pattern with respect to the anatomic site of fracture.

The frequency of hypoglycemia by study [see Clinical Studies (14)] is shown in Table 5. Hypoglycemia was more frequent when Farxiga was added to sulfonylurea or insulin [see Warnings and Precautions (5.3)].

Genital mycotic infections were more frequent with Farxiga treatment. Genital mycotic infections were reported in 0.9% of patients on placebo, 5.7% on Farxiga 5 mg, and 4.8% on Farxiga 10 mg, in the 12-study placebo-controlled pool. Discontinuation from study due to genital infection occurred in 0% of placebo-treated patients and 0.2% of patients treated with Farxiga 10 mg. Infections were more frequently reported in females than in males (see Table 1). The most frequently reported genital mycotic infections were vulvovaginal mycotic infections in females and balanitis in males. Patients with a history of genital mycotic infections were more likely to have a genital mycotic infection during the study than those with no prior history (10.0%, 23.1%, and 25.0% versus 0.8%, 5.9%, and 5.0% on placebo, Farxiga 5 mg, and Farxiga 10 mg, respectively).

Hypersensitivity reactions (e.g., angioedema, urticaria, hypersensitivity) were reported with Farxiga treatment. Across the clinical program, serious anaphylactic reactions and severe cutaneous adverse reactions and angioedema were reported in 0.2% of comparator-treated patients and 0.3% of Farxiga-treated patients. If hypersensitivity reactions occur, discontinue use of Farxiga; treat per standard of care and monitor until signs and symptoms resolve.

Increase in Hematocrit

In the pool of 13 placebo-controlled studies, increases from baseline in mean hematocrit values were observed in Farxiga-treated patients starting at Week 1 and continuing up to Week 16, when the maximum mean difference from baseline was observed. At Week 24, the mean changes from baseline in hematocrit were −0.33% in the placebo group and 2.30% in the Farxiga 10 mg group. By Week 24, hematocrit values >55% were reported in 0.4% of placebo-treated patients and 1.3% of Farxiga 10 mg–treated patients.

Increase in Serum Inorganic Phosphorus

In the pool of 13 placebo-controlled studies, increases from baseline in mean serum phosphorus levels were reported at Week 24 in Farxiga-treated patients compared with placebo-treated patients (mean increase of 0.13 versus −0.04 mg/dL, respectively). Higher proportions of patients with marked laboratory abnormalities of hyperphosphatemia (≥5.6 mg/dL for age 17-65 years or ≥5.1 mg/dL for age ≥66 years) were reported on Farxiga at Week 24 (0.9% versus 1.7% for placebo and Farxiga 10 mg, respectively).

Increase in Low-Density Lipoprotein Cholesterol

In the pool of 13 placebo-controlled studies, changes from baseline in mean lipid values were reported in Farxiga-treated patients compared to placebo-treated patients. Mean percent changes from baseline at Week 24, were 0.0% versus 2.5% for total cholesterol and −1.0% versus 2.9% for LDL cholesterol, in the placebo and Farxiga 10 mg groups, respectively.

Postmarketing Experience

Additional adverse reactions have been identified during postapproval use of Farxiga. 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.

Mechanism of Action

Sodium-glucose cotransporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Dapagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, dapagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.

Pharmacodynamics

Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in patients with type 2 diabetes mellitus following the administration of dapagliflozin (see Figure 1). Dapagliflozin doses of 5 or 10 mg per day in patients with type 2 diabetes mellitus for 12 weeks resulted in excretion of approximately 70 grams of glucose in the urine per day at Week 12. A near maximum glucose excretion was observed at the dapagliflozin daily dose of 20 mg. This urinary glucose excretion with dapagliflozin also results in increases in urinary volume [see Adverse Reactions (6.1)].

Figure 1: Scatter Plot and Fitted Line of Change from Baseline in 24-Hour Urinary Glucose Amount versus Dapagliflozin Dose in Healthy Subjects and Subjects with Type 2 Diabetes Mellitus (T2DM) (Semi-Log Plot)

Dapagliflozin was not associated with clinically meaningful prolongation of QTc interval at daily doses up to 150 mg (15 times the recommended maximum dose) in a study of healthy subjects. In addition, no clinically meaningful effect on QTc interval was observed following single doses of up to 500 mg (50 times the recommended maximum dose) of dapagliflozin in healthy subjects.

Pharmacokinetics

Following oral administration of dapagliflozin, the maximum plasma concentration (Cmax) is usually attained within 2 hours under fasting state. The Cmax and AUC values increase dose proportionally with increase in dapagliflozin dose in the therapeutic dose range. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%. Administration of dapagliflozin with a high-fat meal decreases its Cmax by up to 50% and prolongs Tmax by approximately 1 hour, but does not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful and dapagliflozin can be administered with or without food.

Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in patients with renal or hepatic impairment.

The metabolism of dapagliflozin is primarily mediated by UGT1A9; CYP-mediated metabolism is a minor clearance pathway in humans. Dapagliflozin is extensively metabolized, primarily to yield dapagliflozin 3-O-glucuronide, which is an inactive metabolite. Dapagliflozin 3-O-glucuronide accounted for 61% of a 50 mg [14C]-dapagliflozin dose and is the predominant drug-related component in human plasma.

Dapagliflozin and related metabolites are primarily eliminated via the renal pathway. Following a single 50 mg dose of [14C]-dapagliflozin, 75% and 21% total radioactivity is excreted in urine and feces, respectively. In urine, less than 2% of the dose is excreted as parent drug. In feces, approximately 15% of the dose is excreted as parent drug. The mean plasma terminal half-life (t½) for dapagliflozin is approximately 12.9 hours following a single oral dose of Farxiga 10 mg.

Renal Impairment

At steady state (20 mg once-daily dapagliflozin for 7 days), patients with type 2 diabetes with mild, moderate, or severe renal impairment (as determined by eGFR) had geometric mean systemic exposures of dapagliflozin that were 45%, 2.04-fold, and 3.03-fold higher, respectively, as compared to patients with type 2 diabetes with normal renal function. Higher systemic exposure of dapagliflozin in patients with type 2 diabetes mellitus with renal impairment did not result in a correspondingly higher 24-hour urinary glucose excretion. The steady-state 24-hour urinary glucose excretion in patients with type 2 diabetes and mild, moderate, and severe renal impairment was 42%, 80%, and 90% lower, respectively, than patients with type 2 diabetes with normal renal function. The impact of hemodialysis on dapagliflozin exposure is not known [see Dosage and Administration (2.2), Warnings and Precautions (5.3), Use in Specific Populations (8.6), and Clinical Studies (14.7)].

Hepatic Impairment

In subjects with mild and moderate hepatic impairment (Child-Pugh classes A and B), mean Cmax and AUC of dapagliflozin were up to 12% and 36% higher, respectively, as compared to healthy matched control subjects following single-dose administration of 10 mg dapagliflozin. These differences were not considered to be clinically meaningful. In patients with severe hepatic impairment (Child-Pugh class C), mean Cmax and AUC of dapagliflozin were up to 40% and 67% higher, respectively, as compared to healthy matched controls [see Use in Specific Populations (8.7)].

Effects of Age, Gender, Race, and Body Weight on Pharmacokinetics

Based on a population pharmacokinetic analysis, age, gender, race, and body weight do not have a clinically meaningful effect on the pharmacokinetics of dapagliflozin and thus, no dose adjustment is recommended.

Pediatric

Pharmacokinetics in the pediatric population has not been studied.

In Vitro Assessment of Drug Interactions

In in vitro studies, dapagliflozin and dapagliflozin 3-O-glucuronide neither inhibited CYP 1A2, 2C9, 2C19, 2D6, or 3A4, nor induced CYP 1A2, 2B6, or 3A4. Dapagliflozin is a weak substrate of the P-glycoprotein (P-gp) active transporter, and dapagliflozin 3-O-glucuronide is a substrate for the OAT3 active transporter. Dapagliflozin or dapagliflozin 3-O-glucuronide did not meaningfully inhibit P-gp, OCT2, OAT1, or OAT3 active transporters. Overall, dapagliflozin is unlikely to affect the pharmacokinetics of concurrently administered medications that are P-gp, OCT2, OAT1, or OAT3 substrates.

Effects of Other Drugs on Dapagliflozin

Table 6 shows the effect of coadministered drugs on the pharmacokinetics of dapagliflozin. No dose adjustments are recommended for dapagliflozin.

Effects of Dapagliflozin on Other Drugs

Table 7 shows the effect of dapagliflozin on other coadministered drugs. Dapagliflozin did not meaningfully affect the pharmacokinetics of the coadministered drugs.

Overview of Clinical Studies of Farxiga for Type 2 Diabetes

Farxiga has been studied as monotherapy, in combination with metformin, pioglitazone, sulfonylurea (glimepiride), sitagliptin (with or without metformin), metformin plus a sulfonylurea, or insulin (with or without other oral antidiabetic therapy), and compared to a sulfonylurea (glipizide). Farxiga has also been studied in patients with type 2 diabetes and moderate renal impairment.

Treatment with Farxiga as monotherapy and in combination with metformin, glimepiride, pioglitazone, sitagliptin, or insulin produced statistically significant improvements in mean change from baseline at Week 24 in HbA1c compared to control. Reductions in HbA1c were seen across subgroups including gender, age, race, duration of disease, and baseline BMI.

Monotherapy

A total of 840 treatment-naive patients with inadequately controlled type 2 diabetes participated in 2 placebo-controlled studies to evaluate the safety and efficacy of monotherapy with Farxiga.

In 1 monotherapy study, a total of 558 treatment-naive patients with inadequately controlled diabetes participated in a 24-week study. Following a 2-week diet and exercise placebo lead-in period, 485 patients with HbA1c ≥7% and ≤10% were randomized to Farxiga 5 mg or Farxiga 10 mg once daily in either the morning (QAM, main cohort) or evening (QPM), or placebo.

At Week 24, treatment with Farxiga 10 mg QAM provided significant improvements in HbA1c and FPG compared with placebo (see Table 8).

Initial Combination Therapy with Metformin XR

A total of 1241 treatment-naive patients with inadequately controlled type 2 diabetes (HbA1c ≥7.5% and ≤12%) participated in 2 active-controlled studies of 24-week duration to evaluate initial therapy with Farxiga 5 mg or 10 mg in combination with metformin extended-release (XR) formulation.

In 1 study, 638 patients were randomized to 1 of 3 treatment arms following a 1-week lead-in period: Farxiga 10 mg plus metformin XR (up to 2000 mg per day), Farxiga 10 mg plus placebo, or metformin XR (up to 2000 mg per day) plus placebo. Metformin XR dose was up-titrated weekly in 500 mg increments, as tolerated, with a median dose achieved of 2000 mg.

The combination treatment of Farxiga 10 mg plus metformin XR provided statistically significant improvements in HbA1c and FPG compared with either of the monotherapy treatments and statistically significant reduction in body weight compared with metformin XR alone (see Table 9 and Figure 2). Farxiga 10 mg as monotherapy also provided statistically significant improvements in FPG and statistically significant reduction in body weight compared with metformin alone and was noninferior to metformin XR monotherapy in lowering HbA1c.

Figure 2: Adjusted Mean Change from Baseline Over Time in HbA1c (%) in a 24-Week Active-Controlled Study of Farxiga Initial Combination Therapy with Metformin XR

In a second study, 603 patients were randomized to 1 of 3 treatment arms following a 1-week lead-in period: Farxiga 5 mg plus metformin XR (up to 2000 mg per day), Farxiga 5 mg plus placebo, or metformin XR (up to 2000 mg per day) plus placebo. Metformin XR dose was up-titrated weekly in 500 mg increments, as tolerated, with a median dose achieved of 2000 mg.

The combination treatment of Farxiga 5 mg plus metformin XR provided statistically significant improvements in HbA1c and FPG compared with either of the monotherapy treatments and statistically significant reduction in body weight compared with metformin XR alone (see Table 10).

Add-On to Metformin

A total of 546 patients with type 2 diabetes with inadequate glycemic control (HbA1c ≥7% and ≤10%) participated in a 24-week, placebo-controlled study to evaluate Farxiga in combination with metformin. Patients on metformin at a dose of at least 1500 mg per day were randomized after completing a 2-week, single-blind, placebo lead-in period. Following the lead-in period, eligible patients were randomized to Farxiga 5 mg, Farxiga 10 mg, or placebo in addition to their current dose of metformin.

As add-on treatment to metformin, Farxiga 10 mg provided statistically significant improvements in HbA1c and FPG, and statistically significant reduction in body weight compared with placebo at Week 24 (see Table 11 and Figure 3). Statistically significant (p<0.05 for both doses) mean changes from baseline in systolic blood pressure relative to placebo plus metformin were −4.5 mmHg and −5.3 mmHg with Farxiga 5 mg and 10 mg plus metformin, respectively.

Figure 3: Adjusted Mean Change from Baseline Over Time in HbA1c (%) in a 24-Week Placebo-Controlled Study of Farxiga in Combination with Metformin

Active Glipizide-Controlled Study Add-On to Metformin

A total of 816 patients with type 2 diabetes with inadequate glycemic control (HbA1c >6.5% and ≤10%) were randomized in a 52-week, glipizide-controlled, noninferiority study to evaluate Farxiga as add-on therapy to metformin. Patients on metformin at a dose of at least 1500 mg per day were randomized following a 2-week placebo lead-in period to glipizide or dapagliflozin (5 mg or 2.5 mg, respectively) and were up-titrated over 18 weeks to optimal glycemic effect (FPG <110 mg/dL, <6.1 mmol/L) or to the highest dose level (up to glipizide 20 mg and Farxiga 10 mg) as tolerated by patients. Thereafter, doses were kept constant, except for down-titration to prevent hypoglycemia.

At the end of the titration period, 87% of patients treated with Farxiga had been titrated to the maximum study dose (10 mg) versus 73% treated with glipizide (20 mg). Farxiga led to a similar mean reduction in HbA1c from baseline at Week 52 (LOCF), compared with glipizide, thus demonstrating noninferiority (see Table 12). Farxiga treatment led to a statistically significant mean reduction in body weight from baseline at Week 52 (LOCF) compared with a mean increase in body weight in the glipizide group. Statistically significant (p<0.0001) mean change from baseline in systolic blood pressure relative to glipizide plus metformin was −5.0 mmHg with Farxiga plus metformin.

Add-On Combination Therapy with Other Antidiabetic Agents

A total of 597 patients with type 2 diabetes and inadequate glycemic control (HbA1c ≥7% and ≤10%) were randomized in this 24-week, placebo-controlled study to evaluate Farxiga in combination with glimepiride (a sulfonylurea).

Patients on at least half the maximum recommended dose of glimepiride as monotherapy (4 mg) for at least 8 weeks lead-in were randomized to Farxiga 5 mg, Farxiga 10 mg, or placebo in addition to glimepiride 4 mg per day. Down-titration of glimepiride to 2 mg or 0 mg was allowed for hypoglycemia during the treatment period; no up-titration of glimepiride was allowed.

In combination with glimepiride, Farxiga 10 mg provided statistically significant improvement in HbA1c, FPG, and 2-hour PPG, and statistically significant reduction in body weight compared with placebo plus glimepiride at Week 24 (see Table 13). Statistically significant (p<0.05 for both doses) mean changes from baseline in systolic blood pressure relative to placebo plus glimepiride were −2.8 mmHg and −3.8 mmHg with Farxiga 5 mg and 10 mg plus glimepiride, respectively.

A total of 218 patients with type 2 diabetes and inadequate glycemic control (HbA1c ≥7% and ≤10.5%) participated in a 24-week, placebo-controlled study to evaluate Farxiga in combination with metformin and a sulfonylurea. Patients on a stable dose of metformin (immediate- or extended-release formulations) ≥1500mg/day plus maximum tolerated dose, which must be at least half the maximum dose, of a sulfonylurea for at least 8 weeks prior to enrollment were randomized after an 8-week placebo lead-in period to Farxiga 10 mg or placebo. Dose-titration of Farxiga or metformin was not permitted during the 24 –week treatment period. Down-titration of the sulfonylurea was permitted to prevent hypoglycemia, but no up-titration was permitted. As add-on treatment to combined metformin and a sulfonylurea, treatment with Farxiga 10 mg provided statistically significant improvements in HbA1c and FPG and statistically significant reduction in body weight compared with placebo at Week 24 (Table 13). A statistically significant (p<0.05) mean change from baseline in systolic blood pressure relative to placebo in combination with metformin and a sulfonyl urea was -3.8mmHg with Farxiga 10 mg in combination with metformin and a sulfonylurea at Week 8.

A total of 420 patients with type 2 diabetes with inadequate glycemic control (HbA1c ≥7% and ≤10.5%) participated in a 24-week, placebo-controlled study to evaluate Farxiga in combination with pioglitazone (a thiazolidinedione [TZD]) alone. Patients on a stable dose of pioglitazone of 45 mg per day (or 30 mg per day, if 45 mg per day was not tolerated) for 12 weeks were randomized after a 2-week lead-in period to 5 or 10 mg of Farxiga or placebo in addition to their current dose of pioglitazone. Dose titration of Farxiga or pioglitazone was not permitted during the study.

In combination with pioglitazone, treatment with Farxiga 10 mg provided statistically significant improvements in HbA1c, 2-hour PPG, FPG, the proportion of patients achieving HbA1c <7%, and a statistically significant reduction in body weight compared with the placebo plus pioglitazone treatment groups (see Table 13) at Week 24. A statistically significant (p<0.05) mean change from baseline in systolic blood pressure relative to placebo in combination with pioglitazone was −4.5 mmHg with Farxiga 10 mg in combination with pioglitazone.

A total of 452 patients with type 2 diabetes who were drug naive, or who were treated at entry with metformin or a DPP4 inhibitor alone or in combination, and had inadequate glycemic control (HbA1c ≥7.0% and ≤10.0% at randomization), participated in a 24-week, placebo-controlled study to evaluate Farxiga in combination with sitagliptin (a DPP4 inhibitor) with or without metformin.

Eligible patients were stratified based on the presence or absence of background metformin (≥1500 mg per day), and within each stratum were randomized to either Farxiga 10 mg plus sitagliptin 100 mg once daily, or placebo plus sitagliptin 100 mg once daily. Endpoints were tested for Farxiga 10 mg versus placebo for the total study group (sitagliptin with and without metformin) and for each stratum (sitagliptin alone or sitagliptin with metformin). Thirty-seven percent (37%) of patients were drug naive, 32% were on metformin alone, 13% were on a DPP4 inhibitor alone, and 18% were on a DPP4 inhibitor plus metformin. Dose titration of Farxiga, sitagliptin, or metformin was not permitted during the study.

In combination with sitagliptin (with or without metformin), Farxiga 10 mg provided statistically significant improvements in HbA1c, FPG, and a statistically significant reduction in body weight compared with the placebo plus sitagliptin (with or without metformin) group at Week 24 (see Table 13). These improvements were also seen in the stratum of patients who received Farxiga 10 mg plus sitagliptin alone (placebo-corrected mean change for HbA1c −0.56%; n=110) compared with placebo plus sitagliptin alone (n=111), and the stratum of patients who received Farxiga 10 mg plus sitagliptin and metformin (placebo-corrected mean change for HbA1c −0.40; n=113) compared with placebo plus sitagliptin with metformin (n=113).

A total of 808 patients with type 2 diabetes who had inadequate glycemic control (HbA1c ≥7.5% and ≤10.5%) were randomized in a 24-week, placebo-controlled study to evaluate Farxiga as add-on therapy to insulin. Patients on a stable insulin regimen, with a mean dose of at least 30 IU of injectable insulin per day, for a period of at least 8 weeks prior to enrollment and on a maximum of 2 oral antidiabetic medications (OADs), including metformin, were randomized after completing a 2-week enrollment period to receive either Farxiga 5 mg, Farxiga 10 mg, or placebo in addition to their current dose of insulin and other OADs, if applicable. Patients were stratified according to the presence or absence of background OADs. Up- or down-titration of insulin was only permitted during the treatment phase in patients who failed to meet specific glycemic goals. Dose modifications of blinded study medication or OAD(s) were not allowed during the treatment phase, with the exception of decreasing OAD(s) where there were concerns over hypoglycemia after cessation of insulin therapy.

In this study, 50% of patients were on insulin monotherapy at baseline, while 50% were on 1 or 2 OADs in addition to insulin. At Week 24, Farxiga 10 mg dose provided statistically significant improvement in HbA1c and reduction in mean insulin dose, and a statistically significant reduction in body weight compared with placebo in combination with insulin, with or without up to 2 OADs (see Table 13); the effect of Farxiga on HbA1c was similar in patients treated with insulin alone and patients treated with insulin plus OAD. Statistically significant (p<0.05) mean change from baseline in systolic blood pressure relative to placebo in combination with insulin was −3.0 mmHg with Farxiga 10 mg in combination with insulin.

At Week 24, Farxiga 5 mg (−5.7 IU, difference from placebo) and 10 mg (−6.2 IU, difference from placebo) once daily resulted in a statistically significant reduction in mean daily insulin dose (p<0.0001 for both doses) compared to placebo in combination with insulin, and a statistically significantly higher proportion of patients on Farxiga 10 mg (19.6%) reduced their insulin dose by at least 10% compared to placebo (11.0%).

Use in Patients with Type 2 Diabetes and Renal Impairment

The efficacy of Farxiga was assessed in a study of diabetic patients with moderate renal impairment (252 patients with mean eGFR 45 mL/min/1.73 m2). Farxiga did not show efficacy in this study. The placebo-corrected mean HbA1c change at 24 weeks was −0.1% (95% CI [−0.4%, 0.2%]) for both Farxiga 5 mg (n=83) and 10 mg (n=82).

Usual Adult Dose for Diabetes Type 2:

Initial dose: 5 mg orally once a day
Maximum dose: May increase to 10 mg orally once a day in patients tolerating therapy with 5 mg/day and requiring additional glycemic control

Comments:
-If used in combination with insulin or an insulin secretagogue, a lower dose of insulin or the insulin secretagogue should be considered to reduce the risk of hypoglycemia.

Use: As an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Applies to dapagliflozin: oral tablet

General

The most common adverse reactions included female genital mycotic infections, nasopharyngitis, and urinary tract infections.[Ref]

Genitourinary

Common (1% to 10%): Urinary tract infections increased urination, discomfort with urination, female genital mycotic infections (including vulvovaginal mycotic infection, vaginal infection, vulvovaginal candidiasis, vulvovaginitis, genital infection, genital candidiasis fungal genital infection, vulvitis, genitourinary tract infection, vulval abscess, and vaginitis bacterial), and male mycotic infections (including balanitis, fungal genital infection, balanitis candida, genital candidiasis, genital infection male, penile infection, balanoposthitis, balanoposthitis infective, genital infection, posthitis)[Ref]

Cardiovascular

Common (1% to 10%): Dyslipidemia
Uncommon (0.1% to 1%): adverse reactions related to reduced intravascular volume (postural hypotension, orthostatic hypotension, hypotension, dehydration, and syncope)[Ref]

Metabolic

Very common (10% or more): Hypoglycemia (up to 43%)
Common (1% to 10%): Hyperphosphatemia, increases in low-density lipoprotein cholesterol (LDL-C)
Uncommon (0.1% to 1%): Decreased weight
Postmarketing reports: Acidosis including diabetic ketoacidosis, ketoacidosis, or ketosis[Ref]

Hypoglycemia was reported more frequently when this drug was added to sulfonylurea or insulin (up to 43%). Hypoglycemia was not reported in monotherapy trials, and was reported infrequently in add-on trials with metformin, pioglitazone, and dipeptidyl peptidase-4 inhibitors (up to 1.5%,2.1%, and 1.8% respectively).

Twenty reports of acidosis have been identified in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database during the period March 2013 through 06 June 2014. All patients required emergency room treatment or hospitalization. These cases were not typical of ketoacidosis or diabetic ketoacidosis (DKA) in that they occurred in patients with type 2 diabetes and their blood sugar levels were only slightly increased. Some factors identified as potentially triggering the acidosis included major illness, reduced food and fluid intake, and reduced insulin dose.[Ref]

Gastrointestinal

Common (1% to 10%): Nausea, constipation
Uncommon (0.1% to 1%): Thirst, dry mouth[Ref]

Hypersensitivity

Rare (less than 0.1%): Serious anaphylactic reactions, severe cutaneous reactions, and angioedema[Ref]

Musculoskeletal

Common (1% to 10%): Back pain, extremity pain
Frequency not reported: Bone fracture[Ref]

Immunologic

Common (1% to 10%): Influenza[Ref]

Oncologic

Newly diagnosed bladder cancer was reported in 10 of 6045 (0.17%) patients receiving this drug in clinical trials compared with 1 of 3512 (0.3%) patients receiving placebo or comparator. Upon excluding patients in whom exposure to study drug was less than 1 year at time of diagnosis, there were no cases associated with placebo and 4 cases with this drug. Due to the low number of cases, further studies are needed.[Ref]

Uncommon (0.1% to 1%): Bladder cancer[Ref]

Renal

From March 2013 to October 2015, the US FDA received 101 confirmable case reports of acute kidney injury (AKI) with use of canagliflozin (n=73) or dapagliflozin (the active ingredient contained in Farxiga) (n=28). Hospitalization was necessary for evaluation and management in 96 cases; admission to the intensive care unit occurred in 22 cases, and death occurred in 4 patients, of which 2 were cardiac-related. Dialysis was necessary in 15 patients, 3 of whom had a history of chronic kidney disease or previous AKI. In 58 cases, time to onset of AKI was within 1 month or less of initiating therapy. In 78 cases in which drug discontinuation was reported, 56 reported subsequent improvement; 3 patients recovered with sequelae, 11 patients did not recover (including the 4 deaths mentioned earlier). Median age was 57 years (range 28 to 78 years; based on 84 cases reporting age). Concomitant ACE inhibitor therapy was reported in 51 cases, diuretic use in 26 cases, and NSAID use in 6 cases. Almost half the patients reported a change in renal function at time of diagnosis (median elevation of serum creatinine from baseline 1.6 mg/dL [based on 32 cases reporting serum creatinine] and median decrease in eGFR 46 mL/min/1.73m2 [based on 13 cases reporting eGFR]).[Ref]

Frequency not reported: Renal failure, serum creatinine increase
Postmarketing reports: Acute kidney injury[Ref]

Endocrine

Frequency not reported: Small increases in serum parathyroid hormone levels[Ref]

Nervous system

Common (1% to 10%): Dizziness, headache[Ref]

Hepatic

Very rare (less than 0.01%): Hepatitis[Ref]

Respiratory

Common (1% to 10%): Nasopharyngitis[Ref]

Dermatologic

Postmarketing reports: Rash[Ref]

Some side effects of Farxiga may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.