XIGDUO XR- dapagliflozin and metformin hydrochloride tablet, film coated, extended release

Country: United States

Language: English

Source: NLM (National Library of Medicine)

Active ingredient:

DAPAGLIFLOZIN PROPANEDIOL (UNII: 887K2391VH) (dapagliflozin - UNII:1ULL0QJ8UC), METFORMIN HYDROCHLORIDE (UNII: 786Z46389E) (metformin - UNII:9100L32L2N)

Available from:

AstraZeneca Pharmaceuticals LP

INN (International Name):

DAPAGLIFLOZIN PROPANEDIOL

Composition:

dapagliflozin 10 mg

Administration route:

ORAL

Prescription type:

PRESCRIPTION DRUG

Therapeutic indications:

XIGDUO XR is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Dapagliflozin is indicated to reduce Limitations of Use XIGDUO XR is contraindicated in patients with: Risk Summary Based on animal data showing adverse renal effects, XIGDUO XR is not recommended during the second and third trimesters of pregnancy. Limited data with XIGDUO XR or dapagliflozin in pregnant women are not sufficient to determine drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk (see Data) . There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations) . In animal studies, adverse renal pelvic and tubule dilatations, that were not fully reversible, were observed in rats when dapagliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy, at all doses tested; the lowest of which provided an exposure 15-times the 10 mg clinical dose (see Data) . The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with a HbA1c greater than 7% and has been reported to be as high as 20 to 25% in women with HbA1c greater than 10%. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryofetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Human Data Published data from post-marketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups. Animal Data Dapagliflozin Dapagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 1, 15, or 75 mg/kg/day, increased kidney weights and increased the incidence of renal pelvic and tubular dilatations at all dose levels. Exposure at the lowest dose tested was 15-times the 10 mg clinical dose (based on AUC). The renal pelvic and tubular dilatations observed in juvenile animals did not fully reverse within a 1-month recovery period. In a prenatal and postnatal development study, dapagliflozin was administered to maternal rats from gestation day 6 through lactation day 21 at doses of 1, 15, or 75 mg/kg/day, and pups were indirectly exposed in utero and throughout lactation. Increased incidence or severity of renal pelvic dilatation was observed in 21-day-old pups offspring of treated dams at 75 mg/kg/day (maternal and pup dapagliflozin exposures were 1415-times and 137-times, respectively, the human values at the 10 mg clinical dose, based on AUC). Dose-related reductions in pup body weights were observed at greater or equal to 29-times the 10 mg clinical dose (based on AUC). No adverse effects on developmental endpoints were noted at 1 mg/kg/day (19-times the 10 mg clinical dose, based on AUC). These outcomes occurred with drug exposure during periods of renal development in rats that corresponds to the late second and third trimester of human development. In embryofetal development studies in rats and rabbits, dapagliflozin was administered throughout organogenesis, corresponding to the first trimester of human pregnancy. In rats, dapagliflozin was neither embryolethal nor teratogenic at doses up to 75 mg/kg/day (1441-times the 10 mg clinical dose, based on AUC). Dose related effects on the rat fetus (structural abnormalities and reduced body weight) occurred only at higher dosages, equal to or greater than 150 mg/kg (more than 2344-times the 10 mg clinical dose, based on AUC), which were associated with maternal toxicity. No developmental toxicities were observed in rabbits at doses up to 180 mg/kg/day (1191-times the 10 mg clinical dose, based on AUC). Metformin HCl Metformin HCl did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis. This represents an exposure of about 2- and 6-times a 2000 mg clinical dose based on body surface area (mg/m2 ) for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin. Risk Summary There is no information regarding the presence of XIGDUO XR or dapagliflozin in human milk, the effects on the breastfed infant, or the effects on milk production. Limited published studies report that metformin is present in human milk (see Data) . However, there is insufficient information on the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. Dapagliflozin is present in the milk of lactating rats (see Data) . However, due to species specific differences in lactation physiology, the clinical relevance of these data is not clear. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney. Because of the potential for serious adverse reactions in breastfed infants, advise women that use of XIGDUO XR is not recommended while breastfeeding. Data Dapagliflozin Dapagliflozin was present in rat milk at a milk/plasma ratio of 0.49, indicating that dapagliflozin and its metabolites are transferred into milk at a concentration that is approximately 50% of that in maternal plasma. Juvenile rats directly exposed to dapagliflozin showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation. Metformin HCl Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants. Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some anovulatory women. Safety and effectiveness of XIGDUO XR in pediatric patients under 18 years of age have not been established. XIGDUO XR No XIGDUO XR dosage change is recommended based on age. More frequent assessment of renal function is recommended in elderly patients. Dapagliflozin A total of 1424 (24%) of the 5936 dapagliflozin-treated patients were 65 years and older and 207 (3.5%) patients were 75 years and older in a pool of 21 double-blind, controlled, clinical studies assessing the efficacy of dapagliflozin in improving glycemic control. After controlling for level of renal function (eGFR), efficacy was similar for patients under age 65 years and those 65 years and older. In patients ≥65 years of age, a higher proportion of patients treated with dapagliflozin for glycemic control had adverse reactions of hypotension [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)] . In both the DAPA-HF and DAPA-CKD studies, safety and efficacy were similar for patients age 65 years and younger and those older than 65 in both the overall population and the patients with type 2 diabetes mellitus. In the DAPA-HF study, 2714 (57%) out of 4744 patients with heart failure with reduced ejection fraction (HFrEF) were older than 65 years. Out of 2139 patients with HFrEF and type 2 diabetes mellitus, 1211 (57%) were older than 65 years. In the DAPA-CKD study, 1818 (42%) out of 4304 patients with chronic kidney disease were older than 65 years. Out of 2906 patients with chronic kidney disease and type 2 diabetes mellitus, 1399 (48%) were older than 65 years. Metformin HCl Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently than younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients [see Warnings and Precautions (5.1)] . Initiation of XIGDUO XR is not recommended in patients with an eGFR below 45 mL/min/1.73 m2 and is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2 ), end-stage renal disease or patients on dialysis [see Dosage and Administration (2.4), Contraindications (4) and  Warnings and Precautions  (5.1, 5.3)] . Dapagliflozin Dapagliflozin 10 mg was evaluated in 4304 patients with chronic kidney disease (eGFR 25 to 75 mL/min/1.73 m2 ) in the DAPA-CKD study. Dapagliflozin 10 mg was also evaluated in 1926 patients with an eGFR of 30 to 60 mL/min/1.73 m2 in the DAPA-HF study. The safety profile of dapagliflozin across eGFR subgroups was consistent with the known safety profile [see Adverse Reactions (6.1) and Clinical Studies  (14.3 and 14.4)] . Dapagliflozin 10 mg was evaluated in two glycemic control studies that included patients with moderate renal impairment (an eGFR of 45 to less than 60 mL/min/1.73 m2 , and an eGFR of 30 to less than 60 mL/min/1.73 m2 ) [see Clinical Studies (14.1)] . Patients with diabetes and renal impairment using dapagliflozin 10 mg are more likely to experience hypotension and may be at higher risk for acute kidney injury secondary to volume depletion. In the study of patients with an eGFR 30 to less than 60 mL/min/1.73 m2 , 13 patients receiving dapagliflozin experienced bone fractures compared to none receiving placebo. Use of dapagliflozin 10 mg for glycemic control in patients without established CV disease or CV risk factors is not recommended when eGFR is less than 45 mL/min/1.73 m2  [see Dosage and Administration (2.4)] . Metformin HCl Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. XIGDUO XR is contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2 [see Dosage and Administration (2.4), Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology  (12.3)]. Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. XIGDUO XR is not recommended in patients with hepatic impairment [see Warnings and Precautions (5.1)] .

Product summary:

XIGDUO® XR (dapagliflozin and metformin HCl extended-release) tablets have markings on one side, are plain on the reverse side, and are available in the strengths and packages listed in Table 19. 2.5 mg/ 1,000 mg Light brown to brown, biconvex, oval-shaped "1074" and "2.5/1000" debossed on one side and plain on the reverse side Bottle of 60 0310-6225-60 5 mg/ 500 mg orange, biconvex, capsule-shaped "1070" and "5/500" debossed on one side and plain on the reverse side Bottle of 30 Bottle of 500 0310-6250-30 0310-6250-50 5 mg/ 1,000 mg pink to dark pink, biconvex, oval-shaped "1071" and "5/1000" debossed on one side and plain on the reverse side Bottle of 30 Bottle of 60 Bottle of 90 Bottle of 400 0310-6260-30 0310-6260-60 0310-6260-90 0310-6260-40 10 mg/ 500 mg pink, biconvex, capsule-shaped "1072" and "10/500" debossed on one side and plain on the reverse side Bottle of 30 Bottle of 500 0310-6270-30 0310-6270-50 10 mg/ 1,000 mg yellow to dark yellow, biconvex, oval-shaped "1073" and "10/1000" debossed on one side and plain on the reverse side Bottle of 30 Bottle of 90 Bottle of 400 0310-6280-30 0310-6280-90 0310-6280-40 Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].

Authorization status:

New Drug Application

Patient Information leaflet

AstraZeneca Pharmaceuticals LP
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MEDICATION GUIDE
MEDICATION GUIDE
XIGDUO® XR [ZIG-DO-OH X-R]
(dapagliflozin and metformin hydrochloride extended-release)
tablets, for oral use
What is the most important information I should know about XIGDUO XR?
XIGDUO XR can cause serious side effects, including:
•
Lactic Acidosis. Metformin, one of the medicines in XIGDUO XR, can
cause a rare but serious
condition called lactic acidosis (a build-up of an acid in the blood)
that can cause death. Lactic
acidosis is a medical emergency and must be treated in the hospital.
Stop taking XIGDUO XR and call your healthcare provider right away if
you have any of the following
symptoms, which could be signs of lactic acidosis:
o
you feel cold in your hands or feet
o
you feel dizzy or lightheaded
o
you have a slow or irregular heartbeat
o
you feel very weak or tired
o
you have unusual (not normal) muscle pain
o
you have trouble breathing
o
you feel unusual sleepiness or sleep longer than usual
o
you have stomach pains, nausea or vomiting
Most people who have had lactic acidosis with metformin have other
things that, combined with the
metformin use, led to the lactic acidosis. Tell your healthcare
provider if you have any of the following,
because you have a higher chance for getting lactic acidosis with
XIGDUO XR if you:
o
have severe kidney problems or your kidneys are affected by certain
x-ray tests that use
injectable dye.
o
have liver problems.
o
drink alcohol very often or drink a lot of alcohol in the short-term
("binge" drinking).
o
get dehydrated (lose a large amount of body fluids). This can happen
if you are sick with a
fever, vomiting, or diarrhea. Dehydration can also happen when you
sweat a lot with activity
or exercise and do not drink enough fluids.
o
have surgery.
o
have new or worsening symptoms of congestive heart failure such as
shortness of breath or
increased fluid or swelling of the legs.
o
have a heart attack, severe infection, or stroke.
o
are 65 years of age or older.
The best way to keep from having

Summary of Product characteristics

XIGDUO XR- DAPAGLIFLOZIN AND METFORMIN HYDROCHLORIDE TABLET, FILM
COATED,
EXTENDED RELEASE
ASTRAZENECA PHARMACEUTICALS LP
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HIGHLIGHTS OF PRESCRIBING INFORMATION
THESE HIGHLIGHTS DO NOT INCLUDE ALL THE INFORMATION NEEDED TO USE
XIGDUO XR SAFELY AND
EFFECTIVELY. SEE FULL PRESCRIBING INFORMATION FOR XIGDUO XR.
XIGDUO XR (DAPAGLIFLOZIN AND METFORMIN HYDROCHLORIDE EXTENDED-RELEASE)
TABLETS, FOR ORAL
USE
INITIAL U.S. APPROVAL: 2014
WARNING: LACTIC ACIDOSIS
_SEE FULL PRESCRIBING INFORMATION FOR COMPLETE BOXED WARNING._
•
•
•
RECENT MAJOR CHANGES
Indications and Usage (1) 09/2023
Dosage and Administration (2.6) 09/2023
Warnings and Precautions (5.2) 09/2023
INDICATIONS AND USAGE
XIGDUO XR is a combination of dapagliflozin, a sodium-glucose
cotransporter 2 (SGLT2) inhibitor, and
metformin, a biguanide, indicated as an adjunct to diet and exercise
to improve glycemic control in adults
with type 2 diabetes mellitus. (1)
Dapagliflozin is indicated to reduce:
•
•
•
Limitations of use:
•
•
•
DOSAGE AND ADMINISTRATION
•
•
•
•
•
®
POSTMARKETING CASES OF METFORMIN-ASSOCIATED LACTIC ACIDOSIS HAVE
RESULTED IN
DEATH, HYPOTHERMIA, HYPOTENSION, AND RESISTANT BRADYARRHYTHMIAS.
SYMPTOMS
INCLUDED MALAISE, MYALGIAS, RESPIRATORY DISTRESS, SOMNOLENCE, AND
ABDOMINAL PAIN.
LABORATORY ABNORMALITIES INCLUDED ELEVATED BLOOD LACTATE LEVELS, ANION
GAP
ACIDOSIS, INCREASED LACTATE/PYRUVATE RATIO; AND METFORMIN PLASMA
LEVELS GENERALLY
>5 MCG/ML. (5.1)
RISK FACTORS INCLUDE RENAL IMPAIRMENT, CONCOMITANT USE OF CERTAIN
DRUGS, AGE >65
YEARS OLD, RADIOLOGICAL STUDIES WITH CONTRAST, SURGERY AND OTHER
PROCEDURES,
HYPOXIC STATES, EXCESSIVE ALCOHOL INTAKE, AND HEPATIC IMPAIRMENT.
STEPS TO REDUCE
THE RISK OF AND MANAGE METFORMIN-ASSOCIATED LACTIC ACIDOSIS IN THESE
HIGH-RISK
GROUPS ARE PROVIDED IN THE FULL PRESCRIBING INFORMATION. (5.1)
IF LACTIC ACIDOSIS IS SUSPECTED, DISCONTINUE XIGDUO XR AND INSTITUTE
GENERAL
SUPPORTIVE MEASURES IN A HOSPITAL SETTING. PROMPT HEMODIALYSIS IS
RECOMMENDED.
(5.1)
The risk of hospitalization