Jardiance (Page 6 of 7)

14.2 Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease

The effect of JARDIANCE on cardiovascular risk in adult patients with type 2 diabetes and established, stable, atherosclerotic cardiovascular disease was evaluated in the EMPA-REG OUTCOME study, a multicenter, multi-national, randomized, double-blind parallel group trial. The study compared the risk of experiencing a major adverse cardiovascular event (MACE) between JARDIANCE and placebo when these were added to and used concomitantly with standard of care treatments for diabetes and atherosclerotic cardiovascular disease. Coadministered antidiabetic medications were to be kept stable for the first 12 weeks of the trial. Thereafter, antidiabetic and atherosclerotic therapies could be adjusted, at the discretion of investigators, to ensure participants were treated according to the standard care for these diseases.

A total of 7020 patients were treated (JARDIANCE 10 mg = 2345; JARDIANCE 25 mg = 2342; placebo = 2333) and followed for a median of 3.1 years. Approximately 72% of the study population was Caucasian, 22% was Asian, and 5% was Black. The mean age was 63 years and approximately 72% were male.

All patients in the study had inadequately controlled type 2 diabetes mellitus at baseline (HbA1c greater than or equal to 7%). The mean HbA1c at baseline was 8.1% and 57% of participants had had diabetes for more than 10 years. Approximately 31%, 22% and 20% reported a past history of neuropathy, retinopathy and nephropathy to investigators respectively and the mean eGFR was 74 mL/min/1.73 m2. At baseline, patients were treated with one (~30%) or more (~70%) antidiabetic medications including metformin (74%), insulin (48%), and sulfonylurea (43%).

All patients had established atherosclerotic cardiovascular disease at baseline including one (82%) or more (18%) of the following; a documented history of coronary artery disease (76%), stroke (23%) or peripheral artery disease (21%). At baseline, the mean systolic blood pressure was 136 mmHg, the mean diastolic blood pressure was 76 mmHg, the mean LDL was 86 mg/dL, the mean HDL was 44 mg/dL, and the mean urinary albumin to creatinine ratio (UACR) was 175 mg/g. At baseline, approximately 81% of patients were treated with renin angiotensin system inhibitors, 65% with beta-blockers, 43% with diuretics, 77% with statins, and 86% with antiplatelet agents (mostly aspirin).

The primary endpoint in EMPA-REG OUTCOME was the time to first occurrence of a Major Adverse Cardiac Event (MACE). A major adverse cardiac event was defined as occurrence of either a cardiovascular death or a nonfatal myocardial infarction (MI) or a nonfatal stroke. The statistical analysis plan had pre-specified that the 10 and 25 mg doses would be combined. A Cox proportional hazards model was used to test for non-inferiority against the pre-specified risk margin of 1.3 for the hazard ratio of MACE and superiority on MACE if non-inferiority was demonstrated. Type-1 error was controlled across multiples tests using a hierarchical testing strategy.

JARDIANCE significantly reduced the risk of first occurrence of primary composite endpoint of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (HR: 0.86; 95% CI 0.74, 0.99). The treatment effect was due to a significant reduction in the risk of cardiovascular death in subjects randomized to empagliflozin (HR: 0.62; 95% CI 0.49, 0.77), with no change in the risk of non-fatal myocardial infarction or non-fatal stroke (see Table 13 and Figure 5 and 6). Results for the 10 mg and 25 mg empagliflozin doses were consistent with results for the combined dose groups.

Table 13 Treatment Effect for the Primary Composite Endpoint, and its Componentsa
a Treated set (patients who had received at least one dose of study drug)b p−value for superiority (2−sided) 0.04c Total number of events
Placebo N=2333 JARDIANCE N=4687 Hazard ratio vs placebo (95% CI)
Composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke (time to first occurrence)b 282 (12.1%) 490 (10.5%) 0.86 (0.74, 0.99)
Non-fatal myocardial infarctionc 121 (5.2%) 213 (4.5%) 0.87 (0.70, 1.09)
Non-fatal strokec 60 (2.6%) 150 (3.2%) 1.24 (0.92, 1.67)
Cardiovascular deathc 137 (5.9%) 172 (3.7%) 0.62 (0.49, 0.77)
Figure 5
(click image for full-size original)
Figure 6
(click image for full-size original)

The efficacy of JARDIANCE on cardiovascular death was generally consistent across major demographic and disease subgroups.

Vital status was obtained for 99.2% of subjects in the trial. A total of 463 deaths were recorded during the EMPA-REG OUTCOME trial. Most of these deaths were categorized as cardiovascular deaths. The non-cardiovascular deaths were only a small proportion of deaths, and were balanced between the treatment groups (2.1% in patients treated with JARDIANCE, and 2.4% of patients treated with placebo).

16  HOW SUPPLIED/STORAGE AND HANDLING

JARDIANCE tablets are available in 10 mg and 25 mg strengths as follows:

10 mg tablets: pale yellow, round, biconvex and bevel-edged, film-coated tablets debossed with “S 10” on one side and the Boehringer Ingelheim company symbol on the other side.
Bottles of 30 (NDC 0597-0152-30)
Bottles of 90 (NDC 0597-0152-90)
Cartons containing 3 blister cards of 10 tablets each (3 x 10) (NDC 0597-0152-37), institutional pack.

25 mg tablets: pale yellow, oval, biconvex film-coated tablets, debossed with “S 25” on one side and the Boehringer Ingelheim company symbol on the other side.
Bottles of 30 (NDC 0597-0153-30)
Bottles of 90 (NDC 0597-0153-90)
Cartons containing 3 blister cards of 10 tablets each (3 x 10) (NDC 0597-0153-37), institutional pack.

Dispense in a well-closed container as defined in the USP.

Storage
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].

17  PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Instructions
Instruct patients to read the Patient Information before starting JARDIANCE therapy and to reread it each time the prescription is renewed. Instruct patients to inform their doctor or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.

Inform patients of the potential risks and benefits of JARDIANCE and of alternative modes of therapy. Also inform patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and HbA1c testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. Advise patients to seek medical advice promptly during periods of stress such as fever, trauma, infection, or surgery, as medication requirements may change.

Instruct patients to take JARDIANCE only as prescribed. If a dose is missed, it should be taken as soon as the patient remembers. Advise patients not to double their next dose.

Inform patients that the most common adverse reactions associated with the use of JARDIANCE are urinary tract infections and mycotic genital infections.

Advise pregnant women, and females of reproductive potential of the potential risk to a fetus with treatment with JARDIANCE [see Use in Specific Populations (8.1)]. Instruct females of reproductive potential to report pregnancies to their physicians as soon as possible.

Advise women that breastfeeding is not recommended during treatment with JARDIANCE [see Use in Specific Populations (8.2)].

Hypotension
Inform patients that hypotension may occur with JARDIANCE and advise them to contact their healthcare provider if they experience such symptoms [see Warnings and Precautions (5.1)]. Inform patients that dehydration may increase the risk for hypotension, and to have adequate fluid intake.

Ketoacidosis
Inform patients that ketoacidosis is a serious life-threatening condition. Cases of ketoacidosis have been reported during use of JARDIANCE. Instruct patients to check ketones (when possible) if symptoms consistent with ketoacidosis occur even if blood glucose is not elevated. If symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and labored breathing) occur, instruct patients to discontinue JARDIANCE and seek medical advice immediately [see Warnings and Precautions (5.2)].

Acute Kidney Injury
Inform patients that acute kidney injury has been reported during use of JARDIANCE. Advise patients to seek medical advice immediately if they have reduced oral intake (such as due to acute illness or fasting) or increased fluid losses (such as due to vomiting, diarrhea, or excessive heat exposure), as it may be appropriate to temporarily discontinue JARDIANCE use in those settings [see Warnings and Precautions (5.3)].

Serious Urinary Tract Infections
Inform patients of the potential for urinary tract infections, which may be serious. Provide them with information on the symptoms of urinary tract infections. Advise them to seek medical advice if such symptoms occur [see Warnings and Precautions (5.4) ].

Genital Mycotic Infections in Females (e.g., Vulvovaginitis)
Inform female patients that vaginal yeast infections may occur and provide them with information on the signs and symptoms of vaginal yeast infections. Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.6)].

Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis)
Inform male patients that yeast infection of penis (e.g., balanitis or balanoposthitis) may occur, especially in uncircumcised males and patients with chronic and recurrent infections. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.6)].

Hypersensitivity Reactions
Inform patients that serious hypersensitivity reactions, such as urticaria and angioedema, have been reported with JARDIANCE. Advise patients to report immediately any skin reaction or angioedema, and to discontinue drug until they have consulted prescribing physician [see Warnings and Precautions (5.7)].

Laboratory Tests
Inform patients that renal function should be assessed prior to initiation of JARDIANCE and monitored periodically thereafter.

Inform patients that elevated glucose in urinalysis is expected when taking JARDIANCE.

Inform patients that response to all diabetic therapies should be monitored by periodic measurements of blood glucose and HbA1c levels, with a goal of decreasing these levels toward the normal range. Hemoglobin A1c monitoring is especially useful for evaluating long-term glycemic control.


Distributed by:
Boehringer Ingelheim Pharmaceuticals, Inc.
Ridgefield, CT 06877 USA

Marketed by:
Boehringer Ingelheim Pharmaceuticals, Inc.
Ridgefield, CT 06877 USA
and
Eli Lilly and Company
Indianapolis, IN 46285 USA

Licensed from:
Boehringer Ingelheim International GmbH, Ingelheim, Germany

Boehringer Ingelheim Pharmaceuticals, Inc. either owns or uses the Jardiance® and EMPA-REG OUTCOME® trademarks under license.

The other trademarks referenced are owned by third parties not affiliated with Boehringer Ingelheim Pharmaceuticals, Inc.

Copyright © 2017 Boehringer Ingelheim International GmbHALL RIGHTS RESERVED

IT5728RL112017

This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: December 2017
PATIENT INFORMATIONJARDIANCE® (jar DEE ans)(empagliflozin)Tablets
What is the most important information I should know about JARDIANCE? JARDIANCE can cause serious side effects, including:
  • Dehydration. JARDIANCE can cause some people to have dehydration (the loss of body water and salt). Dehydration may cause you to feel dizzy, faint, light-headed, or weak, especially when you stand up (orthostatic hypotension).You may be at higher risk of dehydration if you:
    • have low blood pressure
    • take medicines to lower your blood pressure, including diuretics (water pills)
    • are on low sodium (salt) diet
    • have kidney problems
    • are 65 years of age or older
  • Vaginal yeast infection. Women who take JARDIANCE may get vaginal yeast infections. Symptoms of a vaginal yeast infection include:
    • vaginal odor
    • white or yellowish vaginal discharge (discharge may be lumpy or look like cottage cheese)
    • vaginal itching
  • Yeast infection of the penis (balanitis or balanoposthitis). Men who take JARDIANCE may get a yeast infection of the skin around the penis. Certain men who are not circumcised may have swelling of the penis that makes it difficult to pull back the skin around the tip of the penis. Other symptoms of yeast infection of the penis include:
    • redness, itching, or swelling of the penis
    • rash of the penis
    • foul smelling discharge from the penis
    • pain in the skin around penis
Talk to your doctor about what to do if you get symptoms of a yeast infection of the vagina or penis. Your doctor may suggest you use an over-the-counter antifungal medicine. Talk to your doctor right away if you use an over-the-counter antifungal medication and your symptoms do not go away.

What is JARDIANCE?

  • JARDIANCE is a prescription medicine used:
    • along with diet and exercise to lower blood sugar in adults with type 2 diabetes.
    • to reduce the risk of cardiovascular death in adults with type 2 diabetes who have known cardiovascular disease.
  • JARDIANCE is not for people with type 1 diabetes.
  • JARDIANCE is not for people with diabetic ketoacidosis (increased ketones in the blood or urine).
  • It is not known if JARDIANCE is safe and effective in children under 18 years of age.
Who should not take JARDIANCE?

Do not take JARDIANCE if you:

  • are allergic to empagliflozin or any of the ingredients in JARDIANCE. See the end of this leaflet for a list of ingredients in JARDIANCE.
  • have severe kidney problems or are on dialysis
What should I tell my doctor before using JARDIANCE?

Before you take JARDIANCE, tell your doctor if you:

  • have kidney problems
  • have liver problems
  • have a history of urinary tract infections or problems with urination
  • are going to have surgery
  • are eating less due to illness, surgery, or a change in your diet
  • have or have had problems with your pancreas, including pancreatitis or surgery on your pancreas
  • drink alcohol very often, or drink a lot of alcohol in the short term (“binge” drinking)
  • have any other medical conditions
  • are pregnant or plan to become pregnant. JARDIANCE may harm your unborn baby. If you become pregnant while taking JARDIANCE, tell your doctor as soon as possible. Talk with your doctor about the best way to control your blood sugar while you are pregnant.
  • are breastfeeding or plan to breastfeed. JARDIANCE may pass into your breast milk and may harm your baby. Talk with your doctor about the best way to feed your baby if you are taking JARDIANCE. Do not breastfeed while taking JARDIANCE.
Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.JARDIANCE may affect the way other medicines work, and other medicines may affect how JARDIANCE works.

Especially tell your doctor if you take:

  • diuretics (water pills)
  • insulin or other medicines that can lower your blood sugar
Ask your doctor or pharmacist for a list of these medicines if you are not sure if your medicine is listed above.
How should I take JARDIANCE?
  • Take JARDIANCE exactly as your doctor tells you to take it.
  • Take JARDIANCE by mouth 1 time in the morning each day, with or without food.
  • Your doctor may change your dose if needed.
  • If you miss a dose, take it as soon as you remember. If you do not remember until it is time for your next dose, skip the missed dose and go back to your regular schedule. Do not take two doses of JARDIANCE at the same time. Talk with your doctor if you have questions about a missed dose.
  • Your doctor may tell you to take JARDIANCE along with other diabetes medicines. Low blood sugar can happen more often when JARDIANCE is taken with certain other diabetes medicines. See “What are the possible side effects of JARDIANCE?”
  • If you take too much JARDIANCE, call your doctor or go to the nearest hospital emergency room right away.
  • When your body is under some types of stress, such as fever, trauma (such as a car accident), infection, or surgery, the amount of diabetes medicine that you need may change. Tell your doctor right away if you have any of these conditions and follow your doctor’s instructions.
  • Check your blood sugar as your doctor tells you to.
  • Stay on your prescribed diet and exercise program while taking JARDIANCE.
  • Talk to your doctor about how to prevent, recognize and manage low blood sugar (hypoglycemia), high blood sugar (hyperglycemia), and complications of diabetes.
  • Your doctor will check your diabetes with regular blood tests, including your blood sugar levels and your hemoglobin HbA1c.
  • When taking JARDIANCE, you may have sugar in your urine, which will show up on a urine test.
What are the possible side effects of JARDIANCE?

JARDIANCE may cause serious side effects, including:

  • See “What is the most important information I should know about JARDIANCE?
  • Ketoacidosis (increased ketones in your blood or urine). Ketoacidosis has happened in people who have type 1 diabetes or type 2 diabetes, during treatment with JARDIANCE. Ketoacidosis is a serious condition, which may need to be treated in a hospital. Ketoacidosis may lead to death. Ketoacidosis can happen with JARDIANCE even if your blood sugar is less than 250 mg/dL. Stop taking JARDIANCE and call your doctor right away if you get any of the following symptoms:
  • nausea
  • vomiting
  • stomach-area (abdominal) pain
  • tiredness
  • trouble breathing
          If you get any of these symptoms during treatment with JARDIANCE, if possible, check for ketones in your urine, even if your           blood sugar is less than 250 mg/dL.
  • Serious urinary tract infections. Serious urinary tract infections that may lead to hospitalization have happened in people who are taking JARDIANCE. Tell your doctor if you have any signs or symptoms of a urinary tract infection such as a burning feeling when passing urine, a need to urinate often, the need to urinate right away, pain in the lower part of your stomach (pelvis), or blood in the urine. Sometimes people also may have a fever, back pain, nausea or vomiting.
  • Low blood sugar (hypoglycemia). If you take JARDIANCE with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you take JARDIANCE. Signs and symptoms of low blood sugar may include:
  • headache
  • drowsiness
  • weakness
  • irritability
  • hunger
  • fast heartbeat
  • confusion
  • shaking or feeling jittery
  • dizziness
  • sweating
  • Kidney problems. Sudden kidney injury has happened to people taking JARDIANCE. Talk to your doctor right away if you:
    • reduce the amount of food or liquid you drink for example, if you are sick or cannot eat or
    • start to lose liquids from your body for example, from vomiting, diarrhea or being in the sun too long
  • Allergic (hypersensitivity) reactions. Serious allergic reactions have happened in people who are taking JARDIANCE. Symptoms may include
    • swelling of your face, lips, throat and other areas of your skin
    • difficulty with swallowing or breathing.
    • raised, red areas on your skin (hives)
    If you have any of these symptoms, stop taking JARDIANCE and call your doctor right away or go to the nearest hospital emergency room.
  • Increased fats in your blood (cholesterol)
These are not all the possible side effects of JARDIANCE. For more information, ask your doctor or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store JARDIANCE? Store JARDIANCE at room temperature 68°F to 77°F (20°C to 25°C).
General information about the safe and effective use of JARDIANCE. Medicines are sometimes prescribed for purposes other than those listed in Patient Information. Do not use JARDIANCE for a condition for which it is not prescribed. Do not give JARDIANCE to other people, even if they have the same symptoms you have. It may harm them.This Patient Information summarizes the most important information about JARDIANCE. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about JARDIANCE that is written for health professionals.For more information about JARDIANCE, go to www.jardiance.com, scan the code below, or call Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257 or (TTY) 1-800-459-9906.qr-code
What are the ingredients in JARDIANCE? Active Ingredient: empagliflozinInactive Ingredients: lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate. In addition, the film coating contains the following inactive ingredients: hypromellose, titanium dioxide, talc, polyethylene glycol, and yellow ferric oxide.
Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc.; Ridgefield, CT 06877 USAMarketed by: Boehringer Ingelheim Pharmaceuticals, Inc.; Ridgefield, CT 06877 USA and Eli Lilly and Company, Indianapolis, IN 46285 USALicensed from: Boehringer Ingelheim International GmbH, Ingelheim, GermanyBoehringer Ingelheim Pharmaceuticals, Inc. either owns or uses the Jardiance® and EMPA-REG OUTCOME® trademarks under license.The other trademarks referenced are owned by third parties not affiliated with Boehringer Ingelheim Pharmaceuticals, Inc.Copyright © 2017 Boehringer Ingelheim International GmbHALL RIGHTS RESERVEDIT5728RL112017

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