Glyxambi

Name: Glyxambi

Glyxambi Precautions

Serious side effects have been reported with Glyxambi including the following:

  • Pancreatitis (inflammation or swelling of the pancreas). Tell your healthcare provider right away if you have some or all of the following symptoms of pancreatitis:
    • Stomach or abdominal pains
    • Swollen or tender stomach/abdomen
    • Nausea
    • Vomiting
    • Fever
  • Low Blood Pressure (hypotension). Tell your healthcare provider right away if you have some or all of the following symptoms of low blood pressure:
    • Dizziness
    • Feeling lightheaded, especially when standing up
    • Fainting
    • Feeling tired or fatigue
    • Having blurry vision
  • Low Blood Sugars (hypoglycemia). Tell your healthcare provider right away if you have some or all of the following symptoms of low blood sugars:
    • Feeling shaky or trembling
    • Feeling nervous or anxious
    • Sweating
    • Confusion
    • Having a fast or irregular heartbeat
    • Having blurry vision
  • Genital fungal infections (yeast infections). Tell your healthcare provider right away if you have some or all of the following symptoms of a yeast infection:
    • Having an abnormal vaginal discharge. Discharge can range from water to think/chunky and white. 
    • Itching or burning of the vaginal area
    • Pain during intercourse or sex
    • Pain when urinating or peeing
    • Redness in the vaginal area
  • Severe and persistent joint pain. If you experience severe and persistent joint pain, contact your doctor right away. Do not stop taking your medication. Your doctor will decide if your medication is the possible cause of severe  joint pain and will discontinue the drug if appropriate.
  • Urinary Tract Infections (UTIs). Tell your healthcare provider right away if you have some or all of the following symptoms of
    • Having pain or burning when urinating (peeing)
    • Having a fever
    • Feeling tired
    • Having an urge to urinate or pee often
    • Having urine or pee that smells bad
    • Urine that looks red or cloudy
    • Pain in the lower back

Do not take Glyxambi if you:

  • are allergic to Glyxambi or to any of its ingredients
  • have severe kidney damage or are on dialysis

Glyxambi Usage

Take Glyxambi exactly as prescribed.

Glyxambi comes in a tablet form, and is taken once daily.

Glyxambi can be taken with or without food.

If you miss a dose, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of Glyxambi at the same time.

Glyxambi Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common
  • Bladder pain
  • bloody or cloudy urine
  • difficult, burning, or painful urination
  • frequent urge to urinate
  • lower back or side pain
Incidence not known
  • Anxiety
  • bloating
  • blurred vision
  • chills
  • cold sweats
  • confusion
  • constipation
  • cool, pale skin
  • darkened urine
  • depression
  • dizziness
  • dry mouth
  • fast heartbeat
  • fever
  • flushed, dry skin
  • fruit-like breath odor
  • headache
  • increased hunger
  • increased thirst
  • indigestion
  • large, hard skin blisters
  • large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
  • loss of appetite
  • loss of consciousness
  • nausea
  • nightmares
  • pains in the stomach, side, or abdomen, radiating to the back
  • seizures
  • severe joint pain
  • shakiness
  • slurred speech
  • stomach pain
  • sweating
  • troubled breathing
  • unexplained weight loss
  • unusual tiredness or weakness
  • vomiting
  • yellow eyes or skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common
  • Body aches or pain
  • difficulty with breathing
  • ear congestion
  • headache
  • loss of voice
  • runny or stuffy nose
  • sneezing
  • sore throat
Incidence not known
  • Discharge with a strong odor from the penis
  • redness, itching, swelling, or pain around the penis
  • vaginal discharge, itching, or odor

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of fluid and electrolyte problems like mood changes, confusion, muscle pain or weakness, a heartbeat that does not feel normal, very bad dizziness or passing out, fast heartbeat, more thirst, seizures, feeling very tired or weak, not hungry, unable to pass urine or change in the amount of urine produced, dry mouth, dry eyes, or very bad upset stomach or throwing up.
  • Signs of kidney problems like unable to pass urine, change in how much urine is passed, blood in the urine, or a big weight gain.
  • Signs of too much acid in the blood (acidosis) like confusion; fast breathing; fast heartbeat; a heartbeat the does not feel normal; very bad stomach pain, upset stomach, or throwing up; feeling very sleepy; shortness of breath; or feeling very tired or weak.
  • Signs of a urinary tract infection (UTI) like blood in the urine, burning or pain when passing urine, feeling the need to pass urine often or right away, fever, lower stomach pain, or pelvic pain.
  • For females, vaginal yeast infection. Report itching or discharge.
  • For men, yeast infection of the penis. Report pain, swelling, rash, or discharge.
  • Flaking, peeling, or swelling of the skin.
  • Trouble swallowing.
  • Very bad headache.
  • Drugs like this one may cause joint pain that can be very bad and disabling. Call your doctor right away if you have very bad joint pain or any joint pain that does not go away.
  • A skin reaction called bullous pemphigoid has happened with drugs like this one. Sometimes, people have had to go to the hospital. Call your doctor right away if you have blisters or if your skin starts to break down.

What are some other side effects of Glyxambi?

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

  • Sore throat.
  • Stuffy nose.
  • Runny nose.
  • Nose or throat irritation.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Adverse reactions

 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 practice.

Empagliflozin and Linagliptin
The safety of concomitantly administered empagliflozin (daily dose 10 mg or 25 mg) and linagliptin (daily dose 5 mg) has been evaluated in a total of 1363 patients with type 2 diabetes treated for up to 52 weeks in active-controlled clinical trials. The most common adverse reactions with concomitant administration of empagliflozin and linagliptin based on a pooled analyses of these studies are shown in Table 1.

Table 1 Adverse Reactions Reported in ≥5% of Patients Treated with Empagliflozin and Linagliptin
aPredefined adverse event grouping, including, but not limited to, urinary tract infection, asymptomatic bacteriuria, cystitis
  Glyxambi
10 mg/5 mg
n=272
Glyxambi
25 mg/5 mg
n=273
  n (%) n (%)
Urinary tract infectiona 34 (12.5) 31 (11.4)
Nasopharyngitis 16 (5.9) 18 (6.6)
Upper respiratory tract infection 19 (7.0) 19 (7.0)

Empagliflozin
Adverse reactions that occurred in ≥2% of patients receiving empagliflozin and more commonly than in patients given placebo included (10 mg, 25 mg, and placebo): urinary tract infection (9.3%, 7.6%, and 7.6%), female genital mycotic infections (5.4%, 6.4%, and 1.5%), upper respiratory tract infection (3.1%, 4.0%, and 3.8%), increased urination (3.4%, 3.2%, and 1.0%), dyslipidemia (3.9%, 2.9%, and 3.4%), arthralgia (2.4%, 2.3%, and 2.2%), male genital mycotic infections (3.1%, 1.6%, and 0.4%), and nausea (2.3%, 1.1%, and 1.4%).

Thirst (including polydipsia) was reported in 0%, 1.7%, and 1.5% for placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively.

Empagliflozin causes an osmotic diuresis, which may lead to intravascular volume contraction and adverse reactions related to volume depletion.

Linagliptin
Adverse reactions reported in ≥2% of patients treated with linagliptin 5 mg and more commonly than in patients treated with placebo included: nasopharyngitis (7.0% and 6.1%), diarrhea (3.3% and 3.0%), and cough (2.1% and 1.4%).

Other adverse reactions reported in clinical studies with treatment of linagliptin monotherapy were hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperreactivity) and myalgia.

In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient year exposure while being treated with linagliptin compared with 3.7 cases per 10,000 patient year exposure while being treated with comparator (placebo and active comparator, sulfonylurea). Three additional cases of pancreatitis were reported following the last administered dose of linagliptin.

Hypoglycemia
Table 2 summarizes the reports of hypoglycemia with empagliflozin and linagliptin over a treatment period of 52 weeks.

Table 2 Incidence of Overalla and Severeb Hypoglycemic Adverse Reactions
aOverall hypoglycemic events: plasma or capillary glucose of less than or equal to 70 mg/dL or requiring assistance
bSevere hypoglycemic events: requiring assistance regardless of blood glucose

Add-on to Metformin
(52 weeks)
Glyxambi
10 mg/5 mg
(n=136)
Glyxambi
25 mg/5 mg
(n=137)
Overall (%) 2.2% 3.6%
Severe (%) 0% 0%

Laboratory Tests
Empagliflozin and Linagliptin
Changes in laboratory findings in patients treated with the combination of empagliflozin and linagliptin included increases in cholesterol and hematocrit compared to baseline.

Empagliflozin
Increase in Low-Density Lipoprotein Cholesterol (LDL-C): Dose-related increases in low-density lipoprotein cholesterol (LDL-C) were observed in patients treated with empagliflozin. LDL-C increased by 2.3%, 4.6%, and 6.5% in patients treated with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively [see Warnings and Precautions (5.10)]. The range of mean baseline LDL-C levels was 90.3 to 90.6 mg/dL across treatment groups.

Increase in Hematocrit: Median hematocrit decreased by 1.3% in placebo and increased by 2.8% in empagliflozin 10 mg and 2.8% in empagliflozin 25 mg treated patients. At the end of treatment, 0.6%, 2.7%, and 3.5% of patients with hematocrits initially within the reference range had values above the upper limit of the reference range with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively.

Linagliptin
Increase in Uric Acid: Changes in laboratory values that occurred more frequently in the linagliptin group and ≥1% more than in the placebo group were increases in uric acid (1.3% in the placebo group, 2.7% in the linagliptin group).

Increase in Lipase: In a placebo-controlled clinical trial with linagliptin in type 2 diabetes mellitus patients with micro- or macroalbuminuria, a mean increase of 30% in lipase concentrations from baseline to 24 weeks was observed in the linagliptin arm compared to a mean decrease of 2% in the placebo arm. Lipase levels above 3 times upper limit of normal were seen in 8.2% compared to 1.7% patients in the linagliptin and placebo arms, respectively.

 Postmarketing Experience

Additional adverse reactions have been identified during postapproval use of linagliptin and empagliflozin. 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.

  • Acute pancreatitis, including fatal pancreatitis [see Indications and Usage (1) and Warnings and Precautions (5.1)]
  • Ketoacidosis [see Warnings and Precautions (5.4)]
  • Urosepsis and pyelonephritis [see Warnings and Precautions (5.6)]
  • Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions [see Warnings and Precautions (5.9)]
  • Severe and disabling arthralgia [see Warnings and Precautions (5.11)]
  • Bullous pemphigoid [see Warnings and Precautions (5.12)]                          
  • Rash
  • Mouth ulceration, stomatitis

Use in specific populations

 Pregnancy

Risk Summary
Based on animal data showing adverse renal effects, from empagliflozin, Glyxambi is not recommended during the second and third trimesters of pregnancy.

The limited available data with Glyxambi, linagliptin, or empagliflozin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects and miscarriage.  There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations).

In animal studies, adverse renal changes were observed in rats when empagliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy. Doses approximately 13-times the maximum clinical dose caused renal pelvic and tubule dilatations that were reversible. No adverse developmental effects were observed when the combination of linagliptin and empagliflozin was administered to pregnant rats during the period of organogenesis at exposures approximately 253 and 353 times the clinical exposure (see Data).

The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20-25% in women with HbA1c >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 2-4% and 15-20%, respectively.

Clinical Considerations
Disease-associated maternal and/or embryo/fetal risk: Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, still birth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity.

Data
Animal Data
The combined components administered during the period of organogenesis were not teratogenic in rats up to and including a combined dose of 700 mg/kg/day empagliflozin and 140 mg/kg/day linagliptin, which is 253 and 353 times the clinical exposure. A pre- and post-natal development study was not conducted with the combined components of Glyxambi.

Empagliflozin:  Empagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 1, 10, 30 and 100 mg/kg/day caused increased kidney weights and renal tubular and pelvic dilatation at 100 mg/kg/day, which approximates 13-times the maximum clinical dose of 25 mg, based on AUC. These findings were not observed after a 13 week drug-free recovery period. These outcomes occurred with drug exposure during periods of renal development in rats that correspond to the late second and third trimester of human renal development.

In embryo-fetal development studies in rats and rabbits, empagliflozin was administered for intervals coinciding with the first trimester period of organogenesis in humans. Doses up to 300 mg/kg/day, which approximates 48-times (rats) and 128-times (rabbits) the maximum clinical dose of 25 mg (based on AUC), did not result in adverse developmental effects. In rats, at higher doses of empagliflozin causing maternal toxicity, malformations of limb bones increased in fetuses at 700 mg/kg/day or 154-times the 25 mg maximum clinical dose. Empagliflozin crosses the placenta and reaches fetal tissues in rats. In the rabbit, higher doses of empagliflozin resulted in maternal and fetal toxicity at 700 mg/kg/day, or 139-times the 25 mg maximum clinical dose.

In pre- and postnatal development studies in pregnant rats, empagliflozin was administered from gestation day 6 through to lactation day 20 (weaning) at up to 100 mg/kg/day (approximately 16 times the 25 mg maximum clinical dose) without maternal toxicity.  Reduced body weight was observed in the offspring at greater than or equal to 30 mg/kg/day (approximately 4 times the 25 mg maximum clinical dose).

Linagliptin:  No adverse developmental outcome was observed when linagliptin was administered to pregnant Wistar Han rats and Himalayan rabbits during the period of organogenesis at doses up to 240 mg/kg/day and 150 mg/kg/day, respectively. These doses represent approximately 943 times (rats) and 1943 times (rabbits) the 5 mg maximum clinical dose, based on exposure.  No adverse functional, behavioral, or reproductive outcome was observed in offspring following administration of linagliptin to Wistar Han rats from gestation day 6 to lactation day 21 at a dose 49 times the maximum recommended human dose, based on exposure.

Linagliptin crosses the placenta into the fetus following oral dosing in pregnant rats and rabbits.

 Lactation

Risk Summary
There is no information regarding the presence of Glyxambi, or its individual components in human milk, the effects on the breastfed infant, or the effects on milk production. Empagliflozin and linagliptin are present in rat milk (see Data). 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, including the potential for empagliflozin to affect postnatal renal development, in a breastfed infant, advise patients that use of Glyxambi is not recommended while breastfeeding.

Data
Empagliflozin was present at a low level in rat fetal tissues after a single oral dose to the dams at gestation day 18. In rat milk, the mean milk to plasma ratio ranged from 0.634 -5, and was greater than one from 2 to 24 hours post-dose. The mean maximal milk to plasma ratio of 5 occurred at 8 hours post-dose, suggesting accumulation of empagliflozin in the milk. Juvenile rats directly exposed to empagliflozin showed a risk to the developing kidney (renal pelvic and tubular dilatations) during maturation.

 Pediatric Use

Safety and effectiveness of Glyxambi in pediatric patients under 18 years of age have not been established.

 Geriatric Use

Glyxambi
Empagliflozin is associated with osmotic diuresis, which could affect hydration status of patients age 75 years and older.

Empagliflozin
No empagliflozin dosage change is recommended based on age [see Dosage and Administration (2)]. A total of 2721 (32%) patients treated with empagliflozin were 65 years of age and older, and 491 (6%) were 75 years of age and older. Empagliflozin is expected to have diminished efficacy in elderly patients with renal impairment [see Use in Specific Populations (8.6)]. The risk of volume depletion-related adverse reactions increased in patients who were 75 years of age and older to 2.1%, 2.3%, and 4.4% for placebo, empagliflozin 10 mg, and empagliflozin 25 mg. The risk of urinary tract infections increased in patients who were 75 years of age and older to 10.5%, 15.7%, and 15.1% in patients randomized to placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)].

Linagliptin
There were 4040 type 2 diabetes patients treated with linagliptin 5 mg from 15 clinical trials of linagliptin; 1085 (27%) were 65 years and over, while 131 (3%) were 75 years and over. Of these patients, 2566 were enrolled in 12 double-blind placebo-controlled studies; 591 (23%) were 65 years and over, while 82 (3%) were 75 years and over. No overall differences in safety or effectiveness were observed between patients 65 years and over and younger patients. Therefore, no dose adjustment is recommended in the elderly population. While clinical studies of linagliptin have not identified differences in response between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.

 Renal Impairment

Empagliflozin
The efficacy and safety of empagliflozin have not been established in patients with severe renal impairment, with ESRD, or receiving dialysis. Empagliflozin is not expected to be effective in these patient populations [see Dosage and Administration (2.2), Contraindications (4) and Warnings and Precautions (5.3, 5.5)].

The glucose lowering benefit of empagliflozin 25 mg decreased in patients with worsening renal function. The risks of renal impairment [see Warnings and Precautions (5.5)], volume depletion adverse reactions and urinary tract infection-related adverse reactions increased with worsening renal function.

 Hepatic Impairment

Glyxambi may be used in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

Description

Glyxambi tablets contain two oral antihyperglycemic drugs used in the management of type 2 diabetes: empagliflozin and linagliptin.

Empagliflozin
Empagliflozin is an orally-active inhibitor of the sodium-glucose co-transporter (SGLT2).

The chemical name of empagliflozin is D-Glucitol,1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-, (1S).

The molecular formula is C23H27ClO7 and the molecular weight is 450.91. The structural formula is:

Empagliflozin is a white to yellowish, non-hygroscopic powder. It is very slightly soluble in water, sparingly soluble in methanol, slightly soluble in ethanol and acetonitrile; soluble in 50% acetonitrile/water; and practically insoluble in toluene.

Linagliptin
Linagliptin is an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme.

The chemical name of linagliptin is 1H-Purine-2,6-dione, 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]-

The molecular formula is C25H28N8O2 and the molecular weight is 472.54. The structural formula is:

Linagliptin is a white to yellowish, not or only slightly hygroscopic solid substance. It is very slightly soluble in water. Linagliptin is soluble in methanol, sparingly soluble in ethanol, very slightly soluble in isopropanol, and very slightly soluble in acetone.

Glyxambi
Glyxambi tablets for oral administration are available in two dosage strengths containing 10 mg or 25 mg empagliflozin in combination with 5 mg linagliptin. The inactive ingredients of Glyxambi are the following: Tablet Core: mannitol, pregelatinized starch, corn starch, copovidone, crospovidone, talc and magnesium stearate. Coating: hypromellose, mannitol, talc, titanium dioxide, polyethylene glycol and ferric oxide, yellow (10 mg/5 mg) or ferric oxide, red (25 mg/5 mg).

How should I take Glyxambi?

Take Glyxambi exactly as it was prescribed for you. Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Glyxambi is usually taken in the morning. You may take this medicine with or without food.

Your blood sugar will need to be checked often, and you may also need to test the level of ketones your urine. Glyxambi can cause life-threatening ketoacidosis (too much acid in the blood). Even if your blood sugar is normal, contact your doctor if a urine test shows that you have ketones in the urine.

Low blood sugar (hypoglycemia) can happen to everyone who has diabetes. Symptoms include headache, hunger, sweating, irritability, dizziness, nausea, fast heart rate, and feeling anxious or shaky. To quickly treat low blood sugar, always keep a fast-acting source of sugar with you such as fruit juice, hard candy, crackers, raisins, or non-diet soda.

Your doctor can prescribe a glucagon emergency injection kit to use in case you have severe hypoglycemia and cannot eat or drink. Be sure your family and close friends know how to give you this injection in an emergency.

Also watch for signs of high blood sugar (hyperglycemia) such as increased thirst or urination, blurred vision, headache, and tiredness.

Blood sugar levels can be affected by stress, illness, surgery, exercise, alcohol use, or skipping meals. Ask your doctor before changing your dose or medication.

Glyxambi can cause unusual results with certain lab tests for glucose (sugar) in the urine. Tell any doctor who treats you that you are using Glyxambi.

Store at room temperature away from moisture and heat.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. A Glyxambi overdose can cause life threatening hypoglycemia.

Symptoms of severe hypoglycemia include extreme weakness, confusion, tremors, sweating, fast heart rate, trouble speaking, nausea, vomiting, rapid breathing, fainting, and seizure (convulsions).

In Summary

Common side effects of Glyxambi include: urinary tract infection. Other side effects include: increased ldl cholesterol. See below for a comprehensive list of adverse effects.

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