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EMPAGLIFLOZIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Empagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor used to improve glycemic control in adults with type 2 diabetes mellitus. It is indicated as an adjunct to diet and exercise.

Specific Substances

    1) BI-10773
    2) CAS 864070-44-0
    1.2.1) MOLECULAR FORMULA
    1) C23-H27-Cl-O7 (Prod Info JARDIANCE(R) oral tablets, 2014)

Available Forms Sources

    A) FORMS
    1) Empagliflozin is available as 10 mg and 25 mg film-coated tablets (Prod Info JARDIANCE(R) oral tablets, 2014).
    B) USES
    1) Empagliflozin is used to treat adult patients with type 2 diabetes mellitus in conjunction with diet and exercise to improve glycemic control (Prod Info JARDIANCE(R) oral tablets, 2014).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Empagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor used to improve glycemic control in adults with type 2 diabetes mellitus. It is indicated as an adjunct to diet and exercise.
    B) PHARMACOLOGY: Empagliflozin lowers the renal threshold for glucose and increases urinary glucose excretion by interfering with the reabsorption of renally-filtered glucose across the tubular lumen of the proximal renal tubules.
    C) EPIDEMIOLOGY: Overdose has not been reported.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse effects following therapeutic administration, with an incidence rate of at least 5%, include urinary tract infections and female genital mycotic infections.
    2) LESS COMMON: Other adverse effects include hypotension, dyslipidemia, increased urination, increased thirst, nausea, an increase in hematocrit, renal impairment, arthralgia, upper respiratory tract infections, and male genital mycotic infections. Ingestion of empagliflozin alone is not expected to cause severe hypoglycemia, but when combined with insulin or insulin secretogogues, hypoglycemia may develop.
    E) WITH POISONING/EXPOSURE
    1) Toxicity following overdose has not been reported. Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses.
    0.2.20) REPRODUCTIVE
    A) Empagliflozin, empagliflozin/linagliptin, and empagliflozin/metformin are classified as FDA pregnancy category C. Although there are no adequate or well controlled studies of empagliflozin use in pregnant women, based on animal studies, empagliflozin may affect renal development and maturation.

Laboratory Monitoring

    A) Monitor vital signs and renal function.
    B) Ingestion of empagliflozin alone is not expected to cause severe hypoglycemia, but when combined with insulin or insulin secretogogues severe hypoglycemia may develop. In patients with empagliflozin overdose who are also taking insulin or insulin secretogogues, obtain hourly blood glucose and monitor for clinical evidence of hypoglycemia for 8 to 12 hours.
    C) Plasma levels are not clinically useful for managing overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Overdose has not been reported. HYPOTENSION: Monitor vital signs. Assess fluid status; osmotic diuresis and intravascular depletion may develop. Replace fluids (oral or IV fluids) as indicated. HYPOGLYCEMIA: Ingestion of empagliflozin alone is not expected to cause severe hypoglycemia, but when combined with insulin or insulin secretogogues severe hypoglycemia may develop. In patients with empagliflozin overdose who are also taking insulin or insulin secretogogues, obtain hourly blood glucose and monitor for clinical evidence of hypoglycemia for 8 to 12 hours. DIET: If the patient is awake and alert, offer carbohydrates. If hypoglycemia persists or becomes severe, treat hypoglycemia with IV dextrose boluses as needed. May need to repeat in patients with profound hypoglycemia. A dextrose infusion may be needed in patients in whom recurrent hypoglycemia develops, despite feeding and dextrose boluses. Titrate carefully to reduce the potential for reactive hypoglycemia. NOT RECOMMENDED: Prophylactic dextrose administration is not recommended in patients who do not become hypoglycemic, as it may make it difficult to distinguish patients who become hypoglycemic and require prolonged hospitalization from those who remain asymptomatic and may be discharged sooner.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. HYPOTENSION: Treat moderate to severe hypotension with IV fluids, dopamine or norepinephrine as necessary. HYPOGLYCEMIA: Ingestion of empagliflozin alone is not expected to cause severe hypoglycemia, but when combined with insulin or insulin secretogogues severe hypoglycemia may develop. In patients with empagliflozin overdose who are also taking insulin or insulin secretogogues, obtain hourly blood glucose and monitor for clinical evidence of hypoglycemia for 8 to 12 hours. Treat hypoglycemia with IV dextrose boluses as needed. May need to repeat in patients with profound hypoglycemia. A dextrose infusion may be needed in patients in whom recurrent hypoglycemia develops, despite feeding and dextrose boluses. Titrate carefully to reduce the potential for reactive hypoglycemia.
    C) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Airway management is very unlikely to be necessary unless other toxic agents have been administered concurrently.
    E) ANTIDOTE
    1) None.
    F) HYPOGLYCEMIA
    1) DEXTROSE: Give dextrose if symptomatic or BS less than 60 mg/dL. DOSE: ADULT: 0.5 to 1 g/kg of D50W (50% dextrose) IV push; ADOLESCENT: 0.5 to 1 g/kg (1 to 2 mL/kg) of 50% dextrose IV push; INFANT and CHILD: 0.5 to 1 g/kg (2 to 4 mL/kg) of 25% dextrose IV push. Follow with an infusion of 10% dextrose; titrate to a BS of 100 mg/dL. DIET: When the patient is awake and alert, supplement IV glucose with carbohydrate intake.
    G) HYPOTENSIVE EPISODE
    1) Administer IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine, if unresponsive to fluids.
    H) ENHANCED ELIMINATION
    1) Hemodialysis is unlikely to be of value because of the high degree of protein binding (86%) and large volume of distribution (74 L).
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: All children with ingestions should be sent to a healthcare facility for evaluation and treatment. Adults with a deliberate overdose should be sent to a healthcare facility for evaluation and treatment. Diabetic adults with an inadvertent ingestion of an extra dose who are asymptomatic can be monitored at home. Asymptomatic non-diabetic adults with an inadvertent ingestion of one or two pills can be monitored at home.
    2) OBSERVATION CRITERIA: There is no information on the onset or duration of hypoglycemia after overdose of these patients; however, due to the prolonged half-life of empagliflozin patients may need to be monitored for a minimum of 8 to 12 hours if they are also taking insulin or an insulin secretagogue.
    3) ADMISSION CRITERIA: Patients who develop hypoglycemia should be admitted for a minimum of 24 hours for frequent blood glucose monitoring. They should only be discharged when free of symptoms and are able to maintain euglycemia without supplemental dextrose for 8 hours.
    4) CONSULT CRITERIA: Consult a medical toxicologist or a poison center for assistance with medical management in patients with severe overdose or in whom the diagnosis is unclear.
    J) PITFALLS
    1) There is no information on the onset and duration of hypoglycemia after overdose of empagliflozin in patients who take insulin or an insulin secretagogue. Patients who develop hypoglycemia should not be discharged until they have been able to maintain euglycemia for at least 8 hours without supplemental dextrose.
    K) PHARMACOKINETICS
    1) Protein binding is approximately 86% and volume of distribution is approximately 74 L. Primary route of empagliflozin metabolism is suggested to be glucuronidation via UGT2B7, UGT1A3, UGT1A8, and UGT1A9. There are no major metabolites in the plasma. Approximately 54.4% of a radiolabeled dose of oral empagliflozin was recovered in the urine, half of which was identified as unchanged drug, and approximately 41.2% of a radiolabeled dose of oral empagliflozin was recovered in the feces, most of which was identified as unchanged drug. Terminal half-life is 12.4 hours.
    L) DIFFERENTIAL DIAGNOSIS
    1) Exposure to other hypoglycemic agents such as insulin or sulfonylureas. The differential diagnosis of hypoglycemia is otherwise very broad and includes sepsis, liver failure, malnutrition, neoplasm, adrenal insufficiency, insulinoma and others.

Range Of Toxicity

    A) TOXICITY: A toxic dose has not been established. There have been no reports of overdose with empagliflozin, although a 200-mg one-time dose was administered to healthy volunteers during clinical trials, with no evidence of QTc interval prolongation.
    B) THERAPEUTIC DOSE: ADULTS: The recommended initial dose is 10 mg orally once daily in the morning. If tolerated, the dose may be increased to 25 mg orally once daily. PEDIATRIC: Safety and efficacy of empagliflozin in pediatric patients have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Empagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor used to improve glycemic control in adults with type 2 diabetes mellitus. It is indicated as an adjunct to diet and exercise.
    B) PHARMACOLOGY: Empagliflozin lowers the renal threshold for glucose and increases urinary glucose excretion by interfering with the reabsorption of renally-filtered glucose across the tubular lumen of the proximal renal tubules.
    C) EPIDEMIOLOGY: Overdose has not been reported.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse effects following therapeutic administration, with an incidence rate of at least 5%, include urinary tract infections and female genital mycotic infections.
    2) LESS COMMON: Other adverse effects include hypotension, dyslipidemia, increased urination, increased thirst, nausea, an increase in hematocrit, renal impairment, arthralgia, upper respiratory tract infections, and male genital mycotic infections. Ingestion of empagliflozin alone is not expected to cause severe hypoglycemia, but when combined with insulin or insulin secretogogues, hypoglycemia may develop.
    E) WITH POISONING/EXPOSURE
    1) Toxicity following overdose has not been reported. Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension due to intravascular volume contraction has been reported. A reduction in intravascular volume may occur secondary to osmotic diuresis caused by empagliflozin. According to pooled data from 5 placebo-controlled clinical studies, volume depletion-related adverse events, including hypotension, orthostatic hypotension, hypovolemia, dehydration, and syncope, were reported in 0.5% and 0.3% of patients treated with empagliflozin 10 mg (n=999) and 25 mg (n=977), respectively, compared with 0.3% of patients who received placebo (n=995) (Prod Info JARDIANCE(R) oral tablets, 2014).
    b) Elderly patients, patients with renal impairment, patients with low systolic blood pressure, and patients receiving diuretics concomitantly are particularly susceptible to hypotension with empagliflozin (Prod Info JARDIANCE(R) oral tablets, 2014).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) UPPER RESPIRATORY INFECTION
    1) WITH THERAPEUTIC USE
    a) According to pooled data from 5 placebo-controlled studies, upper respiratory tract infection was reported in 3.1% and 4% of patients treated with empagliflozin 10 mg (n=999) and 25 mg (n=977), respectively, compared with 3.8% of patients who received placebo (n=995) (Prod Info JARDIANCE(R) oral tablets, 2014).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA
    1) WITH THERAPEUTIC USE
    a) According to pooled data from 5 placebo-controlled studies, nausea was reported in 2.3% and 1.1% of patients treated with empagliflozin 10 mg (n=999) and 25 mg (n=977), respectively, compared with 1.4% of patients who received placebo (n=995) (Prod Info JARDIANCE(R) oral tablets, 2014).
    B) INCREASED THIRST
    1) WITH THERAPEUTIC USE
    a) According to pooled data from 5 placebo-controlled studies, increased thirst was reported in 1.7% and 1.5% of patients treated with empagliflozin 10 mg (n=999) and 25 mg (n=977), respectively, compared with 0% of patients who received placebo (n=995) (Prod Info JARDIANCE(R) oral tablets, 2014).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) URINARY TRACT INFECTIOUS DISEASE
    1) WITH THERAPEUTIC USE
    a) According to pooled data from 5 placebo-controlled studies, urinary tract infections, including asymptomatic bacteriuria and cystitis, were reported in 9.3% and 7.6% of patients treated with empagliflozin 10 mg (n=999) and 25 mg (n=977), respectively, compared with 7.6% of patients who received placebo (n=995) (Prod Info JARDIANCE(R) oral tablets, 2014).
    B) INCREASED FREQUENCY OF URINATION
    1) WITH THERAPEUTIC USE
    a) According to pooled data from 5 placebo-controlled studies, increased urination, including pollakiuria, polyuria, and nocturia, was reported in 3.4% and 3.2% of patients treated with empagliflozin 10 mg (n=999) and 25 mg (n=977), respectively, compared with 1% of patients who received placebo (n=995) (Prod Info JARDIANCE(R) oral tablets, 2014).
    1) Nocturia was specifically reported in 0.3% and 0.8% of patients who received empagliflozin 10 mg (n=999) and 25 mg (n=977), respectively, compared with 0.4% of patients who received placebo (n=995) (Prod Info JARDIANCE(R) oral tablets, 2014).
    C) RENAL IMPAIRMENT
    1) WITH THERAPEUTIC USE
    a) Renal adverse reactions, including increased serum creatinine and decreased estimated GFR, were reported in patients treated with empagliflozin. Elderly patients and patients with pre-existing renal impairment were more susceptible to these events (Prod Info JARDIANCE(R) oral tablets, 2014).
    D) MYCOSIS
    1) WITH THERAPEUTIC USE
    a) FEMALE: According to pooled data from 5 placebo-controlled studies, female genital mycotic infections, including vulvovaginal mycotic infection, vaginal infection, vulvovaginal candidiasis, vulvovaginitis, genital infection, genital candidiasis, fungal genital infection, vulvitis, genitourinary tract infection, cervicitis, fungal urogenital infection, and bacterial vaginitis, were reported in 5.4% and 6.4% of female patients treated with empagliflozin 10 mg (n=443) and 25 mg (n=420), respectively, compared with 1.5% of female patients who received placebo (n=481) (Prod Info JARDIANCE(R) oral tablets, 2014).
    b) MALE: According to pooled data from 5 placebo-controlled studies, male genital mycotic infections, including balanitis, fungal genital infection, balanitis candida, penile infection, balanoposthitis, genitourinary tract infection, and scrotal abscess were reported in 3.1% and 1.6% of male patients treated with empagliflozin 10 mg (n=556) and 25 mg (n=557), respectively, compared with 0.4% of male patients who received placebo (n=514) (Prod Info JARDIANCE(R) oral tablets, 2014).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMATOCRIT - PCV - HIGH
    1) WITH THERAPEUTIC USE
    a) According to pooled data from 4 placebo-controlled studies, the median hematocrit increased by 2.8% in patients treated with 10 mg and 25 mg empagliflozin, compared with a decrease in the hematocrit of 1.3% in placebo-treated patients. By the end of treatment, 2.7% and 3.5% of patients with hematocrit values within the reference range initially and were treated with empagliflozin 10 mg and 25 mg, respectively, had values above the reference range limit, compared with 0.6% of patients who received placebo (Prod Info JARDIANCE(R) oral tablets, 2014).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) According to pooled data from 5 placebo-controlled studies, arthralgia was reported in 2.4% and 2.3% of patients treated with empagliflozin 10 mg (n=999) and 25 mg (n=977), respectively, compared with 2.2% of patients who received placebo (n=995) (Prod Info JARDIANCE(R) oral tablets, 2014).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPOGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) Minor episodes of hypoglycemia were reported when empagliflozin was combined with other antidiabetic agents. Hypoglycemia was most pronounced when combined with insulin or an insulin secretagogue (ie, sulfonylureas) during clinical trials (Prod Info JARDIANCE(R) oral tablets, 2014).
    B) DYSLIPIDEMIA
    1) WITH THERAPEUTIC USE
    a) According to pooled data from 5 placebo-controlled studies, dyslipidemia was reported in 3.9% and 2.9% of patients treated with empagliflozin 10 mg (n=999) and 25 mg (n=977), respectively, compared with 3.4% of patients who received placebo (n=995) (Prod Info JARDIANCE(R) oral tablets, 2014).

Reproductive

    3.20.1) SUMMARY
    A) Empagliflozin, empagliflozin/linagliptin, and empagliflozin/metformin are classified as FDA pregnancy category C. Although there are no adequate or well controlled studies of empagliflozin use in pregnant women, based on animal studies, empagliflozin may affect renal development and maturation.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) EMPAGLIFLOZIN/LINAGLIPTIN
    a) At the time of this review, no data were available to assess the teratogenic potential of this agent (Prod Info GLYXAMBI(R) oral tablets, 2015).
    B) ANIMAL STUDIES
    1) EMPAGLIFLOZIN
    a) There are no adequate and well-controlled studies of empagliflozin in pregnant women. Embryofetal development studies in rats administered maternally toxic doses of empagliflozin 154 times the maximum human dose (MHD) revealed increased fetal limb bone malformations. Studies in pregnant rats administered empagliflozin doses approximately 16 times the MHD from gestation day 6 through lactation day 20 revealed no maternal toxicity. However, at doses about 4 times the MHD, reduced offspring body weights were observed. In another study, maternal and fetal toxicity occurred in rabbits after the administration of 139 times the MHD (Prod Info JARDIANCE(R) oral tablets, 2016).
    2) EMPAGLIFLOZIN/LINAGLIPTIN
    a) RATS: Empagliflozin/linagliptin was not teratogenic in rats up to and including a combined dose of 700 mg/kg/day empagliflozin and 140 mg/kg/day linagliptin (253 and 353 times the clinical exposure). In rats, dose-related reduced body weight gain and reduced food consumption resulted from a combination of greater than or equal to 300 mg/kg/day empagliflozin and 60 mg/kg/day linagliptin (99 and 227 times the clinical exposure) (Prod Info GLYXAMBI(R) oral tablets, 2015).
    3) EMPAGLIFLOZIN/METFORMIN
    a) Coadministration of empagliflozin and metformin in pregnant animals did not result in teratogenicity at exposures up to 35 times the clinical AUC exposure (Prod Info SYNJARDY(R) oral tablets, 2015).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) EMPAGLIFLOZIN/LINAGLIPTIN
    a) At the time of this review, no data were available to assess the potential effects of exposure to empagliflozin/linagliptin during pregnancy in humans (Prod Info GLYXAMBI(R) oral tablets, 2015).
    B) PREGNANCY CATEGORY
    1) EMPAGLIFLOZIN
    a) Empagliflozin is classified as FDA pregnancy category C (Prod Info JARDIANCE(R) oral tablets, 2016).
    b) There are no adequate or well controlled studies of empagliflozin use in pregnant women. Animal studies have shown that empagliflozin crosses the placenta and may adversely affect renal development. Accordingly, consider using alternative therapies during pregnancy, especially the second and third trimesters The manufacturer recommends the use of empagliflozin during pregnancy only if the potential maternal benefit outweighs the potential fetal risk (Prod Info JARDIANCE(R) oral tablets, 2016).
    c) Embryofetal studies in rabbits administered empagliflozin doses 139 times the maximum human dose showed maternal and fetal toxicity (Prod Info JARDIANCE(R) oral tablets, 2016).
    2) EMPAGLIFLOZIN/LINAGLIPTIN
    a) Empagliflozin/linagliptin is classified as FDA pregnancy category C (Prod Info GLYXAMBI(R) oral tablets, 2015).
    b) There are no adequate or well controlled studies of empagliflozin/linagliptin use in pregnant women. In animal studies, the individual substances empagliflozin and linagliptin both cross the placenta. Due to the lack of human safety information, empagliflozin/linagliptin should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus (Prod Info GLYXAMBI(R) oral tablets, 2015).
    3) EMPAGLIFLOZIN/METFORMIN
    a) Empagliflozin/metformin is classified as FDA pregnancy category C (Prod Info SYNJARDY(R) oral tablets, 2015).
    b) Administer empagliflozin/metformin hydrochloride combination to a pregnant woman only if the potential benefit outweighs the potential risk (Prod Info SYNJARDY(R) oral tablets, 2015).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) EMPAGLIFLOZIN
    a) It is unknown whether empagliflozin is excreted in human breast milk; however, its use during breastfeeding may adversely affect the developing human kidney (Prod Info JARDIANCE(R) oral tablets, 2016).
    2) EMPAGLIFLOZIN/LINAGLIPTIN
    a) It is unknown whether the combined components of empagliflozin/linagliptin are excreted into human breast milk (Prod Info GLYXAMBI(R) oral tablets, 2015).
    B) EMPAGLIFLOZIN/METFORMIN
    1) Metformin is known to be secreted into human milk; however, no effects on breastfed infants have been reported. Empagliflozin is excreted into the milk of lactating animals at a dose 5 times higher than that of maternal plasma and because kidney development occurs in utero and during the first 2 years of life, there is an increased risk of harm to a developing human kidney (Prod Info SYNJARDY(R) oral tablets, 2015).
    2) Empagliflozin/metformin hydrochloride combination should not be used by nursing mothers (Prod Info SYNJARDY(R) oral tablets, 2015).
    C) ANIMAL STUDIES
    1) EMPAGLIFLOZIN
    a) Animal studies have shown that empagliflozin is excreted in lactating rats reaching concentrations up to 5 times higher than that of maternal plasma (Prod Info JARDIANCE(R) oral tablets, 2016).
    2) EMPAGLIFLOZIN/LINAGLIPTIN
    a) Animal data have shown excretion of empagliflozin and linagliptin in milk (Prod Info GLYXAMBI(R) oral tablets, 2015).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) EMPAGLIFLOZIN
    a) There was no evidence of fertility impairment in male or female rats administered empagliflozin at 155 times the maximum human dose (Prod Info JARDIANCE(R) oral tablets, 2016).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) NEOPLASMS
    1) During 2-year carcinogenicity studies conducted in CD-1 mice and Wister rats, an increased incidence of mesenteric lymph node hemangiomas occurred in male rats given empagliflozin at doses of 700 mg/kg/day (approximately 42 times the maximum clinical dose of 25 mg). Renal tubule adenomas and carcinomas occurred in male mice who received empagliflozin at doses of 1000 mg/kg/day (approximately 45 times the maximum clinical dose). However, empagliflozin did not increase the incidence of tumors in female rats at doses up to 72 times the exposure from the maximum clinical dose of 25 mg (Prod Info JARDIANCE(R) oral tablets, 2014).

Genotoxicity

    A) Based on the results of the in vitro Ames bacterial mutagenicity assay, the in vitro mouse lymphoma cell assay, and the in vivo micronucleus assay in rats, empagliflozin was not mutagenic or clastogenic with or without metabolic activation (Prod Info JARDIANCE(R) oral tablets, 2014).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and renal function.
    B) Ingestion of empagliflozin alone is not expected to cause severe hypoglycemia, but when combined with insulin or insulin secretogogues severe hypoglycemia may develop. In patients with empagliflozin overdose who are also taking insulin or insulin secretogogues, obtain hourly blood glucose and monitor for clinical evidence of hypoglycemia for 8 to 12 hours.
    C) Plasma levels are not clinically useful for managing overdose.
    4.1.2) SERUM/BLOOD
    A) SUMMARY
    1) Monitor renal function.
    2) Plasma levels are not clinically useful for managing overdose.
    B) HYPOGLYCEMIA
    1) Ingestion of empagliflozin alone is not expected to cause severe hypoglycemia, but when combined with insulin or insulin secretogogues severe hypoglycemia may develop. In patients with empagliflozin overdose who are also taking insulin or insulin secretogogues, obtain hourly blood glucose and monitor for clinical evidence of hypoglycemia for 8 to 12 hours.
    4.1.3) URINE
    A) Because empagliflozin increases urinary glucose excretion, glucosuria is an expected finding in patients taking this medication. Measuring urine glucose is not clinically helpful in evaluating for toxicity and overdose (Prod Info JARDIANCE(R) oral tablets, 2014).
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor vital signs.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who develop hypoglycemia should be admitted for a minimum of 24 hours for frequent blood glucose monitoring. They should only be discharged when free of symptoms and are able to maintain euglycemia without supplemental dextrose for 8 hours.
    6.3.1.2) HOME CRITERIA/ORAL
    A) All children with ingestions should be sent to a healthcare facility for evaluation and treatment. Adults with a deliberate overdose should be sent to a healthcare facility for evaluation and treatment. Diabetic adults with an inadvertent ingestion of an extra dose who are asymptomatic can be monitored at home. Asymptomatic non-diabetic adults with an inadvertent ingestion of one or two pills can be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or a poison center for assistance with medical management in patients with severe overdose or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) There is no information on the onset or duration of hypoglycemia after overdose of these patients; however, due to the prolonged half-life of empagliflozin patients may need to be monitored for a minimum of 8 to 12 hours if they are also taking insulin or an insulin secretagogue.

Monitoring

    A) Monitor vital signs and renal function.
    B) Ingestion of empagliflozin alone is not expected to cause severe hypoglycemia, but when combined with insulin or insulin secretogogues severe hypoglycemia may develop. In patients with empagliflozin overdose who are also taking insulin or insulin secretogogues, obtain hourly blood glucose and monitor for clinical evidence of hypoglycemia for 8 to 12 hours.
    C) Plasma levels are not clinically useful for managing overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) Activated charcoal can be used if the patient presents early and is able to protect their airway.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Overdose has not been reported. HYPOTENSION: Monitor vital signs. Assess fluid status; osmotic diuresis and intravascular depletion may develop. Replace fluids (oral or IV fluids) as indicated. HYPOGLYCEMIA: Ingestion of empagliflozin alone is not expected to cause severe hypoglycemia, but when combined with insulin or insulin secretogogues severe hypoglycemia may develop. In patients with empagliflozin overdose who are also taking insulin or insulin secretogogues, obtain hourly blood glucose and monitor for clinical evidence of hypoglycemia for 8 to 12 hours. DIET: If the patient is awake and alert, offer carbohydrates. If hypoglycemia persists or becomes severe, treat hypoglycemia with IV dextrose boluses as needed. May need to repeat in patients with profound hypoglycemia. A dextrose infusion may be needed in patients in whom recurrent hypoglycemia develops, despite feeding and dextrose boluses. Titrate carefully to reduce the potential for reactive hypoglycemia. NOT RECOMMENDED: Prophylactic dextrose administration is not recommended in patients who do not become hypoglycemic, as it may make it difficult to distinguish patients who become hypoglycemic and require prolonged hospitalization from those who remain asymptomatic and may be discharged sooner.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. HYPOTENSION: Treat moderate to severe hypotension with IV fluids, dopamine or norepinephrine as necessary. HYPOGLYCEMIA: Ingestion of empagliflozin alone is not expected to cause severe hypoglycemia, but when combined with insulin or insulin secretogogues severe hypoglycemia may develop. In patients with empagliflozin overdose who are also taking insulin or insulin secretogogues, obtain hourly blood glucose and monitor for clinical evidence of hypoglycemia for 8 to 12 hours. Treat hypoglycemia with IV dextrose boluses as needed. May need to repeat in patients with profound hypoglycemia. A dextrose infusion may be needed in patients in whom recurrent hypoglycemia develops, despite feeding and dextrose boluses. Titrate carefully to reduce the potential for reactive hypoglycemia.
    B) MONITORING OF PATIENT
    1) Monitor vital signs and renal function.
    2) Ingestion of empagliflozin alone is not expected to cause severe hypoglycemia, but when combined with insulin or insulin secretogogues severe hypoglycemia may develop. In patients with empagliflozin overdose who are also taking insulin or insulin secretogogues, obtain hourly blood glucose and monitor for clinical evidence of hypoglycemia for 8 to 12 hours.
    3) Plasma levels are not clinically useful for managing overdose.
    C) HYPOGLYCEMIA
    1) SUMMARY
    a) There is little clinical experience with empagliflozin in overdose. Treatment is symptomatic and supportive. Severe hypoglycemia may develop when empagliflozin is combined with insulin or sulfonylureas, but is not expected after ingestion of empagliflozin alone.
    b) DIET: If the patient is awake and alert, offer carbohydrates.
    2) DEXTROSE
    a) Treat patients who develop laboratory evidence of hypoglycemia (blood glucose less than 60 mg/dL) or significant clinical effects (altered mental status, seizures) with IV dextrose.
    b) DOSE
    1) ADULT
    a) BOLUS: Symptomatic patients require immediate treatment with 0.5 to 1 g/kg of D50W (50% dextrose) IV push (Bosse, 2006). Patients with profound hypoglycemia may require a second dose.
    b) INFUSION: Initiation of a continuous 10% to 20% dextrose intravenous infusion is recommended in any patient who develops recurrent hypoglycemia (Sonnenblick & Shilo, 1986; Palatnick et al, 1991).
    1) Do not stop IV dextrose infusion abruptly. Intravenous dextrose may need to be prolonged or repeated, depending upon the amount ingested.
    2) Slowly decrease the rate of the dextrose infusion with hourly monitoring of blood glucose after blood glucose levels have been stable for 6 to 8 hours.
    3) Prophylactic dextrose administration is NOT recommended in patients who do not become hypoglycemic, as it may make it difficult to distinguish patients who become hypoglycemic and require prolonged hospitalization from those who remain asymptomatic and may be discharged sooner .
    2) PEDIATRIC
    a) NEONATE: BOLUS: 0.2 g/kg IV (2 mL/kg) of D10W (10% dextrose) (Committee on Fetus and Newborn & Adamkin, 2011; Jain et al, 2008; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    b) INFANTS AND CHILDREN: BOLUS: 0.5 to 1 g/kg IV (usually given as 2 to 4 mL/kg/dose) D25W (25% dextrose) (Kleinman et al, 2010; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) ADOLESCENTS: BOLUS: 0.5 to 1 g/kg IV (usually give as 1 to 2 mL/kg/dose) D50W (50% dextrose) (Kleinman et al, 2010; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    d) INFUSION: Initiation of a continuous 10% to 20% dextrose in 0.2% normal saline intravenous infusion is recommended in any patient who develops recurrent hypoglycemia (Sonnenblick & Shilo, 1986; Palatnick et al, 1991). Titrate to maintain blood glucose above 100 mg/dL.
    1) Do not stop the IV dextrose infusion abruptly. Intravenous dextrose may need to be prolonged or repeated, depending upon the amount of ingested.
    2) Slowly decrease the rate of dextrose infusion with hourly monitoring of blood glucose after blood glucose levels have been stable for 6 to 8 hours.
    3) Prophylactic dextrose administration is not recommended in patients who do not become hypoglycemic, as it may make it difficult to distinguish patients who become hypoglycemic and require prolonged hospitalization from those who remain asymptomatic and may be discharged sooner .
    c) PRECAUTIONS
    1) Avoid subcutaneous administration.
    2) Avoid fluid overload with intravenous infusion.
    3) Be cautious in using an IV infusion in patients with congestive heart failure.
    4) Hyperosmolar coma may occur in diabetics receiving an intravenous infusion.
    5) Do not stop the intravenous glucose abruptly.
    D) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is unlikely to be of value because of the high degree of protein binding (86%) and large volume of distribution (74 L) (Prod Info JARDIANCE(R) oral tablets, 2014).

Range Of Toxicity

Summary

    A) TOXICITY: A toxic dose has not been established. There have been no reports of overdose with empagliflozin, although a 200-mg one-time dose was administered to healthy volunteers during clinical trials, with no evidence of QTc interval prolongation.
    B) THERAPEUTIC DOSE: ADULTS: The recommended initial dose is 10 mg orally once daily in the morning. If tolerated, the dose may be increased to 25 mg orally once daily. PEDIATRIC: Safety and efficacy of empagliflozin in pediatric patients have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) EMPAGLIFLOZIN
    1) INITIAL DOSE: 10 mg ORALLY once daily in the morning; may be increased to 25 mg ORALLY once daily (Prod Info JARDIANCE(R) oral tablets, 2014).
    B) EMPAGLIFLOZIN/LINAGLIPTIN
    1) INITIAL DOSE: Empagliflozin 10 mg/linagliptin 5 mg ORALLY once daily in the morning; may be increased to empagliflozin 25 mg/linagliptin 5 mg ORALLY once daily (Prod Info GLYXAMBI(R) oral tablets, 2015).
    C) EMPAGLIFLOZIN/METFORMIN
    1) PATIENTS ON METFORMIN ONLY: Choose strength that will provide empagliflozin 5 mg orally twice daily plus a similar total daily metformin dose, then titrate as needed (Prod Info SYNJARDY(R) oral tablets, 2015)
    2) PATIENTS ON EMPAGLIFLOZIN ONLY: Choose strength that will provide metformin 500 mg orally twice daily plus similar total daily empagliflozin dose, then titrate as needed (Prod Info SYNJARDY(R) oral tablets, 2015).
    3) PATIENTS TAKING BOTH COMPONENTS SEPARATELY: Choose strength that provides the same daily dose of both components when administered orally twice daily, then titrate as needed (Prod Info SYNJARDY(R) oral tablets, 2015).
    4) MAX DOSE: Empagliflozin 25 mg/metformin 2000 mg per day (Prod Info SYNJARDY(R) oral tablets, 2015).
    7.2.2) PEDIATRIC
    A) Safety and efficacy in pediatric patients have not been established (Prod Info SYNJARDY(R) oral tablets, 2015; Prod Info GLYXAMBI(R) oral tablets, 2015; Prod Info JARDIANCE(R) oral tablets, 2014).

Maximum Tolerated Exposure

    A) A toxic dose has not been established. There have been no reports of overdose with empagliflozin; however, as part of clinical trials, healthy subjects were administered 200 mg of empagliflozin as a one-time oral dose. This represents 8 times the maximum recommended daily dose. At this dose, there was no prolongation of QTc intervals. No other information was provided concerning adverse effects at this time (Prod Info JARDIANCE(R) oral tablets, 2014).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, lowers the renal threshold for glucose and increases urinary glucose excretion by interfering with the reabsorption of renally-filtered glucose across the tubular lumen of the proximal renal tubules (Prod Info JARDIANCE(R) oral tablets, 2014).

Physicochemical

Physical Characteristics

    A) Empagliflozin is a white to yellowish non-hygroscopic powder that is very slightly soluble in water, sparingly soluble in methanol, and soluble in 50% acetonitrile/water (Prod Info JARDIANCE(R) oral tablets, 2014).

Molecular Weight

    A) 450.91 (Prod Info JARDIANCE(R) oral tablets, 2014)

References

General Bibliography

    1) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    2) Bosse GM: Antidiabetics and Hypoglycemics. In: Flomenbaum NE, Goldfrank LR, Hoffma RS, et al, eds. Goldfrank's Toxicologic Emergencies, McGraw Hill, New York, NY, 2006, pp 749-763.
    3) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    4) Committee on Fetus and Newborn & Adamkin DH : Postnatal glucose homeostasis in late-preterm and term infants. Pediatrics 2011; 127(3):575-579.
    5) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    6) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    7) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    8) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    9) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    10) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
    11) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    12) Hegenbarth MA & American Academy of Pediatrics Committee on Drugs: Preparing for pediatric emergencies: drugs to consider. Pediatrics 2008; 121(2):433-443.
    13) Jain A , Aggarwal R , Jeevasanker M , et al: Hypoglycemia in the newborn. Indian J Pediatr 2008; 75(1):63-67.
    14) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    15) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    16) Palatnick W, Meatherall RC, & Tenenbein M: Clinical spectrum of sulfonylurea overdose and experience with diazoxide therapy. Arch Intern Med 1991; 151:1859-1862.
    17) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
    18) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    19) Product Information: GLYXAMBI(R) oral tablets, empagliflozin linagliptin oral tablets. Boehringer Ingelheim Pharmaceuticals Inc. (per manufacturer), Ridgefield, CT, 2015.
    20) Product Information: JARDIANCE(R) oral tablets, empagliflozin oral tablets. Boehringer Ingelheim Pharmaceuticals (per manufacturer), Ridgefield, CT, 2014.
    21) Product Information: JARDIANCE(R) oral tablets, empagliflozin oral tablets. Boehringer Ingelheim Pharmaceuticals, Inc. (per FDA), Ridgefield, CT, 2016.
    22) Product Information: SYNJARDY(R) oral tablets, empagliflozin metformin HCl oral tablets. Boehringer Ingelheim Pharmaceuticals, Inc. (per manufacturer), Ridgefield , CT, 2015.
    23) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    24) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    25) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    26) Sonnenblick M & Shilo S: Glibenclamide induced prolonged hypoglycaemia. Age Ageing 1986; 15:185-189.
    27) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    28) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.