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INVOKAMET XR SIDE EFFECTS

  • Generic Name: canagliflozin and metformin hydrochloride
  • Brand Name: Invokamet XR
Last updated on MDtodate: 10/04/2022

SIDE EFFECTS

The following adverse reactions are also discussed elsewhere in the labeling:

  • Lactic Acidosis
  • Lower Limb Amputation
  • Hypotension
  • Ketoacidosis
  • Acute Kidney Injury and Impairment in Renal Function
  • Hyperkalemia
  • Urosepsis and Pyelonephritis
  • Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin
  • Genital Mycotic Infections
  • Hypersensitivity Reactions
  • Bone Fracture
  • Vitamin B12 Deficiency
  • Increases in Low-Density Lipoprotein (LDL-C)

Clinical Studies 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 the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Pool Of Placebo-Controlled Trials

Canagliflozin

The data in Table 1 is derived from four 26-week placebo-controlled trials. In one trial canagliflozin was used as monotherapy and in three trials canagliflozin was used as add-on therapy with metformin (with or without other agents). These data reflect exposure of 1667 patients to canagliflozin and a mean duration of exposure to canagliflozin of 24 weeks with 1275 patients exposed to a combination of canagliflozin and metformin. Patients received canagliflozin 100 mg (N=833), canagliflozin 300 mg (N=834) or placebo (N=646) once daily. The mean daily dose of metformin was 2138 mg (SD 337.3) for the 1275 patients in the three placebo-controlled metformin add-on studies. The mean age of the population was 56 years and 2% were older than 75 years of age. Fifty percent (50%) of the population was male and 72% were Caucasian, 12% were Asian, and 5% were Black or African American. At baseline the population had diabetes for an average of 7.3 years, had a mean HbA1C of 8.0% and 20% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean eGFR 88 mL/min/1.73 m²).

Table 1 shows common adverse reactions associated with the use of canagliflozin. These adverse reactions were not present at baseline, occurred more commonly on canagliflozin than on placebo, and occurred in at least 2% of patients treated with either canagliflozin 100 mg or canagliflozin 300 mg.

Table 1: Adverse Reactions From Pool of Four 26-Week Placebo-Controlled Studies Reported in ≥ 2% of Canagliflozin-Treated Patients*

Adverse Reaction Placebo
N=646
Canagliflozin 100 mg
N=833
Canagliflozin 300 mg
N=834
Urinary tract infections‡ 3.8% 5.9% 4.4%
Increased urination§ 0.7% 5.1% 4.6%
Thirst# 0.1% 2.8% 2.4%
Constipation 0.9% 1.8% 2.4%
Nausea 1.6% 2.1% 2.3%
N=312 N=425 N=430
Female genital mycotic infections† 2.8% 10.6% 11.6%
Vulvovaginal pruritus 0.0% 1.6% 3.2%
N=334 N=408 N=404
Male genital mycotic infections¶ 0.7% 4.2% 3.8%
* The four placebo-controlled trials included one monotherapy trial and three add-on combination trials with metformin, metformin and sulfonylurea, or metformin and pioglitazone.
† Female genital mycotic infections include the following adverse reactions: Vulvovaginal candidiasis, Vulvovaginal mycotic infection, Vulvovaginitis, Vaginal infection, Vulvitis, and Genital infection fungal.
‡ Urinary tract infections include the following adverse reactions: Urinary tract infection, Cystitis, Kidney infection, and Urosepsis.
§ Increased urination includes the following adverse reactions: Polyuria, Pollakiuria, Urine output increased, Micturition urgency, and Nocturia.
¶ Male genital mycotic infections include the following adverse reactions: Balanitis or Balanoposthitis, Balanitis candida, and Genital infection fungal.
# Thirst includes the following adverse reactions: Thirst, Dry mouth, and Polydipsia.
Note: Percentages were weighted by studies. Study weights were proportional to the harmonic mean of the three treatment sample sizes.

 

Abdominal pain was also more commonly reported in patients taking canagliflozin 100 mg (1.8%), 300 mg (1.7%) than in patients taking placebo (0.8%).

Canagliflozin And Metformin

The incidence and type of adverse reactions in the three 26-week placebo-controlled metformin add-on studies, representing a majority of data from the four 26-week placebo-controlled trials, was similar to the adverse reactions described in Table 1. There were no additional adverse reactions identified in the pooling of these three placebo-controlled studies that included metformin relative to the four placebo-controlled studies.

In a trial with canagliflozin as initial combination therapy with metformin , an increased incidence of diarrhea was observed in the canagliflozin and metformin combination groups (4.2%) compared to canagliflozin or metformin monotherapy groups (1.7%).

Pool Of Placebo- And Active-Controlled Trials – Canagliflozin

The occurrence of adverse reactions for canagliflozin was evaluated in a larger pool of patients participating in placebo- and active-controlled trials.

The data combined eight clinical trials and reflect exposure of 6177 patients to canagliflozin. The mean duration of exposure to canagliflozin was 38 weeks with 1832 individuals exposed to canagliflozin for greater than 50 weeks. Patients received canagliflozin 100 mg (N=3092), canagliflozin 300 mg (N=3085) or comparator (N=3262) once daily. The mean age of the population was 60 years and 5% were older than 75 years of age. Fifty-eight percent (58%) of the population was male and 73% were Caucasian, 16% were Asian, and 4% were Black or African

American. At baseline, the population had diabetes for an average of 11 years, had a mean HbA1C of 8.0% and 33% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean eGFR 81 mL/min/1.73 m²).

The types and frequency of common adverse reactions observed in the pool of eight clinical trials were consistent with those listed in Table 1. Percentages were weighted by studies. Study weights were proportional to the harmonic mean of the three treatment sample sizes. In this pool, canagliflozin was also associated with the adverse reactions of fatigue (1.8% with comparator, 2.2% with canagliflozin 100 mg, and 2.0% with canagliflozin 300 mg) and loss of strength or energy (i.e., asthenia) (0.6% with comparator, 0.7% with canagliflozin 100 mg, and 1.1% with canagliflozin 300 mg).

In the pool of eight clinical trials, the incidence rate of pancreatitis (acute or chronic) was 0.1%, 0.2%, and 0.1% receiving comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively.

In the pool of eight clinical trials, hypersensitivity-related adverse reactions (including erythema, rash, pruritus, urticaria, and angioedema) occurred in 3.0%, 3.8%, and 4.2% of patients receiving comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Five patients experienced serious adverse reactions of hypersensitivity with canagliflozin, which included 4 patients with urticaria and 1 patient with a diffuse rash and urticaria occurring within hours of exposure to canagliflozin. Among these patients, 2 patients discontinued canagliflozin. One patient with urticaria had recurrence when canagliflozin was re-initiated.

Photosensitivity-related adverse reactions (including photosensitivity reaction, polymorphic light eruption, and sunburn) occurred in 0.1%, 0.2%, and 0.2% of patients receiving comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Other adverse reactions occurring more frequently on canagliflozin than on comparator were:

Lower Limb Amputation

An approximately 2-fold increased risk of lower limb amputations associated with canagliflozin, a component of INVOKAMET XR, was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled trials evaluating patients with type 2 diabetes who had either established cardiovascular disease or were at risk for cardiovascular disease. Patients in CANVAS and CANVAS-R were followed for an average of 5.7 and 2.1 years, respectively. The amputation data for CANVAS and CANVAS-R are shown in Tables 2 and 3, respectively.

Table 2: CANVAS Amputations

Placebo
N=1441
Canagliflozin 100 mg
N=1445
Canagliflozin 300 mg
N=1441
Canagliflozin (Pooled)
N=2886
Patients with an amputation, n (%) 22 (1.5) 50 (3.5) 45 (3.1) 95 (3.3)
Total amputations 33 83 79 162
Amputation incidence rate (per 1000 patient-years) 2.8 6.2 5.5 5.9
Hazard Ratio (95% CI) 2.24 (1.36, 3.69) 2.01 (1.20, 3.34) 2.12 (1.34, 3.38)
Note: Incidence is based on the number of patients with at least one amputation, and not the total number of amputation events. A patient’s follow-up is calculated from Day 1 to the first amputation event date. Some patients had more than one amputation.

 

Table 3: CANVAS-R Amputations

Placebo
N=2903
Canagliflozin 100 mg (with up-titration to 300 mg)
N=2904
Patients with an amputation, n (%) 25 (0.9) 45 (1.5)
Total amputations 36 59
Amputation incidence rate (per 1000 patient-years) 4.2 7.5
Hazard Ratio (95% CI) 1.80 (1.10, 2.93)
Note: Incidence is based on the number of patients with at least one amputation, and not the total number of amputation events. A patient’s follow-up is calculated from Day 1 to the first amputation event date. Some patients had more than one amputation.

 

Volume Depletion-Related Adverse Reactions

Canagliflozin results in an osmotic diuresis, which may lead to reductions in intravascular volume. In clinical studies, treatment with canagliflozin was associated with a dose-dependent increase in the incidence of volume depletion-related adverse reactions (e.g., hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration). An increased incidence was observed in patients on the 300 mg dose. The three factors associated with the largest increase in volume depletion-related adverse reactions were the use of loop diuretics, moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m²), and age 75 years and older (Table 4.

Table 4: Proportion of Patients With at Least One Volume Depletion-Related Adverse Reaction (Pooled Results from 8 Clinical Trials)

Baseline Characteristic Comparator Group* % Canagliflozin 100 mg % Canagliflozin 300 mg %
Overall population 1.5% 2.3% 3.4%
75 years of age and older† 2.6% 4.9% 8.7%
eGFR less than 60 mL/min/1.73 m²† 2.5% 4.7% 8.1%
Use of loop diuretic† 4.7% 3.2% 8.8%
* Includes placebo and active-comparator groups
† Patients could have more than 1 of the listed risk factors

 

Falls

In a pool of nine clinical trials with mean duration of exposure to canagliflozin of 85 weeks, the proportion of patients who experienced falls was 1.3%, 1.5%, and 2.1% with comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. The higher risk of falls for patients treated with canagliflozin was observed within the first few weeks of treatment.

Impairment In Renal Function

Canagliflozin is associated with a dose-dependent increase in serum creatinine and a concomitant fall in estimated GFR (Table 5). Patients with moderate renal impairment at baseline had larger mean changes.

Table 5: Changes in Serum Creatinine and eGFR Associated with Canagliflozin in the Pool of Four Placebo-Controlled Trials and Moderate Renal Impairment Trial

Placebo
N=646
Canagliflozin 100 mg
N=833
Canagliflozin 300 mg
N=834
Pool of Four Placebo-Controlled Trials Baseline Creatinine (mg/dL) 0.84 0.82 0.82
eGFR (mL/min/1.73 m²) 87.0 88.3 88.8
Week 6 Change Creatinine (mg/dL) 0.01 0.03 0.05
eGFR (mL/min/1.73 m²) -1.6 -3.8 -5.0
End of Treatment Change* Creatinine (mg/dL) 0.01 0.02 0.03
eGFR (mL/min/1.73 m²) -1.6 -2.3 -3.4
Placebo
N=90
Canagliflozin 100 mg
N=90
Canagliflozin 300 mg
N=89
Moderate Renal Impairment Trial Baseline Creatinine (mg/dL) 1.61 1.62 1.63
eGFR (mL/min/1.73 m²) 40.1 39.7 38.5
Week 3 Change Creatinine (mg/dL) 0.03 0.18 0.28
eGFR (mL/min/1.73 m²) -0.7 -4.6 -6.2
End of Treatment Change* Creatinine (mg/dL) 0.07 0.16 0.18
;GFR (mL/min/1.73 m²) -1.5 -3.6 -4.0
* Week 26 in mITT LOCF population

 

In the pool of four placebo-controlled trials where patients had normal or mildly impaired baseline renal function, the proportion of patients who experienced at least one event of significant renal function decline, defined as an eGFR below 80 mL/min/1.73 m² and 30% lower than baseline, was 2.1% with placebo, 2.0% with canagliflozin 100 mg, and 4.1% with canagliflozin 300 mg. At the end of treatment, 0.5% with placebo, 0.7% with canagliflozin 100 mg, and 1.4% with canagliflozin 300 mg had a significant renal function decline.

In a trial carried out in patients with moderate renal impairment with a baseline eGFR of 30 to less than 50 mL/min/1.73 m² (mean baseline eGFR 39 mL/min/1.73 m²), the proportion of patients who experienced at least one event of significant renal function decline, defined as an eGFR 30% lower than baseline, was 6.9% with placebo, 18% with canagliflozin 100 mg, and 22.5% with canagliflozin 300 mg. At the end of treatment, 4.6% with placebo, 3.4% with canagliflozin 100 mg, and 2.2% with canagliflozin 300 mg had a significant renal function decline.

In a pooled population of patients with moderate renal impairment (N=1085) with baseline Egfr of 30 to less than 60 mL/min/1.73 m² (mean baseline eGFR 48 mL/min/1.73 m²), the overall incidence of these events was lower than in the dedicated trial but a dose-dependent increase in incident episodes of significant renal function decline compared to placebo was still observed. Use of canagliflozin has been associated with an increased incidence of renal-related adverse reactions (e.g., increased blood creatinine, decreased glomerular filtration rate, renal impairment, and acute renal failure), particularly in patients with moderate renal impairment.

In the pooled analysis of patients with moderate renal impairment, the incidence of renal-related adverse reactions was 3.7% with placebo, 8.9% with canagliflozin 100 mg, and 9.3% with canagliflozin 300 mg. Discontinuations due to renal-related adverse events occurred in 1.0% with placebo, 1.2% with canagliflozin 100 mg, and 1.6% with canagliflozin 300 mg.

Genital Mycotic Infections

In the pool of four placebo-controlled clinical trials, female genital mycotic infections (e.g., vulvovaginal mycotic infection, vulvovaginal candidiasis, and vulvovaginitis) occurred in 2.8%, 10.6%, and 11.6% of females treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections on canagliflozin. Female patients who developed genital mycotic infections on canagliflozin were more likely to experience recurrence and require treatment with oral or topical antifungal agents and anti-microbial agents. In females, discontinuation due to genital mycotic infections occurred in 0% and 0.7% of patients treated with placebo and canagliflozin, respectively.

In the pool of four placebo-controlled clinical trials, male genital mycotic infections (e.g., candidal balanitis, balanoposthitis) occurred in 0.7%, 4.2%, and 3.8% of males treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Male genital mycotic infections occurred more commonly in uncircumcised males and in males with a prior history of balanitis or balanoposthitis. Male patients who developed genital mycotic infections on canagliflozin were more likely to experience recurrent infections (22% on canagliflozin versus none on placebo), and require treatment with oral or topical antifungal agents and anti-microbial agents than patients on comparators. In males, discontinuations due to genital mycotic infections occurred in 0% and 0.5% of patients treated with placebo and canagliflozin, respectively. In the pooled analysis of 8 controlled trials, phimosis was reported in 0.3% of uncircumcised male patients treated with canagliflozin and 0.2% required circumcision to treat the phimosis.

Hypoglycemia

In canagliflozin clinical trials, hypoglycemia was defined as any event regardless of symptoms, where biochemical hypoglycemia was documented (any glucose value below or equal to 70 mg/dL). Severe hypoglycemia was defined as an event consistent with hypoglycemia where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained). In individual clinical trials], episodes of hypoglycemia occurred at a higher rate when canagliflozin was co-administered with insulin or sulfonylureas (Table 6).

Table 6: Incidence of Hypoglycemia* in Controlled Clinical Studies

Monotherapy (26 weeks) Placebo
(N=192)
Canagliflozin 100 mg
(N=195)
Canagliflozin 300 mg
(N=197)
Overall [N (%)] 5 (2.6) 7 (3.6) 6 (3.0)
In Combination with Metformin (26 weeks) Placebo + Metformin
(N=183)
Canagliflozin 100 mg + Metformin
(N=368)
Canagliflozin 300 mg + Metformin
(N=367)
Overall [N (%)] 3 (1.6) 16 (4.3) 17 (4.6)
Severe [N (%)]† 0 (0) 1 (0.3) 1 (0.3)
In Combination with Metformin (18 weeks)‡ Placebo
(N=93)
Canagliflozin 100 mg
(N=93)
Canagliflozin 300 mg
(N=93)
Overall [N (%)] 3 (3.2) 4 (4.3) 3 (3.2)
In Combination with Metformin + Sulfonylurea (26 weeks) Placebo + Metformin + Sulfonylurea
(N=156)
Canagliflozin 100 mg + Metformin + Sulfonylurea
(N=157)
Canagliflozin 300 mg + Metformin + Sulfonylurea
(N=156)
Overall [N (%)] 24 (15.4) 43 (27.4) 47 (30.1)
Severe [N (%)]† 1 (0.6) 1 (0.6) 0
In Combination with Metformin + Pioglitazone (26 weeks) Placebo + Metformin + Pioglitazone
(N=115)
Canagliflozin 100 mg + Metformin + Pioglitazone
(N=113)
Canagliflozin 300 mg + Metformin + Pioglitazone
(N=114)
Overall [N (%)] 3 (2.6) 3 (2.7) 6 (5.3)
In Combination with Insulin (18 weeks) Placebo
(N=565)
Canagliflozin 100 mg
(N=566)
Canagliflozin 300 mg
(N=587)
Overall [N (%)] 208 (36.8) 279 (49.3) 285 (48.6)
Severe [N (%)]† 14 (2.5) 10 (1.8) 16 (2.7)
In Combination with Insulin and Metformin (18 weeks)§ Placebo
(N=145)
Canagliflozin 100 mg
(N=139)
Canagliflozin 300 mg
(N=148)
Overall [N (%)] 66 (45.5) 58 (41.7) 70 (47.3)
Severe [N (%)]† 4 (2.8) 1 (0.7) 3 (2.0)
* Number of patients experiencing at least one event of hypoglycemia based on either biochemically documented episodes or severe hypoglycemic events in the intent-to-treat population
† Severe episodes of hypoglycemia were defined as those where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained)
‡ Phase 2 clinical study with twice daily dosing (50 mg or 150 mg twice daily in combination with metformin)
§ Subgroup of patients (N=287) from insulin substudy on canagliflozin in combination with metformin and insulin (with or without other antiglycemic agents)

 

Bone Fracture

The occurrence of bone fractures was evaluated in a pool of nine clinical trials with a mean duration of exposure to canagliflozin of 85 weeks. The incidence rates of adjudicated bone fractures were 1.1, 1.4, and 1.5 per 100 patient-years of exposure in the comparator, canagliflozin 100 mg, and canagliflozin 300 mg groups, respectively. Fractures were observed as early as 12 weeks after treatment initiation and were more likely to be low trauma (e.g., fall from no more than standing height), and affect the upper extremities.

Metformin

The most common adverse reactions (5% or greater incidence) due to initiation of metformin are diarrhea, nausea, vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.

Long-term treatment with metformin has been associated with a decrease in vitamin B12, which may very rarely result in clinically significant vitamin B12 deficiency (e.g., megaloblastic anemia).

Laboratory And Imaging Tests

Increases In Serum Potassium

In a pooled population of patients (N=723) with moderate renal impairment (eGFR 45 to less than 60 mL/min/1.73 m²), increases in serum potassium to greater than 5.4 mEq/L and 15% above baseline occurred in 5.3%, 5.0%, and 8.8% of patients treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Severe elevations (greater than or equal to 6.5 mEq/L) occurred in 0.4% of patients treated with placebo, no patients treated with canagliflozin 100 mg, and 1.3% of patients treated with canagliflozin 300 mg.

In these patients, increases in potassium were more commonly seen in those with elevated potassium at baseline. Among patients with moderate renal impairment, approximately 84% were taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, angiotensin-converting-enzyme inhibitors, and angiotensin-receptor blockers.

Increases In Serum Magnesium

Dose-related increases in serum magnesium were observed early after initiation of canagliflozin (within 6 weeks) and remained elevated throughout treatment. In the pool of four placebo-controlled trials, the mean percent change in serum magnesium levels was 8.1% and 9.3% with canagliflozin 100 mg and canagliflozin 300 mg, respectively, compared to -0.6% with placebo. In a trial of patients with moderate renal impairment, serum magnesium levels increased by 0.2%, 9.2%, and 14.8% with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively.

Increases In Serum Phosphate

Dose-related increases in serum phosphate levels were observed with canagliflozin. In the pool of four placebo-controlled trials, the mean percent change in serum phosphate levels were 3.6% and 5.1% with canagliflozin 100 mg and canagliflozin 300 mg, respectively, compared to 1.5% with placebo. In a trial of patients with moderate renal impairment, the mean serum phosphate levels increased by 1.2%, 5.0%, and 9.3% with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively.

Increases In Low-Density Lipoprotein Cholesterol (LDL-C) And Non-High-Density Lipoprotein Cholesterol (non-HDL-C)

In the pool of four placebo-controlled trials, dose-related increases in LDL-C with canagliflozin were observed. Mean changes (percent changes) from baseline in LDL-C relative to placebo were 4.4 mg/dL (4.5%) and 8.2 mg/dL (8.0%) with canagliflozin 100 mg and canagliflozin 300 mg, respectively. The mean baseline LDL-C levels were 104 to 110 mg/dL across treatment groups.

Dose-related increases in non-HDL-C with canagliflozin were observed. Mean changes (percent changes) from baseline in non-HDL-C relative to placebo were 2.1 mg/dL (1.5%) and 5.1 mg/dL (3.6%) with canagliflozin 100 mg and 300 mg, respectively. The mean baseline non-HDL-C levels were 140 to 147 mg/dL across treatment groups.

Increases In Hemoglobin

In the pool of four placebo-controlled trials, mean changes (percent changes) from baseline in hemoglobin were -0.18 g/dL (-1.1%) with placebo, 0.47 g/dL (3.5%) with canagliflozin 100 mg, and 0.51 g/dL (3.8%) with canagliflozin 300 mg. The mean baseline hemoglobin value was approximately 14.1 g/dL across treatment groups. At the end of treatment, 0.8%, 4.0%, and 2.7% of patients treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively, had hemoglobin levels above the upper limit of normal.

Decreases In Bone Mineral Density

Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry in a clinical trial of 714 older adults (mean age 64 years). At 2 years, patients randomized to canagliflozin 100 mg and canagliflozin 300 mg had placebo-corrected declines in BMD at the total hip of 0.9% and 1.2%, respectively, and at the lumbar spine of 0.3% and 0.7%, respectively. Additionally, placebo-adjusted BMD declines were 0.1% at the femoral neck for both canagliflozin doses and 0.4% at the distal forearm for patients randomized to canagliflozin 300 mg. The placebo-adjusted change at the distal forearm for patients randomized to canagliflozin 100 mg was 0%.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of canagliflozin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Canagliflozin

Ketoacidosis

Acute Kidney Injury and Impairment in Renal Function

Anaphylaxis, Angioedema

Urosepsis and Pyelonephritis

Metformin Hydrochloride

Cholestatic, hepatocellular, and mixed hepatocellular liver injury

 

 

SRC: NLM .

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