Tacrolimus (Page 4 of 12)

5.13 Myocardial Hypertrophy

Myocardial hypertrophy has been reported in infants, children, and adults, particularly those with high tacrolimus trough concentrations, and is generally manifested by echocardiographically demonstrated concentric increases in left ventricular posterior wall and interventricular septum thickness. This condition appears reversible in most cases following dose reduction or discontinuance of therapy. In patients who develop renal failure or clinical manifestations of ventricular dysfunction while receiving tacrolimus therapy, echocardiographic evaluation should be considered. If myocardial hypertrophy is diagnosed, dosage reduction or discontinuation of tacrolimus should be considered [see Adverse Reactions ( 6.2)].

5.14 Immunizations

Whenever possible, administer the complete complement of vaccines before transplantation and treatment with tacrolimus.

The use of live vaccines should be avoided during treatment with tacrolimus; examples include (not limited to) the following: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.

Inactivated vaccines noted to be safe for administration after transplantation may not be sufficiently immunogenic during treatment with tacrolimus.

5.15 Pure Red Cell Aplasia

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. A mechanism for tacrolimus-induced PRCA has not been elucidated. All patients reported risk factors for PRCA such as parvovirus B19 infection, underlying disease, or concomitant medications associated with PRCA. If PRCA is diagnosed, discontinuation of tacrolimus should be considered [see Adverse Reactions ( 6.2)].

6 ADVERSE REACTIONS

The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:

  • Lymphoma and Other Malignancies [see Boxed Warning, Warnings and Precautions ( 5.1)]
  • Serious Infections [see Boxed Warning, Warnings and Precautions ( 5.2)]
  • New Onset Diabetes After Transplant [see Warnings and Precautions ( 5.4)]
  • Nephrotoxicity [see Warnings and Precautions ( 5.5)]
  • Neurotoxicity [see Warnings and Precautions ( 5.6)]
  • Hyperkalemia [see Warnings and Precautions ( 5.7)]
  • Hypertension [see Warnings and Precautions ( 5.8)]
  • Anaphylactic Reactions with Tacrolimus Injection [see Warnings and Precautions ( 5.9)]
  • Myocardial Hypertrophy [see Warnings and Precautions ( 5.13)]
  • Pure Red Cell Aplasia [see Warnings and Precautions ( 5.15)]

6.1 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 rates in the clinical trials of another drug and may not reflect the rates observed in practice. In addition, the clinical trials were not designed to establish comparative differences across study arms with regards to the adverse reactions discussed below.

Kidney Transplantation The incidence of adverse reactions was determined in three randomized kidney transplant trials. One of the trials used azathioprine (AZA) and corticosteroids and two of the trials used mycophenolate mofetil (MMF) and corticosteroids concomitantly for maintenance immunosuppression.

Tacrolimus-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in a trial where 205 patients received tacrolimus-based immunosuppression and 207 patients received cyclosporine-based immunosuppression. The trial population had a mean age of 43 years (mean±SD was 43±13 years on tacrolimus and 44±12 years on cyclosporine arm), the distribution was 61% male, and the composition was White (58%), African-American (25%), Hispanic (12%), and Other (5%). The 12 month post-transplant information from this trial is presented below.

The most common adverse reactions (≥ 30%) observed in tacrolimus-treated kidney transplant patients are: infection, tremor, hypertension, abnormal renal function, constipation, diarrhea, headache, abdominal pain, insomnia, nausea, hypomagnesemia, urinary tract infection, hypophosphatemia, peripheral edema, asthenia, pain, hyperlipidemia, hyperkalemia and anemia. Based on reported adverse reactions terms related to decreased renal function, nephrotoxicity was reported in approximately 52% of kidney transplantation patients.

Adverse reactions that occurred in ≥ 15% of kidney transplant patients treated with tacrolimus in conjunction with azathioprine are presented below:

Table 4. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with Azathioprine (AZA)

Tacrolimus/AZA (N=205)

Cyclosporine/AZA (N=207)

Nervous System Tremor Headache Insomnia Paresthesia Dizziness

54% 44% 32% 23% 19%

34% 38% 30% 16% 16%

Gastrointestinal

Diarrhea Nausea Constipation Vomiting Dyspepsia

44% 38% 35% 29% 28%

41% 36% 43% 23% 20%

Cardiovascular

Hypertension Chest Pain

50% 19%

52% 13%

Urogenital

Creatinine Increased Urinary Tract Infection

45% 34%

42% 35%

Metabolic and Nutritional

Hypophosphatemia Hypomagnesemia Hyperlipemia Hyperkalemia Diabetes Mellitus Hypokalemia Hyperglycemia Edema

49% 34% 31% 31% 24% 22% 22% 18%

53% 17% 38% 32% 9% 25% 16% 19%

Hemic and Lymphatic

Anemia Leukopenia

30% 15%

24% 17%

Miscellaneous

Infection

45%

49%

Peripheral Edema Asthenia Abdominal Pain Pain Fever Back Pain

36% 34% 33% 32% 29% 24%

48% 30% 31% 30% 29% 20%

Respiratory System

Dyspnea Cough Increased

22% 18%

18% 15%

Musculoskeletal

Arthralgia

25%

24%

Skin

Rash Pruritus

17% 15%

12% 7%

Two trials were conducted for tacrolimus-based immunosuppression in conjunction with MMF and corticosteroids. In the non-US trial (Study 1), the incidence of adverse reactions was based on 1195 kidney transplant patients that received tacrolimus (Group C, n=403), or one of two cyclosporine (CsA) regimens (Group A, n=384 and Group B, n=408) in combination with MMF and corticosteroids; all patients, except those in one of the two cyclosporine groups, also received induction with daclizumab. The trial population had a mean age of 46 years (range 17 to 76), the distribution was 65% male, and the composition was 93% Caucasian. The 12 month post-transplant information from this trial is presented below.

Adverse reactions that occurred in ≥ 10% of kidney transplant patients treated with tacrolimus in conjunction with MMF in Study 1 [Note: This trial was conducted entirely outside of the United States. Such trials often report a lower incidence of adverse reactions in comparison to U.S. trials] are presented below:

Table 5. Kidney Transplantation: Adverse Reactions Occurring in ≥ 10% of Patients Treated with Tacrolimus in Conjunction with MMF (Study 1)

Tacrolimus

Cyclosporine

Cyclosporine

(Group C)

(Group A)

(Group B)

(N=403)

(N=384)

(N=408)

Diarrhea

25%

16%

13%

Urinary Tract Infection

24%

28%

24%

Anemia

17%

19%

17%

Hypertension

13%

14%

12%

Leukopenia

13%

10%

10%

Edema Peripheral

11%

12%

13%

Hyperlipidemia

10%

15%

13%

Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C=Tac/MMF/CS/Daclizumab CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, MMF = mycophenolate mofetil

In the U.S. trial (Study 2) with tacrolimus-based immunosuppression in conjunction with MMF and corticosteroids, 424 kidney transplant patients received tacrolimus (n=212) or cyclosporine (n=212) in combination with MMF 1 gram twice daily, basiliximab induction, and corticosteroids. The trial population had a mean age of 48 years (range 17 to 77), the distribution was 63% male, and the composition was White (74%), African-American (20%), Asian (3%), and Other (3%). The 12 month post-transplant information from this trial is presented below.

Adverse reactions that occurred in ≥15% of kidney transplant patients treated with tacrolimus in conjunction with MMF in Study 2 are presented below:

Table 6. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with MMF (Study 2)

Tacrolimus/MMF

Cyclosporine/MMF

(N=212)

(N=212)

Gastrointestinal Disorders

Diarrhea

44%

26%

Nausea

39%

47%

Constipation

36%

41%

Vomiting

26%

25%

Dyspepsia

18%

15%

Injury, Poisoning, and Procedural Complications

Post-Procedural Pain

29%

27%

Incision Site Complication

28%

23%

Graft Dysfunction

24%

18%

Metabolism and Nutrition Disorders

Hypomagnesemia

28%

22%

Hypophosphatemia

28%

21%

Hyperkalemia

26%

19%

Hyperglycemia

21%

15%

Hyperlipidemia

18%

25%

Hypokalemia

16%

18%

Nervous System Disorders

Tremor

34%

20%

Headache

24%

25%

Blood and Lymphatic System Disorders

Anemia

30%

28%

Leukopenia

16%

12%

Miscellaneous

Edema Peripheral

35%

46%

Hypertension

32%

35%

Insomnia

30%

21%

Urinary Tract Infection

26%

22%

Blood Creatinine Increased

23%

23%

Less frequently observed adverse reactions in kidney transplantation patients are described under the subsection Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies.”

Liver Transplantation There were two randomized comparative liver transplant trials. In the U.S. trial, 263 adult and pediatric patients received tacrolimus and steroids and 266 patients received cyclosporine-based immunosuppressive regimen (CsA/AZA). The trial population had a mean age of 44 years (range 0.4 to70), the distribution was 52% male, and the composition was White (78%), African-American (5%), Asian (2%), Hispanic (13%), and Other (2%). In the European trial, 270 patients received tacrolimus and steroids and 275 patients received CsA/AZA. The trial population had a mean age of 46 years (range 15 to 68), the distribution was 59% male, and the composition was White (95.4%), Black (1%), Asian (2%), and Other (2%).

The proportion of patients reporting more than one adverse event was > 99% in both the tacrolimus group and the CsA/AZA group. Precautions must be taken when comparing the incidence of adverse reactions in the U.S. trial to that in the European trial. The 12-month post-transplant information from the U.S. trial and from the European trial is presented below. The two trials also included different patient populations and patients were treated with immunosuppressive regimens of differing intensities. Adverse reactions reported in ≥15% in tacrolimus patients (combined trial results) are presented below for the two controlled trials in liver transplantation.

The most common adverse reactions (≥ 40%) observed in tacrolimus-treated liver transplant patients are: tremor, headache, diarrhea, hypertension, nausea, abnormal renal function, abdominal pain, insomnia, paresthesia, anemia, pain, fever, asthenia, hyperkalemia, hypomagnesemia, and hyperglycemia. These all occur with oral and IV administration of tacrolimus and some may respond to a reduction in dosing (e.g., tremor, headache, paresthesia, hypertension). Diarrhea was sometimes associated with other gastrointestinal complaints such as nausea and vomiting. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 40% and 36% of liver transplantation patients receiving tacrolimus in the U.S. and European randomized trials.

Table 7. Liver Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus

U.S. TRIAL

EUROPEAN TRIAL

Tacrolimus

Cyclosporine/AZA

Tacrolimus

Cyclosporine/AZA

(N=250)

(N=250)

(N=264)

(N=265)

Nervous System

Headache

64%

60%

37%

26%

Insomnia

64%

68%

32%

23%

Tremor

56%

46%

48%

32%

Paresthesia

40%

30%

17%

17%

Gastrointestinal

Diarrhea

72%

47%

37%

27%

Nausea

46%

37%

32%

27%

LFT Abnormal

36%

30%

6%

5%

Anorexia

34%

24%

7%

5%

Vomiting

27%

15%

14%

11%

Constipation

24%

27%

23%

21%

Cardiovascular

Hypertension

47%

56%

38%

43%

Urogenital

Kidney Function Abnormal

40%

27%

36%

23%

Creatinine Increased

39%

25%

24%

19%

BUN Increased

30%

22%

12%

9%

Oliguria

18%

15%

19%

12%

Urinary Tract Infection

16%

18%

21%

19%

Metabolic and Nutritional

Hypomagnesemia

48%

45%

16%

9%

Hyperglycemia

47%

38%

33%

22%

Hyperkalemia

45%

26%

13%

9%

Hypokalemia

29%

34%

13%

16%

Hemic and Lymphatic

Anemia

47%

38%

5%

1%

Leukocytosis

32%

26%

8%

8%

Thrombocytopenia

24%

20%

14%

19%

Miscellaneous

Pain

63%

57%

24%

22%

Abdominal Pain

59%

54%

29%

22%

Asthenia

52%

48%

11%

7%

Fever

48%

56%

19%

22%

Back Pain

30%

29%

17%

17%

Ascites

27%

22%

7%

8%

Peripheral Edema

26%

26%

12%

14%

Respiratory System

Pleural Effusion

30%

32%

36%

35%

Dyspnea

29%

23%

5%

4%

Atelectasis

28%

30%

5%

4%

Skin and Appendages

Pruritus

36%

20%

15%

7%

Rash

24%

19%

10%

4%

Less frequently observed adverse reactions in liver transplantation patients are described under the subsection “Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies.”

Heart Transplantation The incidence of adverse reactions was determined based on two trials in primary orthotopic heart transplantation. In a trial conducted in Europe, 314 patients received a regimen of antibody induction, corticosteroids and azathioprine (AZA) in combination with tacrolimus (n=157) or cyclosporine (n=157) for 18 months. The trial population had a mean age of 51 years (range 18 to 65), the distribution was 82% male, and the composition was White (96%), Black (3%), and Other (1%).

The most common adverse reactions (≥ 15%) observed in tacrolimus-treated heart transplant patients are: abnormal renal function, hypertension, diabetes mellitus, CMV infection, tremor, hyperglycemia, leukopenia, infection, anemia, bronchitis, pericardial effusion, urinary tract infection and hyperlipemia. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 59% of heart transplantation patients in the European trial.

Adverse reactions in heart transplant patients in the European trial are presented below:

Table 9. Heart Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with Azathioprine (AZA)

Tacrolimus/AZA (N=157)

Cyclosporine/AZA (N=157)

Cardiovascular System

Hypertension

62%

69%

Pericardial Effusion

15%

14%

Body as a Whole

CMV Infection

32%

30%

Infection

24%

21%

Metabolic and Nutritional Disorders

Diabetes Mellitus

26%

16%

Hyperglycemia

23%

17%

Hyperlipemia

18%

27%

Hemic and Lymphatic System

Anemia

50%

36%

Leukopenia

48%

39%

Urogenital System

Kidney Function Abnormal

56%

57%

Urinary Tract Infection

16%

12%

Respiratory System

Bronchitis

17%

18%

Nervous System

Tremor

15%

6%

In the European trial, the cyclosporine trough concentrations were above the pre-defined target range (i.e., 100 to 200 ng/mL) at Day 122 and beyond in 32% to 68% of the patients in the cyclosporine treatment arm, whereas the tacrolimus trough concentrations were within the pre-defined target range (i.e., 5 to 15 ng/mL) in 74% to 86% of the patients in the tacrolimus treatment arm.

In a U.S. trial, the incidence of adverse reactions was based on 331 heart transplant patients that received corticosteroids and tacrolimus in combination with sirolimus (n=109), tacrolimus in combination with MMF (n=107) or cyclosporine modified in combination with MMF (n=115) for 1 year. The trial population had a mean age of 53 years (range 18 to 75), the distribution was 78% male, and the composition was White (83%), African-American (13%), and Other (4%).

Only selected targeted treatment-emergent adverse reactions were collected in the U.S. heart transplantation trial. Those reactions that were reported at a rate of 15% or greater in patients treated with tacrolimus and MMF include the following: any target adverse reactions (99%), hypertension (89%), hyperglycemia requiring antihyperglycemic therapy (70%), hypertriglyceridemia (65%), anemia (hemoglobin <10.0 g/dL) (65%), fasting blood glucose >140 mg/dL (on two separate occasions) (61%), hypercholesterolemia (57%), hyperlipidemia (34%), WBCs <3,000 cells/mcL (34%), serious bacterial infections (30%), magnesium <1.2 mEq/L (24%), platelet count <75,000 cells/mcL (19%), and other opportunistic infections (15%).

Other targeted treatment-emergent adverse reactions in tacrolimus-treated patients occurred at a rate of less than 15%, and include the following: Cushingoid features, impaired wound healing, hyperkalemia, Candida infection, and CMV infection/syndrome. Other less frequently observed adverse reactions in heart transplantation patients are described under the subsection “Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney and Heart Transplant Studies.”

New Onset Diabetes After Transplant
Kidney Transplantation New Onset Diabetes After Transplant (NODAT) is defined as a composite of fasting plasma glucose ≥126 mg/dL, HbA 1C ≥ 6%, insulin use ≥ 30 days or oral hypoglycemic use. In a trial in kidney transplant patients (Study 2), NODAT was observed in 75% in the tacrolimus-treated and 61% in the NEORAL-treated patients without pre-transplant history of diabetes mellitus (Table 10) [see Clinical Studies ( 14.1)].

Table 10. Incidence of New Onset Diabetes After Transplant at 1 year in Kidney Transplant Recipients in a Phase 3 Trial (Study 2)

Parameter

Treatment Group

Tacrolimus/MMF (n = 212)

Neoral/MMF (n = 212)

NODAT

112/150 (75%)

93/152 (61%)

Fasting Plasma Glucose ≥ 126 mg/dL

96/150 (64%)

80/152 (53%)

HbA 1C ≥ 6%

59/150 (39%)

28/152 (18%)

Insulin Use ≥ 30 days

9/150 (6%)

4/152 (3%)

Oral Hypoglycemic Use

15/150 (10%)

5/152 (3%)

In early trials of tacrolimus, Post-Transplant Diabetes Mellitus (PTDM) was evaluated with a more limited criterion of “use of insulin for 30 or more consecutive days with < 5 day gap” in patients without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. Data are presented in Tables 11 to 14. PTDM was reported in 20% of Tacrolimus/Azathioprine (AZA)-treated kidney transplant patients without pre-transplant history of diabetes mellitus in a Phase 3 trial (Table 11). The median time to onset of PTDM was 68 days. Insulin dependence was reversible in 15% of these PTDM patients at one year and in 50% at 2 years post-transplant. African-American and Hispanic kidney transplant patients were at an increased risk of development of PTDM (Table 12).

Table 11. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 2 Years in Kidney Transplant Recipients in a Phase 3 Trial using Azathioprine (AZA)

*
Use of insulin for 30 or more consecutive days, with < 5 day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.

Status of PTDM *

Tacrolimus/AZA

CsA/AZA

Patients without pre-transplant history of diabetes mellitus

151

151

New onset PTDM *, 1 st Year

30/151 (20%)

6/151 (4%)

Still insulin-dependent at one year in those without prior history of diabetes

25/151 (17%)

5/151 (3%)

New onset PTDM * post 1 year

1

0

Patients with PTDM * at 2 years

16/151 (11%)

5/151 (3%)

Table 12. Development of Post-Transplant Diabetes Mellitus by Race or Ethnicity and by Treatment Group During First Year Post Kidney Transplantation in a Phase 3 Trial

*
Use of insulin for 30 or more consecutive days, with < 5 day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.

Patient Race

Patients Who Developed PTDM *

Tacrolimus

Cyclosporine

African-American

15/41 (37%)

3 (8%)

Hispanic

5/17 (29%)

1 (6%)

Caucasian

10/82 (12%)

1 (1%)

Other

0/11 (0%)

1 (10%)

Total

30/151 (20%)

6 (4%)

Liver Transplantation Insulin-dependent PTDM was reported in 18% and 11% of tacrolimus-treated liver transplant patients and was reversible in 45% and 31% of these patients at 1 year post-transplant, in the U.S. and European randomized trials, respectively, (Table 13). Hyperglycemia was associated with the use of tacrolimus in 47% and 33% of liver transplant recipients in the U.S. and European randomized trials, respectively, and may require treatment [see Adverse Reactions ( 6.1)].

Table 13. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Liver Transplant Recipients

*
Use of insulin for 30 or more consecutive days, with < 5 day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.
Patients without pre-transplant history of diabetes mellitus.
Use of insulin for 30 or more consecutive days without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.

Status of PTDM *

U.S. Trial

European Trial

Tacrolimus

Cyclosporine

Tacrolimus

Cyclosporine

Patients at risk

239

236

239

249

New Onset PTDM

42 (18%)

30 (13%)

26 (11%)

12 (5%)

Patients still on insulin at 1 year

23 (10%)

19 (8%)

18 (8%)

6 (2%)

Heart Transplantation Insulin-dependent PTDM was reported in 13% and 22% of tacrolimus-treated heart transplant patients receiving mycophenolate mofetil (MMF) or azathioprine (AZA) and was reversible in 30% and 17% of these patients at one year post-transplant, in the U.S. and European randomized trials, respectively (Table 14). Hyperglycemia, defined as two fasting plasma glucose levels ≥126 mg/dL, was reported with the use of tacrolimus plus MMF or AZA in 32% and 35% of heart transplant recipients in the U.S. and European randomized trials, respectively, and may require treatment [see Adverse Reactions ( 6.1)].

Table 14. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Heart Transplant Recipients

*
Patients without pre-transplant history of diabetes mellitus.
7 to 12 months for the U.S. trial.

Status of PTDM

U.S. Trial

European Trial

Tacrolimus /MMF

Cyclosporine/MMF

Tacrolimus/ AZA

Cyclosporine/AZA

Patients at risk *

75

83

132

138

New Onset PTDM

10 (13%)

6 (7%)

29 (22%)

5 (4%)

Patients still on insulin at1 year

7 (9%)

1 (1%)

24 (18%)

4 (3%)

Less Frequently Reported Adverse Reactions (>3% and <15%) in Liver, Kidney, and Heart Transplant Studies The following adverse reactions were reported in either liver, kidney, and/or heart transplant recipients who were treated with tacrolimus in clinical trials.

  • Nervous System [see Warnings and Precautions ( 5.6)]: Abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, crying, depression, elevated mood, emotional lability, encephalopathy, hemorrhagic stroke, hallucinations, hypertonia, incoordination, monoparesis, myoclonus, nerve compression, nervousness, neuralgia, neuropathy, paralysis flaccid, psychomotor skills impaired, psychosis, quadriparesis, somnolence, thinking abnormal, vertigo, writing impaired
  • Special Senses: Abnormal vision, amblyopia, ear pain, otitis media, tinnitus
  • Gastrointestinal: Cholangitis, cholestatic jaundice, duodenitis, dysphagia, esophagitis, flatulence, gastritis, gastroesophagitis, gastrointestinal hemorrhage, GGT increase, GI disorder, GI perforation, hepatitis, hepatitis granulomatous, ileus, increased appetite, jaundice, liver damage, esophagitis ulcerative, oral moniliasis, pancreatic pseudocyst, stomatitis
  • Cardiovascular: Abnormal ECG, angina pectoris, arrhythmia, atrial fibrillation, atrial flutter, bradycardia, cardiac fibrillation, cardiopulmonary failure, congestive heart failure, deep thrombophlebitis, echocardiogram abnormal, electrocardiogram QRS complex abnormal, electrocardiogram ST segment abnormal, heart failure, heart rate decreased, hemorrhage, hypotension, phlebitis, postural hypotension, syncope, tachycardia, thrombosis, vasodilatation
  • Urogenital: Acute kidney failure [see Warnings and Precautions ( 5.5)], albuminuria, BK nephropathy, bladder spasm, cystitis, dysuria, hematuria, hydronephrosis, kidney failure, kidney tubular necrosis, nocturia, pyuria, toxic nephropathy, urge incontinence, urinary frequency, urinary incontinence, urinary retention, vaginitis
  • Metabolic/Nutritional: Acidosis, alkaline phosphatase increased, alkalosis, ALT (SGPT) increased, AST (SGOT) increased, bicarbonate decreased, bilirubinemia, dehydration, GGT increased, gout, healing abnormal, hypercalcemia, hypercholesterolemia, hyperphosphatemia, hyperuricemia, hypervolemia, hypocalcemia, hypoglycemia, hyponatremia, hypoproteinemia, lactic dehydrogenase increased, weight gain
  • Endocrine: Cushing’s syndrome
  • Hemic/Lymphatic: Coagulation disorder, ecchymosis, hematocrit increased, hypochromic anemia, leukocytosis, polycythemia, prothrombin decreased, serum iron decreased
  • Miscellaneous: Abdomen enlarged, abscess, accidental injury, allergic reaction, cellulitis, chills, fall, flu syndrome, generalized edema, hernia, mobility decreased, peritonitis, photosensitivity reaction, sepsis, temperature intolerance, ulcer
  • Musculoskeletal: Arthralgia, cramps, generalized spasm, leg cramps, myalgia, myasthenia, osteoporosis
  • Respiratory: Asthma, emphysema, hiccups, lung function decreased, pharyngitis, pneumonia, pneumothorax, pulmonary edema, rhinitis, sinusitis, voice alteration
  • Skin: Acne, alopecia, exfoliative dermatitis, fungal dermatitis, herpes simplex, herpes zoster, hirsutism, neoplasm skin benign, skin discoloration, skin ulcer, sweating

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