Prograf: Package Insert and Label Information (Page 3 of 8)

5.13 Use with CYP3A4 Inhibitors and Inducers

When coadministering Prograf with strong CYP3A4-inhibitors (e.g., telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) and strong inducers (e.g., rifampin, rifabutin) adjustments in the dosing regimen of Prograf and subsequent frequent monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions are recommended [see Drug Interactions (7)].

5.14 QT Prolongation

Prograf may prolong the QT/QTc interval and may cause Torsade de Pointes. Avoid Prograf in patients with congenital long QT syndrome. In patients with congestive heart failure, bradyarrhythmias, those taking certain antiarrhythmic medications or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances such as hypokalemia, hypocalcemia, or hypomagnesemia, consider obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment.

When coadministering Prograf with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval, a reduction in Prograf dose, frequent monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended. Use of Prograf with amiodarone has been reported to result in increased tacrolimus whole blood concentrations with or without concurrent QT prolongation [see Drug Interactions (7)].

5.15 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 Prograf therapy, echocardiographic evaluation should be considered. If myocardial hypertrophy is diagnosed, dosage reduction or discontinuation of Prograf should be considered [see Adverse Reactions (6.2)].

5.16 Immunizations

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.

5.17 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 Prograf should be considered [see Adverse Reactions (6.2)].

5.18 Gastrointestinal Perforation

Gastrointestinal perforation has been reported in patients treated with Prograf; all reported cases were considered to be a complication of transplant surgery or accompanied by infection, diverticulum, or malignant neoplasm. As gastrointestinal perforation may be serious or life-threatening, appropriate medical/surgical management should be instituted promptly [see Adverse Reactions (6.1)].

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 (5.2)]
Serious Infections [see Boxed Warning, Warnings and Precautions (5.3)]
Polyoma Virus Infections [see Boxed Warning, Warnings and Precautions (5.4)]
CMV Infections [see Boxed Warning, Warnings and Precautions (5.5)]
New Onset Diabetes After Transplant [see Warnings and Precautions (5.6)]
Nephrotoxicity [see Warnings and Precautions (5.7)]
Neurotoxicity [see Warnings and Precautions (5.8)]
Hyperkalemia [see Warnings and Precautions (5.9)]
Hypertension [see Warnings and Precautions (5.10)]
Anaphylaxis with Prograf Injection [see Warnings and Precautions (5.11)]
Myocardial Hypertrophy [see Warnings and Precautions (5.15)]
Pure Red Cell Aplasia [see Warnings and Precautions (5.17)]
Gastrointestinal Perforation [see Warnings and Precautions (5.18)]

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 Transplant

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.

Prograf-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in trial where 205 patients received Prograf 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 Prograf and 44±12 years on cyclosporine arm), the distribution was 61% male, and the composition was White (58%), Black (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 Prograf-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.

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

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

Prograf/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

Peripheral Edema

Asthenia

Abdominal Pain

Pain

Fever

Back Pain

45%

36%

34%

33%

32%

29%

24%

49%

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 Prograf-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 Prograf (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 Prograf 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 Prograf in Conjunction with MMF (Study 1)
Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C= Tac/MMF/CS/DaclizumabCsA= Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, MMF = mycophenolate mofetil

Prograf(Group C)

Cyclosporine(Group A)

Cyclosporine(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%

In the U.S. trial (Study 2) with Prograf-based immunosuppression in conjunction with MMF and corticosteroids, 424 kidney transplant patients received Prograf (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%), Black (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 Prograf in conjunction with MMF in Study 2 are presented below:

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

Prograf/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 both liver transplantation and kidney transplantation patients are described under the subsection Less Frequently Reported Adverse Reactions.
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%), Black (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 Prograf-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 Prograf 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.

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

U.S. TRIAL

EUROPEAN TRIAL

Prograf

(N=250)

Cyclosporine/AZA(N=250)

Prograf

(N=264)

Cyclosporine/AZA(N=265)

Nervous System

Headache

Insomnia

Tremor

Paresthesia

64%

64%

56%

40%

60%

68%

46%

30%

37%

32%

48%

17%

26%

23%

32%

17%

Gastrointestinal

Diarrhea

Nausea

LFT Abnormal

Anorexia

Vomiting

Constipation

72%

46%

36%

34%

27%

24%

47%

37%

30%

24%

15%

27%

37%

32%

6%

7%

14%

23%

27%

27%

5%

5%

11%

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

Hyperglycemia

Hyperkalemia

Hypokalemia

48%

47%

45%

29%

45%

38%

26%

34%

16%

33%

13%

13%

9%

22%

9%

16%

Hemic and Lymphatic

Anemia

Leukocytosis

Thrombocytopenia

47%

32%

24%

38%

26%

20%

5%

8%

14%

1%

8%

19%

Miscellaneous

Pain

Abdominal Pain

Asthenia

Fever

Back Pain

Ascites

Peripheral Edema

63%

59%

52%

48%

30%

27%

26%

57%

54%

48%

56%

29%

22%

26%

24%

29%

11%

19%

17%

7%

12%

22%

22%

7%

22%

17%

8%

14%

Respiratory System

Pleural Effusion

Dyspnea

Atelectasis

30%

29%

28%

32%

23%

30%

36%

5%

5%

35%

4%

4%

Skin and Appendages

Pruritus

Rash

36%

24%

20%

19%

15%

10%

7%

4%

Less frequently observed adverse reactions in both liver transplantation and kidney transplantation patients are described under the subsection Less Frequently Reported Adverse Reactions.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 Prograf (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 Prograf-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.

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

Table 8. Heart Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Prograf in Conjunction with Azathioprine (AZA)

Prograf/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 Prograf in combination with sirolimus (n=109), Prograf 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%), Black (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 Prograf 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 <3000 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 Prograf-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.

New Onset Diabetes After Transplant

Kidney Transplant

New Onset Diabetes After Transplant (NODAT) is defined as a composite of fasting plasma glucose ≥126 mg/dL, HbA1C ≥ 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 Prograf-treated and 61% in the Neoral-treated patients without pre-transplant history of diabetes mellitus (Table 9) [see Clinical Studies (14.1)].

Table 9. Incidence of New Onset Diabetes After Transplant at 1 year in Kidney Transplant Recipients in a Phase 3 Trial (Study 2)

Parameter

Treatment Group

Prograf/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%)

HbA1C ≥ 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 Prograf, Post-Transplant Diabetes Mellitus (PTDM) was evaluated with a more limited criteria 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 10 to 13. PTDM was reported in 20% of Prograf/Azathioprine (AZA)-treated kidney transplant patients without pre-transplant history of diabetes mellitus in a Phase 3 trial (Table 10). 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. Black and Hispanic kidney transplant patients were at an increased risk of development of PTDM (Table 11).

Table 10. 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 *

Prograf/AZA

CsA/AZA

Patients without pre-transplant history of diabetes mellitus

151

151

New onset PTDM *, 1st 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 11. 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 *

Prograf

Cyclosporine

Black

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 Transplant

Insulin-dependent PTDM was reported in 18% and 11% of Prograf-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 12). Hyperglycemia was associated with the use of Prograf 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 12. 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.

Status of PTDM *

US Trial

European Trial

Prograf

Cyclosporine

Prograf

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 Transplant

Insulin-dependent PTDM was reported in 13% and 22% of Prograf-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 13). Hyperglycemia defined as two fasting plasma glucose levels ≥126 mg/dL was reported with the use of Prograf 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 13. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Heart Transplant Recipients
*
Use of insulin for 30 or more consecutive days without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.
Patients without pre-transplant history of diabetes mellitus.
7-12 months for the U.S. trial.

Status of PTDM *

US Trial

European Trial

Prograf/MMF

Cyclosporine/MMF

Prograf/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 at 1 year

7 (9%)

1 (1%)

24 (18%)

4 (3%)

Less Frequently Reported Adverse Reactions (>3% and <15%)

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 (5.8)]

Abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, crying, depression, elevated mood, emotional lability, encephalopathy, haemorrhagic 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, oesophagitis ulcerative, oral moniliasis, pancreatic pseudocyst, rectal disorder, stomatitis
Cardiovascular

Abnormal ECG, angina pectoris, arrhythmia, atrial fibrillation, atrial flutter, bradycardia, cardiac fibrillation, cardiopulmonary failure, cardiovascular disorder, congestive heart failure, deep thrombophlebitis, echocardiogram abnormal, electrocardiogram QRS complex abnormal, electrocardiogram ST segment abnormal, heart failure, heart rate decreased, hemorrhage, hypotension, peripheral vascular disorder, phlebitis, postural hypotension, syncope, tachycardia, thrombosis, vasodilatation
Urogenital

Acute kidney failure [see Warnings and Precautions (5.7)], 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 increase, weight gain
Endocrine

Cushing’s syndrome
Hemic/Lymphatic

Coagulation disorder, ecchymosis, haematocrit increased, haemoglobin abnormal, hypochromic anemia, leukocytosis, polycythemia, prothrombin decreased, serum iron decreased
Miscellaneous

Abdomen enlarged, abscess, accidental injury, allergic reaction, cellulitis, chills, fall, feeling abnormal, flu syndrome, generalized edema, hernia, mobility decreased, peritonitis, photosensitivity reaction, sepsis, temperature intolerance, ulcer
Musculoskeletal

Arthralgia, cramps, generalized spasm, joint disorder, leg cramps, myalgia, myasthenia, osteoporosis
Respiratory

Asthma, emphysema, hiccups, lung disorder, lung function decreased, pharyngitis, pneumonia, pneumothorax, pulmonary edema, respiratory disorder, rhinitis, sinusitis, voice alteration
Skin

Acne, alopecia, exfoliative dermatitis, fungal dermatitis, herpes simplex, herpes zoster, hirsutism, neoplasm skin benign, skin discoloration, skin disorder, skin ulcer, sweating

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