Tacrolimus (Page 5 of 13)

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 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)].

5.16 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 tacrolimus should be considered [see Adverse Reactions (6.2)].

5.18 Gastrointestinal Perforation

Gastrointestinal perforation has been reported in patients treated with tacrolimus; 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:

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.

Tacrolimus-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in 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%), 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 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.

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

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

17%

12%

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)
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
Tacrolimus (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 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%), 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 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 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 to 70), 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 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.

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

Tacrolimus

(N=250)
Cyclosporine/AZA (N=250)

Tacrolimus

(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%

37%

32%

6%

7%

14%

27%

27%

5%

5%

11%

Cardiovascular

Hypertension

47%

56%

38%

43%

Urogenital

Kidney Function Abnormal

Creatinine Increased

BUN Increased

Oliguria

Urinary Tract Infection

40%

39%

30%

18%

27%

25%

22%

15%

36%

24%

12%

19%

23%

19%

9%

12%

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

36%

20%

15%

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 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.

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 Tacrolimus in Conjunction with Azathioprine (AZA)

Tacrolimus/AZA

(n=157)

Cyclosporine/AZA

(n=157)

Cardiovascular System

Hypertension

Pericardial Effusion

62%

15%

69%

14%

Body as a Whole

CMV Infection

Infection

32%

24%

30%

21%

Metabolic and Nutritional Disorders

Diabetes Mellitus

Hyperglycemia

Hyperlipemia

26%

23%

18%

16%

17%

27%

Hemic and Lymphatic System

Anemia

Leukopenia

50%

48%

36%

39%

Urogenital System

Kidney Function Abnormal

Urinary Tract Infection

56%

16%

57%

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%), 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 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 <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 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.

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, 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 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

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 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 tacrolimus/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 * 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 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 *
Tacrolimus 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 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 12). 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 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
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 Transplant

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 13). 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 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 to 12 months for the U.S. trial.
Status of PTDM * US 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 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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