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Prograf (Tacrolimus) - Side Effects and Adverse Reactions

 
 



ADVERSE REACTIONS

Liver Transplantation

The principal adverse reactions of Prograf are tremor, headache, diarrhea, hypertension, nausea, and abnormal renal function. These occur with oral and IV administration of Prograf and may respond to a reduction in dosing. Diarrhea was sometimes associated with other gastrointestinal complaints such as nausea and vomiting.

Hyperkalemia and hypomagnesemia have occurred in patients receiving Prograf therapy. Hyperglycemia has been noted in many patients; some may require insulin therapy (see WARNINGS).

The incidence of adverse events was determined in two randomized comparative liver transplant trials among 514 patients receiving tacrolimus and steroids and 515 patients receiving a cyclosporine-based regimen (CBIR). The proportion of patients reporting more than one adverse event was 99.8% in the tacrolimus group and 99.6% in the CBIR group. Precautions must be taken when comparing the incidence of adverse events in the U.S. study to that in the European study. The 12-month posttransplant information from the U.S. study and from the European study is presented below. The two studies also included different patient populations and patients were treated with immunosuppressive regimens of differing intensities. Adverse events reported in ≥ 15% in tacrolimus patients (combined study results) are presented below for the two controlled trials in liver transplantation:

LIVER TRANSPLANTATION: ADVERSE EVENTS OCCURRING IN ≥ 15% OF PROGRAF-TREATED PATIENTS
U.S. STUDYEUROPEAN STUDY

Prograf

(N=250)

CBIR

(N=250)

Prograf

(N=264)

CBIR

(N=265)

Nervous System

Headache (see WARNINGS)

Tremor (see WARNINGS)

Insomnia

Paresthesia

64%

56%

64%

40%

60%

46%

68%

30%

37%

48%

32%

17%

26%

32%

23%

17%

Gastrointestinal

Diarrhea

Nausea

Constipation

LFT Abnormal

Anorexia

Vomiting

72%

46%

24%

36%

34%

27%

47%

37%

27%

30%

24%

15%

37%

32%

23%

6%

7%

14%

27%

27%

21%

5%

5%

11%

Cardiovascular

Hypertension (see PRECAUTIONS)

47%

56%

38%

43%

Urogenital

Kidney Function Abnormal (see WARNINGS)

Creatinine Increased (see WARNINGS)

BUN Increased (see WARNINGS)

Urinary Tract Infection

Oliguria

40%

39%

30%

16%

18%

27%

25%

22%

18%

15%

36%

24%

12%

21%

19%

23%

19%

9%

19%

12%

Metabolic and Nutritional

Hyperkalemia (see WARNINGS)

Hypokalemia

Hyperglycemia (see WARNINGS)

Hypomagnesemia

45%

29%

47%

48%

26%

34%

38%

45%

13%

13%

33%

16%

9%

16%

22%

9%

Hemic and Lymphatic

Anemia

Leukocytosis

Thrombocytopenia

47%

32%

24%

38%

26%

20%

5%

8%

14%

1%

8%

19%

Miscellaneous

Abdominal Pain

Pain

Fever

Asthenia

Back Pain

Ascites

Peripheral Edema

59%

63%

48%

52%

30%

27%

26%

54%

57%

56%

48%

29%

22%

26%

29%

24%

19%

11%

17%

7%

12%

22%

22%

22%

7%

17%

8%

14%

Respiratory System

Pleural Effusion

Atelectasis

Dyspnea

30%

28%

29%

32%

30%

23%

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 below.

Kidney Transplantation

The most common adverse reactions reported were infection, tremor, hypertension, abnormal renal function, constipation, diarrhea, headache, abdominal pain and insomnia.

Adverse events that occurred in ≥15% of Prograf-treated kidney transplant patients are presented below:

KIDNEY TRANSPLANTATION: ADVERSE EVENTS OCCURRING IN ≥ 15% OF PROGRAF-TREATED PATIENTS

Prograf

(N=205)

CBIR

(N=207)

Nervous System

Tremor (see WARNINGS)

Headache (see WARNINGS)

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 (see PRECAUTIONS)

Chest pain

50%

19%

52%

13%

Urogenital

Creatinine Increased (see WARNINGS)

Urinary Tract Infection

45%

34%

42%

35%

Metabolic and Nutritional

Hypophosphatemia

Hypomagnesemia

Hyperlipemia

Hyperkalemia (see WARNINGS)

Diabetes Mellitus (see WARNINGS)

Hypokalemia

Hyperglycemia (see WARNINGS)

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%

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

Heart Transplantation

The more common adverse reactions in Prograf-treated heart transplant recipients were abnormal renal function, hypertension, diabetes mellitus, CMV infection, tremor, hyperglycemia, leukopenia, infection, and hyperlipemia.

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

HEART TRANSPLANTATION: ADVERSE EVENTS OCCURRING IN ≥15% OF PROGRAF-TREATED PATIENTS

COSTART Body System

COSTART Term

Prograf+

Azathioprine 

(n=157)

CsA + Azathioprine

(n=157)

Cardiovascular System
Hypertension (See PRECAUTIONS)62%69%
Pericardial effusion15%14%
Body as a Whole
CMV infection32%30%
Infection24%21%
Metabolic and Nutritional Disorders
Hyperlipemia18%27%
Diabetes Mellitus (See WARNINGS)26%16%
Hyperglycemia (See WARNINGS)23%17%
Hemic and Lymphatic System
Leukopenia48%39%
Anemia 50%36%
Urogenital System
Kidney function abnormal (See WARNINGS)56%57%
Urinary tract infection16%12%
Respiratory System
Bronchitis17%18%
Nervous System
Tremor (See WARNINGS)15%6%

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

Only selected targeted treatment-emergent adverse events were collected in the US heart transplantation study. Those events that were reported at a rate of 15% or greater in patients treated with Prograf and mycophenolate mofetil include the following: any target adverse events (99.1%), hypertension (88.8%), hyperglycemia requiring antihyperglycemic therapy (70.1%) (see WARNINGS), hypertriglyceridemia (65.4%), anemia (hemoglobin <10.0 g/dL) (65.4%), fasting blood glucose >140 mg/dL (on two separate occasions) (60.7%) (see WARNINGS), hypercholesterolemia (57.0%), hyperlipidemia (33.6%), WBCs <3000 cells/mcL (33.6%), serious bacterial infections (29.9%), magnesium <1.2 mEq/L (24.3%), platelet count <75,000 cells/mcL (18.7%), and other opportunistic infections (15.0%).

Other targeted treatment-emergent adverse events 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.

Less Frequently Reported Adverse Reactions

The following adverse events were reported in either liver, kidney, and/or heart transplant recipients who were treated with tacrolimus in clinical trials.

Nerv o us System (see WARNINGS)

Abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, crying, depression, dizziness, elevated mood, emotional lability, encephalopathy, haemorrhagic stroke, hallucinations, headache, hypertonia, incoordination, insomnia, monoparesis, myoclonus, nerve compression, nervousness, neuralgia, neuropathy, paresthesia, paralysis flaccid, psychomotor skills impaired, psychosis, quadriparesis, somnolence, thinking abnormal, vertigo, writing impaired

Special Senses

Abnormal vision, amblyopia, ear pain, otitis media, tinnitus

Gastrointestinal

Anorexia, cholangitis, cholestatic jaundice, diarrhea, duodenitis, dyspepsia, dysphagia, esophagitis, flatulence, gastritis, gastroesophagitis, gastrointestinal hemorrhage, GGT increase, GI disorder, GI perforation, hepatitis, hepatitis granulomatous, ileus, increased appetite, jaundice, liver damage, liver function test abnormal, nausea, nausea and vomiting, oesophagitis ulcerative, oral moniliasis, pancreatic pseudocyst, rectal disorder, stomatitis, vomiting

Cardiovascular

Abnormal ECG, angina pectoris, arrhythmia, atrial fibrillation, atrial flutter, bradycardia, cardiac fibrillation, cardiopulmonary failure, cardiovascular disorder, chest pain, 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 (see WARNINGS)

Acute kidney failure, albuminuria, bladder spasm, cystitis, dysuria, hematuria, hydronephrosis, kidney failure, kidney tubular necrosis, nocturia, oliguria, 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, BUN increased, dehydration, edema, GGT increased, gout, healing abnormal, hypercalcemia, hypercholesterolemia, hyperkalemia, hyperlipemia, hyperphosphatemia, hyperuricemia, hypervolemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, hypoproteinemia, lactic dehydrogenase increase, peripheral edema, weight gain

Endocrine (see PRECAUTIONS)

Cushing’s syndrome, diabetes mellitus

Hemic/Lymphatic

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

Miscellaneous

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

Musculoskeletal

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

Respiratory

Asthma, bronchitis, cough increased, dyspnea, emphysema, hiccups, lung disorder, lung function decreased, pharyngitis, pleural effusion, 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.

Post Marketing

Post Marketing Adverse Events

The following adverse events have been reported from worldwide marketing experience with Prograf. Because these events are reported voluntarily from a population of uncertain size, are associated with concomitant diseases and multiple drug therapies and surgical procedures, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these events in labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2) frequency of the reporting, or (3) strength of causal connection to the drug.

There have been rare spontaneous reports of myocardial hypertrophy associated with clinically manifested ventricular dysfunction in patients receiving Prograf therapy (see PRECAUTIONS- Myocardial Hypertrophy).

Other events include:

Cardiovascular

Atrial fibrillation, atrial flutter, cardiac arrhythmia, cardiac arrest, electrocardiogram T wave abnormal, flushing, myocardial infarction, myocardial ischaemia, pericardial effusion, QT prolongation, Torsade de Pointes, venous thrombosis deep limb, ventricular extrasystoles, ventricular fibrillation

Gastrointestinal

Bile duct stenosis, colitis, enterocolitis, gastroenteritis, gastrooesophageal reflux disease, hepatic cytolysis, hepatic necrosis, hepatotoxicity, impaired gastric emptying, liver fatty, mouth ulceration, pancreatitis haemorrhagic, pancreatitis necrotizing, stomach ulcer, venoocclusive liver disease

Hemic/Lymphatic

Disseminated intravascular coagulation, neutropenia, pancytopenia, thrombocytopenic purpura, thrombotic thrombocytopenic purpura

Metabolic/Nutritional

Glycosuria, increased amylase including pancreatitis, weight decreased

Miscellaneous

Feeling hot and cold, feeling jittery, hot flushes, multi-organ failure, primary graft dysfunction

Nervous System

Carpal tunnel syndrome, cerebral infarction, hemiparesis, leukoencephalopathy, mental disorder, mutism, quadriplegia, speech disorder, syncope

Respiratory

Acute respiratory distress syndrome, lung infiltration, respiratory distress, respiratory failure

Skin

Stevens-Johnson syndrome, toxic epidermal necrolysis

Special Senses

Blindness, blindness cortical, hearing loss including deafness, photophobia

Urogenital

Acute renal failure, cystitis haemorrhagic, hemolytic-uremic syndrome, micturition disorder.



REPORTS OF SUSPECTED PROGRAF SIDE EFFECTS / ADVERSE REACTIONS

Below is a sample of reports where side effects / adverse reactions may be related to Prograf. The information is not vetted and should not be considered as verified clinical evidence.

Possible Prograf side effects / adverse reactions in 68 year old male

Reported by a physician from Japan on 2011-10-03

Patient: 68 year old male

Reactions: Bladder Cancer

Adverse event resulted in: death

Suspect drug(s):
Prograf

Other drugs received by patient: Rheumatrex; Rheumatrex; Celecoxib; Rheumatrex; Lansoprazole



Possible Prograf side effects / adverse reactions in 77 year old female

Reported by a consumer/non-health professional from Colombia on 2011-10-03

Patient: 77 year old female

Reactions: Cardio-Respiratory Arrest, Pulmonary Oedema

Adverse event resulted in: death

Suspect drug(s):
Prograf

Other drugs received by patient: Lovastatin; Mycophenolate Mofetil; Valganciclovir; Prednisone



Possible Prograf side effects / adverse reactions in 70 year old male

Reported by a health professional (non-physician/pharmacist) from Austria on 2011-10-03

Patient: 70 year old male weighing 72.0 kg (158.4 pounds)

Reactions: Pneumonia, Cardiac Failure, Sepsis, Enteritis

Adverse event resulted in: death

Suspect drug(s):
Prograf

Other drugs received by patient: Aprednislon



See index of all Prograf side effect reports >>

Drug label data at the top of this Page last updated: 2006-06-19

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