A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Prograf Side Effects, and Drug Interactions - Tacrolimus
Prograf Side Effects, and Drug Interactions - Tacrolimus
SIDE EFFECTS
Liver Transplantation
The principal adverse reactions of Prograf are tremor, headache, diarrhea,
hypertension, nausea, and renal dysfunction. 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.
STUDY (%) |
EUROPEAN
STUDY (%) |
|
U.S.
STUDY (%) |
EUROPEAN
STUDY (%) |
|
|
Prograf
(N=250) |
CBIR
(N=250) |
Prograf
(N=264) |
CBIR
(N=265) |
|
Prograf
(N=250) |
CBIR
(N=250) |
Prograf
(N=264) |
CBIR
(N=265) |
|
Nervous System
|
Metabolic and Nutritional
|
|
Headache
(see
|
64 |
60 |
37 |
26 |
Hyperkalemia
(see WARNINGS)
|
45 |
26 |
13 |
9 |
|
Tremor
(see
|
56 |
46 |
48 |
32 |
Hypokalemia
|
29 |
34 |
13 |
16 |
|
Hyperglycemia
(see WARNINGS)
|
47 |
38 |
33 |
22 |
|
Insomnia
|
64 |
68 |
32 |
23 |
|
Paresthesia
|
40 |
30 |
17 |
17 |
Hypomagnesemia
|
48 |
45 |
16 |
9 |
|
Gastrointestinal
|
Hemic and Lymphatic
|
|
Diarrhea
|
72 |
47 |
37 |
27 |
Anemia
|
47 |
38 |
5 |
1 |
|
Nausea
|
46 |
37 |
32 |
27 |
Leukocytosis
|
32 |
26 |
8 |
8 |
|
Constipation
|
24 |
27 |
23 |
21 |
Thrombocytopenia
|
24 |
20 |
14 |
19 |
|
LFT Abnormal
|
36 |
30 |
6 |
5 |
Miscellaneous
|
|
Anorexia
|
34 |
24 |
7 |
5 |
Abdominal Pain
|
59 |
54 |
29 |
22 |
|
Vomiting
|
27 |
15 |
14 |
11 |
Pain
|
63 |
57 |
24 |
22 |
|
Cardiovascular
|
Fever
|
48 |
56 |
19 |
22 |
|
Hypertension (see
|
47 |
56 |
38 |
43 |
Asthenia
|
52 |
48 |
11 |
7 |
|
Back Pain
|
30 |
29 |
17 |
17 |
|
Urogenital
|
Ascites
|
27 |
22 |
7 |
8 |
|
Kidney Function Abnormal (see
|
40 |
27 |
36 |
23 |
Peripheral Edema
|
26 |
26 |
12 |
14 |
|
Respiratory System
|
|
Pleural Effusion
|
30 |
32 |
36 |
35 |
|
Creatinine
Increased
see
|
39 |
25 |
24 |
19 |
Atelectasis
|
28 |
30 |
5 |
4 |
|
Dyspnea
|
29 |
23 |
5 |
4 |
|
Skin and Appendages
|
|
BUN Increased
(see WARNINGS)
|
30 |
22 |
12 |
9 |
Pruritus
|
36 |
20 |
15 |
7 |
|
Rash
|
24 |
19 |
10 |
4 |
|
Urinary Tract Infection
|
16 |
18 |
21 |
19 |
|
|
|
|
|
| |
|
|
|
|
|
Oliguria
|
18 |
15 |
19 |
12 |
|
|
|
|
|
Less frequently observed adverse reactions in both liver transplantation
and kidney transplantation patients are described under the subsection
Less Frequently Reported Adverse REACTIONSbelow.
Kidney Transplantation
The most common adverse reactions reported were infection, tremor, hypertension,
decreased 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) |
|
Prograf
(N=205) |
CBIR
(N=207) |
|
Prograf
(N=205) |
CBIR
(N=207) |
|
Nervous System
|
Urogenital
|
Hemic and Lymphatic
|
|
Tremor
(See
|
54 |
34 |
Creatinine increased
(See WARNINGS)
|
45 |
42 |
Anemia
|
30 |
24 |
|
Leukopenia
|
15 |
17 |
|
Headache
(See WARNINGS)
|
44 |
38 |
Urinary tract
infection
|
34 |
35 |
Miscellaneous
|
|
Infection
|
45 |
49 |
|
Insomnia
|
32 |
30 |
|
|
|
Peripheral
edema
|
36 |
48 |
|
Paresthesia
|
23 |
16 |
|
|
|
|
Dizziness
|
19 |
16 |
|
|
|
Asthenia
|
34 |
30 |
| |
|
|
|
|
|
Abdominal
pain
|
33 |
31 |
| |
|
|
Metabolic and Nutritional
|
|
Gastrointestinal
|
Hypophosphatemia
|
49 |
53 |
Pain
|
32 |
30 |
|
Diarrhea
|
44 |
41 |
Hypomagnesemia
|
34 |
17 |
Fever
|
29 |
29 |
|
Nausea
|
38 |
36 |
Hyperlipemia
|
31 |
38 |
Back pain
|
24 |
20 |
|
Constipation
|
35 |
43 |
Hyperkalemia
(See
|
31 |
32 |
|
|
|
|
Vomiting
|
29 |
23 |
Respiratory System
|
|
Dyspepsia
|
28 |
20 |
Diabetes mellitus
(See WARNINGS)
|
24 |
9 |
Dyspnea
|
22 |
18 |
|
Cardiovascular
|
Cough
increased
|
18 |
15 |
|
Hypertension
(See
|
50 |
52 |
Hypokalemia
|
22 |
25 |
|
Hyperglycemia
(See
|
22 |
16 |
Musculoskeletal
|
|
Chest pain
|
19 |
13 |
Arthralgia
|
25 |
24 |
| |
|
|
Edema
|
18 |
19 |
Skin
|
| |
|
|
|
|
|
Rash
|
17 |
12 |
| |
|
|
|
|
|
Pruritus
|
15 |
7 |
Less frequently observed adverse reactions in both liver transplantation
and kidney transplantation patients are described under the subsection
Less Frequently Reported Adverse REACTIONSbelow.
Less Frequently Reported Adverse Reactions
The following adverse events were reported in the range of 3% to less
than 15% incidence in either liver or kidney transplant recipients who
were treated with tacrolimus in the Phase 3 comparative trials.
NERVOUS SYSTEM: (see WARNINGS)
abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, depression,
dizziness, emotional lability, encephalopathy, hallucinations, hypertonia,
incoordination, myoclonus, nervousness, neuropathy, psychosis, somnolence,
thinking abnormal; SPECIAL SENSES: abnormal vision, amblyopia, ear pain,
otitis media, tinnitus; GASTROINTESTINAL: anorexia, cholangitis, cholestatic
jaundice, dyspepsia, dysphagia, esophagitis, flatulence, gastritis, gastrointestinal
hemorrhage, GGT increase, GI perforation, hepatitis, ileus, increased
appetite, jaundice, liver damage, liver function test abnormal, oral moniliasis,
rectal disorder, stomatitis; CARDIOVASCULAR: angina pectoris, chest pain,
deep thrombophlebitis, abnormal ECG, hemorrhage, hypotension, postural
hypotension, peripheral vascular disorder, phlebitis, tachycardia, thrombosis,
vasodilatation; UROGENITAL: (see WARNINGS
) albuminuria, cystitis, dysuria, hematuria, hydronephrosis, kidney
failure, kidney tubular necrosis, nocturia, pyuria, toxic nephropathy,
oliguria, urinary frequency, urinary incontinence, vaginitis; METABOLIC/NUTRITIONAL:
acidosis, alkaline phosphatase increased, alkalosis, ALT (SGPT) increased,
AST (SGOT) increased, bicarbonate decreased, bilirubinemia, BUN increased,
dehydration, GGT increased, healing abnormal, hypercalcemia, hypercholesterolemia,
hyperlipemia, hyperphosphatemia, hyperuricemia, hypervolemia, hypocalcemia,
hypoglycemia, hyponatremia, hypophophatemia, hypoproteinemia, lactic dehydrogenase
increase, weight gain; ENDOCRINE: (see PRECAUTIONS
) Cushing's syndrome, diabetes mellitus; HEMIC/LYMPHATIC: coagulation
disorder, ecchymosis, hypochromic anemia, leukocytosis, leukopenia, polycythemia,
prothrombin decreased, serum iron decreased, thrombocytopenia; MISCELLANEOUS:
abdomen enlarged, abscess, accidental injury, allergic reaction, cellulitis,
chills, flu syndrome, generalized edema, hernia, peritonitis, photosensitivity
reaction, sepsis; MUSCULOSKELETAL: arthralgia, cramps, generalized spasm,
joint disorder, leg cramps, myalgia, myasthenia, osteoporosis; RESPIRATORY:
asthma, bronchitis, cough increased, lung disorder, pneumothorax, pulmonary
edema, pharyngitis, pneumonia, respiratory disorder, rhinitis, sinusitis,
voice alteration; SKIN: acne, alopecia, exfoliative dermatitis, fungal
dermatitis, herpes simplex, hirsutism, skin discoloration, skin disorder,
skin ulcer, sweating.
There have been rare spontaneous reports of myocardial hypertrophy associated
with clinically manifested ventricular dysfunction in patients receiving
Prograf therapy (see PRECAUTIONS -
Myocardial Hypertrophy ).
DRUG INTERACTIONS
Drug interaction studies with tacrolimus have not been conducted. Due
to the potential for additive or synergistic impairment of renal function,
care should be taken when administering Prograf with drugs that may be
associated with renal dysfunction. These include, but are not limited
to, aminoglycosides, amphotericin B, and cisplatin. Initial clinical experience
with the co-administration of Prograf and cyclosporine resulted in additive/synergistic
nephrotoxicity. Patients switched from cyclosporine to Prograf should
receive the first Prograf dose no sooner than 24 hours after the last
cyclosporine dose. Dosing may be further delayed in the presence of elevated
cyclosporine levels.
Drugs that May Alter Tacrolimus Concentrations
Since tacrolimus is metabolized mainly by the CYP3A enzyme systems, substances
known to inhibit these enzymes may decrease the metabolism of tacrolimus
with resultant increases in whole blood or plasma concentrations. Drugs
known to induce these enzyme systems may result in an increased metabolism
of tacrolimus and decreased whole blood or plasma concentrations. Monitoring
of blood concentrations and appropriate dosage adjustments are essential
when such drugs are used concomitantly.
|
* Drugs That May Increase Tacrolimus Blood
Concentrations:
|
|
Calcium
|
Antifungal
|
Macrolide
|
Gastrointestinal
|
Other
|
|
Channel
|
Agents
|
Antibiotics
|
Prokinetic
|
Drugs
|
|
Blockers
|
clotrimazole
|
clarithromycin
|
Agents
|
bromocriptine
|
|
diltiazem
|
fluconazole
|
erythromycin
|
cisapride
|
cimetidine
|
|
nicardipine
|
itraconazole
|
troleandomycin
|
metoclopramide
|
cyclosporine
|
|
nifedipine
|
ketoconazole
|
|
|
danazol
|
|
verapamil
|
|
|
|
methylprednisolone
|
| |
|
|
|
protease inhibitors
|
|
* Drugs That May Decrease Tacrolimus Blood
Concentrations:
|
|
Anticonvulsants
|
Antibiotics
|
|
|
|
|
carbamazepine
|
rifabutin
|
|
|
|
|
phenobarbital
|
rifampin
|
|
|
|
|
phenytoin
|
|
|
|
|
|
* This table is not all inclusive
|
Interaction studies with drugs used in HIV therapy have not been conducted.
However, care should be exercised when drugs that are nephrotoxic (e.g.,
ganciclovir) or that are metabolized by CYP3A (e.g., ritonavir) are administered
concomitantly with tacrolimus. Grapefruit juice affects CYP3A-mediated
metabolism and should be avoided (See DOSAGE
AND ADMINISTRATION ) .
Other Drug Interactions
Immunosuppressants may affect vaccination. Therefore, during treatment
with Prograf, vaccination may be less effective. The use of live vaccines
should be avoided; live vaccines may include, but are not limited to measles,
mumps, rubella, oral polio, BCG, yellow fever, and TY21a typhoid. 1
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