|
|Metabolic and Nutritional | | | | |
|Hyperkalemia (see WARNINGS) |45 |26 |13 |9 |
|Hypokalemia |29 |34 |13 |16 |
|Hyperglycemia (see WARNINGS) |47 |38 |33 |22 |
|Hypomagnesemia |48 |45 |16 |9 |
|Hemic and Lymphatic | | | | |
|Anemia |47 |38 |5 |1 |
|Leukocytosis |32 |26 |8 |8 |
|Thrombocytopenia |24 |20 |14 |19 |
|Miscellaneous | | | | |
|Abdominal Pain |59 |54 |29 |22 |
|Pain |63 |57 |24 |22 |
|Fever |48 |56 |19 |22 |
|Asthenia |52 |48 |11 |7 |
|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 |
|Atelectasis |28 |30 |5 |4 |
|Dyspnea |29 |23 |5 |4 |
|Skin and Appendages | | | | |
|Pruritus |36 |20 |15 |7 |
|Rash |24 |19 |10 |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, 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 |CBIR |
| |(N=205) |(N=207) |
|Nervous System | | |
|Tremor (see WARNINGS) |54 |34 |
|Headache (see WARNINGS) |44 |38 |
|Insomnia |32 |30 |
|Paresthesia |23 |16 |
|Dizziness |19 |16 |
|Gastrointestinal | | |
|Diarrhea |44 |41 |
|Nausea |38 |36 |
|Constipation |35 |43 |
|Vomiting |29 |23 |
|Dyspepsia |28 |20 |
|Cardiovascular | | |
|Hypertension (see PRECAUTIONS) |50 |52 |
|Chest Pain |19 |13 |
|Urogenital | | |
|Creatinine Increased (see WARNINGS) |45 |42 |
|Urinary Tract Infection |34 |35 |
|Metabolic and Nutritional | | |
|Hypophosphatemia |49 |53 |
|Hypomagnesemia |34 |17 |
|Hyperlipemia |31 |38 |
|Hyperkalemia (see WARNINGS) |31 |32 |
|Diabetes Mellitus (see WARNINGS) |24 |9 |
|Hypokalemia |22 |25 |
|Hyperglycemia (see WARNINGS) |22 |16 |
|Edema |18 |19 |
|Hemic and Lymphatic | | |
|Anemia |30 |24 |
|Leukopenia |15 |17 |
|Miscellaneous | | |
|Infection |45 |49 |
|Peripheral Edema |36 |48 |
|Asthenia |34 |30 |
|Abdominal Pain |33 |31 |
|Pain |32 |30 |
|Fever |29 |29 |
|Back Pain |24 |20 |
|Respiratory System | | |
|Dyspnea |22 |18 |
|Cough Increased |18 |15 |
|Musculoskeletal | | |
|Arthralgia |25 |24 |
|Skin | | |
|Rash |17 |12 |
|Pruritis |15 |7 |
Less frequently observed adverse reactions in both liver transplantion and
kidney transplantation patients are described under the subsection Less
Frequently Reported Adverse Reactions shown below.
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, hypophosphatemia,
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).
Post Marketing
The following have been reported: increased amylase including pancreatitis,
hearing loss including deafness, leukoencephalopathy, thrombocytopenic
purpura, hemolytic-uremia syndrome, acute renal failure, Stevens-Johnson
syndrome, stomach ulcer, glycosuria, cardiac arrhythmia and
gastroenteritis.
OVERDOSAGE:
Limited overdosage experience is available. Acute overdosages of up to 30
times the intended dose have been reported. Almost all cases have been
asymptomatic and all patients recovered with no sequelae. Occasionally,
acute overdosage has been followed by adverse reactions consistent with
those listed in the ADVERSE REACTIONS section except in one case where
transient urticaria and lethargy were observed. Based on the poor aqueous
solubility and extensive erythrocyte and plasma protein binding, it is
anticipated that tacrolimus is not dialyzable to any significant extent;
there is no experience with charcoal hemoperfusion. The oral use of
activated charcoal has been reported in treating acute overdoses, but
experience has not been sufficient to warrant recommending its use. General
supportive measures and treatment of specific symptoms should be followed
in all cases of overdosage.
In acute oral and IV toxicity studies, mortalities were seen at or above
the following doses: in adult rats, 52X the recommended human oral dose; in
immature rats, 16X the recommended oral dose; and in adult rats, 16X the
recommended human IV dose (all based on body surface area corrections).
DOSAGE AND ADMINISTRATION:
Prograf injection (tacrolimus injection)
For IV Infusion Only
NOTE: Anaphylactic reactions have occurred with injectables containing
castor oil derivatives. See WARNINGS.
In patients unable to take oral Prograf capsules, therapy may be initiated
with Prograf injection. The initial dose of Prograf should be administered
no sooner than 6 hours after transplantation. The recommended starting dose
of Prograf injection is 0.03-0.05 mg/kg/day as a continuous IV infusion.
Adult patients should receive doses at the lower end of the dosing range.
Concomitant adrenal corticosteroid therapy is recommended early post-
transplantation. Continuous IV infusion of Prograf injection should be
continued only until the patient can tolerate oral administration of
Prograf capsules.
Preparation for Administration/Stability
Prograf injection must be diluted with 0.9% Sodium Chloride Injection or 5%
Dextrose Injection to a concentration between 0.004 mg/mL and 0.02 mg/mL
prior to use. Diluted infusion solution should be stored in glass or
polyethylene containers and should be discarded after 24 hours. The diluted
infusion solution should not be stored in a PVC container due to decreased
stability and the potential for extraction of phthalates. In situations
where more dilute solutions are utilized (e.g., pediatric dosing, etc.),
PVC-free tubing should likewise be used to minimize the potential for
significant drug adsorption onto the tubing. Parenteral drug products
should be inspected visually for particulate matter and discoloration prior
to administration, whenever solution and container permit. Due to the
chemical instability of tacrolimus in alkaline media, Prograf injection
should not be mixed or co-infused with solutions of pH 9 or greater (e.g.,
ganciclovir or acyclovir).
Prograf capsules (tacrolimus capsules)
Summary of Initial Oral Dosage Recommendations and Typical Whole Blood
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