Реферат: Такролимус
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) | |
| 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 Trough Concentrations
| Patient Population | Recommended Initial Oral Dose* | Typical Whole Blood Trough Concentrations |
| Adult kidney transplant patients | 0.2 mg/kg/day | month 1-3 : 7-20 ng/mL month 4-12 : 5-15 ng/mL |
| Adult liver transplant patients | 0.10-0.15 mg/kg/day | month 1-12 : 5-20 ng/mL |
| Pediatric liver transplant patients | 0.15-0.20 mg/kg/day | month 1-12 : 5-20 ng/mL |
*Note: two divided doses, q12h
Liver Transplantation
It is recommended that patients initiate oral therapy with Prograf capsules if possible. If IV therapy is necessary, conversion from IV to oral Prograf is recommended as soon as oral therapy can be tolerated. This usually occurs within 2-3 days. The initial dose of Prograf should be administered no sooner than 6 hours after transplantation. In a patient receiving an IV infusion, the first dose of oral therapy should be given 8-12 hours after discontinuing the IV infusion. The recommended starting oral dose of Prograf capsules is 0.10-0.15 mg/kg/day administered in two divided daily doses every 12 hours. Co-administered grapefruit juice has been reported to increase tacrolimus blood trough concentrations in liver transplant patients. (See Drugs That May Alter Tacrolimus Concentrations .)
Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower Prograf dosages may be sufficient as maintenance therapy. Adjunct therapy with adrenal corticosteroids is recommended early post transplant.
Dosage and typical tacrolimus whole blood trough concentrations are shown in the table above; blood concentration details are described in Blood Concentration Monitoring : Liver Transplantation below.
Kidney Transplantation
The recommended starting oral dose of Prograf is 0.2 mg/kg/day administered every 12 hours in two divided doses. The initial dose of Prograf may be administered within 24 hours of transplantation, but should be delayed until renal function has recovered (as indicated for example by a serum creatinine< 4 mg/dL). Black patients may require higher doses to achieve comparable blood concentrations. Dosage and typical tacrolimus whole blood trough concentrations are shown in the table above; blood concentration details are described in Blood Concentration Monitoring: Kidney Transplantation below.
The data in kidney transplant patients indicate that the Black patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients.
| Time After Transplant | Caucasian n=114 | Black n=56 | ||||
| Dose (mg/kg) | Trough Concentrations (ng/mL) | Dose (mg/kg) | Trough Concentrations (ng/mL) | |||
| Day 7 | 0.18 | 12.0 | 0.23 | 10.9 | ||
| Month 1 | 0.17 | 12.8 | 0.26 | 12.9 | ||
| Month 6 | 0.14 | 11.8 | 0.24 | 11.5 | ||
| Month 12 | 0.13 | 10.1 | 0.19 | 11.0 | ||
Pediatric Patients
Pediatric liver transplantation patients without pre-existing renal or hepatic dysfunction have required and tolerated higher doses than adults to achieve similar blood concentrations. Therefore, it is recommended that therapy be initiated in pediatric patients at a starting IV dose of 0.03-0.05 mg/kg/day and a starting oral dose of 0.15-0.20 mg/kg/day. Dose adjustments may be required. Experience in pediatric kidney transplantation patients is limited.
Patients with Hepatic or Renal Dysfunction
Due to the reduced clearance and prolonged half-life, patients with severe hepatic impairment (Pugh > 10) may require lower doses of Prograf. Close monitoring of blood concentrations is warranted.