Prograf


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tacrolimus

Advagraf, Prograf, Protopic

Pharmacologic class: Macrolide

Therapeutic class: Immunosuppressant

Pregnancy risk category C

FDA Box Warning

Immunosuppression may increase patient's susceptibility to infection and lymphoma development. Give under supervision of physician experienced in immunosuppressive therapy and management of organ transplant patients, in facility with adequate diagnostic and treatment resources. Physician responsible for maintenance therapy should have complete information needed for patient follow-up.

Be aware that long-term safety of topical calcineurin inhibitors hasn't been established.

Although a causal relationship hasn't been established, rare cases of malignancy (such as skin cancers and lymphoma) have been reported in patients treated with topical calcineurin inhibitors, including tacrolimus ointment. Therefore, continuous long-term use of tacrolimus ointment in any age-group should be avoided and application limited to areas of atopic dermatitis involvement. Tacrolimus ointment isn't indicated for use in children younger than age 2. Only 0.03% tacrolimus ointment is indicated for use in children ages 2 to 15.

Action

Unknown. Thought to inhibit T-lymphocyte activation.

Availability

Capsules: 0.5 mg, 1 mg, 5 mg

Injection: 5 mg/ml

Topical ointment: 0.03%, 0.1%

Indications and dosages

Prevention of organ rejection in patients with allogeneic liver transplants

Adults: Initially, 0.1 to 0.15 mg/kg/day P.O. in two divided doses q 12 hours. Alternatively, 0.03 to 0.05 mg/kg/day by continuous I.V. infusion.

Children: 0.15 to 0.2 mg/kg/day P.O. in two divided doses q 12 hours. Alternatively, 0.03 to 0.05 mg/kg/day by continuous I.V. infusion.

Prevention of organ rejection in patients with allogeneic kidney transplants

Adults: Initially, 0.2 mg/kg/day P.O. in two divided doses q 12 hours when used in combination with azathioprine, or 0.1 mg/kg/day P.O. when used in combination with mycophenolate mofetil (MMF). Alternatively, 0.03 to 0.05 mg/kg/day by continuous I.V. infusion until oral dosing can be tolerated.

Prevention of heart transplant rejection

Adults: Initially, 0.075 mg/kg/day P.O. q 12 hours in two divided doses in combination with azathioprine or MMF.

Moderate to severe atopic dermatitis

Adults: 0.03% or 0.1% ointment applied b.i.d. to affected area, continued 1 week after dermatitis symptoms resolve

Children ages 2 and older: 0.03% ointment applied b.i.d. to affected area, continued 1 week after dermatitis symptoms resolve

Dosage adjustment

• Hepatic or renal impairment

• Concurrent use of CYP3A inducers or inhibitors

• Black patients

Contraindications

• Hypersensitivity to drug or its components (including castor oil derivatives)

Precautions

Use cautiously in:

• severe hepatic disease, renal impairment, diabetes mellitus, hypertension, hyperkalemia, hyperuricemia, lymphoma, serious infections

• skin barrier defect with increased potential for systemic absorption of tacrolimus ointment

• premalignant and malignant skin conditions (avoid use)

• concurrent use of cyclosporine, nelfinavir, or live vaccines (avoid use)

• concurrent use of strong CYP3A4 inhibitors (such as boceprevir, clarithromycin, itraconazole, ketoconazole, ritonavir, telaprevir, voriconazole,) and strong inducers (such as rifampin, rifabutin) (not recommended)

• concurrent use of other substrates or CYP3A4 inhibitors that also have potential to prolong QT interval

• concurrent use of sirolimus (not recommended in liver and heart transplant; use with sirolimus in kidney transplant not established)

• concurrent use of other nephrotoxic drugs or drugs that cause hyperkalemia

• prolonged exposure to ultraviolet (UV) light and sunlight (avoid)

• pregnant or breastfeeding patients

• children younger than age 12 (age 2 for ointment use).

Administration

• Give oral form consistently with or without food but not with grapefruit juice.

• Give I.V. doses by infusion only. Be aware that I.V. use is reserved for patients who can't tolerate capsules orally.

• Start therapy within 24 hours of kidney transplantation and no earlier than 6 hours after liver or heart transplantation. Switch to oral dosing as soon as tolerable, starting 8 to 12 hours after I.V. dosing ends.

Before giving I.V., ensure that epinephrine 1:1,000 and oxygen are at hand in case of emergency.

• For I.V. use, dilute in normal saline solution or dextrose 5% in water to a concentration of 0.004 to 0.02 mg/ml. Give by infusion only.

• Be aware that ointment is used only as second-line therapy for the short-term and noncontinuous treatment of moderate to severe atopic dermatitis in nonimmunocompromised patients who have failed to respond adequately to other topical prescription treatments for atopic dermatitis.

• After applying ointment, don't place occlusive dressing or wrapping over affected area.

Adverse reactions

CNS: tremor, headache, insomnia, paresthesia, delirium, asthenia, neurotoxicities (including posterior reversible encephalopathy syndrome, delirium, seizures, and coma)

CV: hypertension, peripheral edema, myocardial hypertrophy

GI: nausea, vomiting, diarrhea, constipation, abdominal pain, ascites, anorexia

GU: hematuria, proteinuria, urinary tract infection, albuminuria, abnormal renal function, oliguria, renal failure, nephrotoxicity

Hematologic: anemia, leukocytosis, thrombocytopenia, agranulocytosis, hemolytic anemia, pure red cell aplasia

Metabolic: new-onset diabetes mellitus, hyperglycemia, hypomagnesemia, hypokalemia, hyperkalemia

Musculoskeletal: back pain

Respiratory: dyspnea, pleural effusion, atelectasis

Skin: burning (with ointment), rash, flushing, pruritus, alopecia

Other: pain, fever, chills, lymphadenopathy, serious infections (including cytomegalovirus infections and polyoma virus infections), lymphoma and other malignancies, anaphylaxis

Interactions

Drug-drug. Bromocriptine, chloramphenicol, cimetidine, clarithromycin, clotrimazole, cyclosporine, danazol, diltiazem, erythromycin, fluconazole, itraconazole, ketoconazole, methylprednisolone, metoclopramide, metronidazole, nicardipine, omeprazole, protease inhibitors, verapamil: increased tacrolimus blood level

Cyclosporine: increased risk of nephrotoxicity

CYP450 inducers (such as carbamazepine, phenobarbital, phenytoin, rifampin): decreased tacrolimus metabolism Immunosuppressants (except adrenocorticoids): immunologic oversuppression

Live-virus vaccines: interference with immune response to vaccine

Mycophenolate mofetil: increased mycophenolate blood level

Nephrotoxic drugs (such as aminoglycosides, amphotericin B, cisplatin, cyclosporine): additive or synergistic effects

Drug-diagnostic tests. Blood urea nitrogen, creatinine, glucose: increased levels

Hemoglobin, magnesium, platelets, white blood cells: decreased levels

Liver function tests: abnormal values

Potassium: increased or decreased level

Drug-food. Any food: inhibited drug absorption

Grapefruit or grapefruit juice: increased drug blood level

Drug-herbs. Astragalus, echinacea, melatonin: decreased immunosuppression

St. John's wort: decreased tacrolimus blood level

Patient monitoring

Once I.V. infusion starts, watch closely for signs and symptoms of anaphylaxis.

• Monitor cardiac, liver, and kidney function test results. Watch for signs and symptoms of cardiovascular disorder, nephrotoxicity, and hepatic dysfunction.

Assess neurologic status for evidence of neurotoxicity (including posterior encephalopathy syndrome and seizures).

• Monitor potassium level closely. Stay alert for signs and symptoms of hyperkalemia.

• Monitor blood glucose. Watch for indications of hyperglycemia.

• Evaluate respiratory status regularly.

Patient teaching

Teach patient to recognize and immediately report serious adverse reactions.

• Tell patient to take oral doses consistently with or without food, but not with grapefruit or grapefruit juice.

• Tell diabetic patient to expect increased blood glucose level, which may warrant further antidiabetic therapy. Advise him to monitor glucose level carefully.

• Instruct patient not to place occlusive dressings or wrappings over affected area after applying ointment. Tell him to use drug for 1 week after dermatitis symptoms resolve.

• Advise patient to avoid live vaccines and prolonged exposure to UV light or sunlight.

• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs, tests, foods, and herbs mentioned above.

tacrolimus (oral, IV)

(ta-kroe-li-mus) ,

Prograf

(trade name)

Classification

Therapeutic: immunosuppressants
Pregnancy Category: C

Indications

Prevention of organ rejection in patients who have undergone allogenic liver, kidney, or heart transplantation (used concurrently with corticosteroids).

Action

Inhibits T-lymphocyte activation.

Therapeutic effects

Prevention of transplanted organ rejection.

Pharmacokinetics

Absorption: Absorption following oral administration is erratic and incomplete (5–67%).
Distribution: Crosses the placenta and enters breast milk.
Protein Binding: 99%.
Metabolism and Excretion: 99% metabolized by the liver; <1% excreted unchanged in the urine.
Half-life: Liver transplant patients—11.7 hr; healthy volunteers—21.2 hr.

Time/action profile (immunosuppression)

ROUTEONSETPEAKDURATION
POrapid1.3–3.2 hr†12 hr
IVrapidunknown8–12 hr
†Blood level

Contraindications/Precautions

Contraindicated in: Hypersensitivity to tacrolimus or to castor oil (a component in the injection). Lactation: Breastfeeding should be avoided.
Use Cautiously in: Renal or hepatic impairment (dose ↓ may be required; if oliguria occurs, wait 48 hr before initiating tacrolimus).Concurrent use with cyclosporine should be avoided.Exposure to sunlight/UV light (may ↑ risk of malignant skin changes). Obstetric: Hyperkalemia and renal impairment may occur in the newborn; use only if benefit to mother justifies risk to the fetus.

Adverse Reactions/Side Effects

Central nervous system

  • seizures (life-threatening)
  • dizziness (most frequent)
  • headache (most frequent)
  • insomnia (most frequent)
  • tremor (most frequent)
  • abnormal dreams
  • agitation
  • anxiety
  • confusion
  • emotional lability
  • depression
  • hallucinations
  • psychoses
  • somnolence

Ear, Eye, Nose, Throat

  • abnormal vision
  • amblyopia
  • tinnitus

Respiratory

  • cough (most frequent)
  • pleural effusion (most frequent)
  • asthma
  • bronchitis
  • pharyngitis
  • pneumonia
  • pulmonary edema

Cardiovascular

  • hypertension (most frequent)
  • peripheral edema (most frequent)
  • QTc interval prolongation

Gastrointestinal

  • GI bleeding (life-threatening)
  • abdominal pain (most frequent)
  • anorexia (most frequent)
  • ascites (most frequent)
  • constipation (most frequent)
  • diarrhea (most frequent)
  • dyspepsia (most frequent)
  • ↑ liver enzymes (most frequent)
  • nausea (most frequent)
  • vomiting (most frequent)
  • cholangitis
  • cholestatic jaundice
  • dysphagia
  • flatulence
  • ↑ appetite
  • oral thrush

Genitourinary

  • nephrotoxicity (most frequent)
  • urinary tract infection (most frequent)

Dermatologic

  • pruritus (most frequent)
  • rash (most frequent)
  • alopecia
  • herpes simplex
  • hirsutism
  • sweating
  • photosensitivity

Endocrinologic

  • hyperglycemia (most frequent)

Fluid and Electrolyte

  • hyperkalemia (most frequent)
  • hyperlipidemia (most frequent)
  • hypokalemia (most frequent)
  • hypomagnesemia (most frequent)
  • hypophosphatemia (most frequent)
  • hyperphosphatemia
  • hyperuricemia
  • hypocalcemia
  • hyponatremia
  • metabolic acidosis
  • metabolic alkalosis

Hematologic

  • anemia (most frequent)
  • leukocytosis (most frequent)
  • leukopenia (most frequent)
  • thrombocytopenia (most frequent)
  • coagulation defects
  • pure red cell aplasia

Musculoskeletal

  • arthralgia (most frequent)
  • hypertonia
  • leg cramps
  • muscle spasm
  • myalgia
  • myasthenia
  • osteoporosis

Neurologic

  • paresthesia (most frequent)
  • neuropathy

Miscellaneous

  • allergic reactions including anaphylaxis (life-threatening)
  • fever (most frequent)
  • generalized pain (most frequent)
  • abnormal healing
  • chills
  • risk of lymphoma/skin cancer

Interactions

Drug-Drug interaction

Risk of nephrotoxicity is ↑ by concurrent use of aminoglycosides, amphotericin B, cisplatin, or cyclosporine (allow 24 hr to pass after stopping cyclosporine before starting tacrolimus).Concurrent use of potassium-sparing diuretics, ACE inhibitors, or angiotensin II receptor antagonists ↑ risk of hyperkalemia.The following drugs ↑ tacrolimus blood levels: azoleantifungals, bromocriptine, calcium channel blockers, chloramphenicol, cimetidine, clarithromycin, cyclosporine, danazol, erythromycin, lansoprazole, magnesium/aluminum hydroxidemethylprednisolone, omeprazole, nefazodone, metoclopramide, protease inhibitors, and voriconazole.Phenobarbital, phenytoin, caspofungin, sirolimuscarbamazepine, and rifamycins may ↓ tacrolimus blood levels.Vaccinations may be less effective if given concurrently with tacrolimus (avoid use of live-virus vaccines). Concomitant use with astragalus, echinacea, and melatonin may interfere with immunosuppression.St. John's wort may ↓ tacrolimus blood levels.Food ↓ the rate and extent of GI absorption.Grapefruit juice ↑ absorption.

Route/Dosage

Because of the potential risk for anaphylaxis, the IV route of administration of tacrolimus should be reserved for those patients unable to take the drug orally.Kidney Transplantation
Oral (Adults) Initial dose—0.2 mg/kg/day in 2 divided doses; titrate to achieve recommended blood concentration.
Oral (Children) 0.15–0.4 mg/kg/day in 2 divided doses.
Intravenous (Adults) Initial dose—0.03–0.1 mg/kg/day as a continuous infusion; titrate to achieve recommended blood concentration.
Intravenous (Children) 0.03–0.15 mg/kg/day.
Liver Transplantation
Oral (Adults) Initial dose—0.1–0.15 mg/kg/day in 2 divided doses; titrate to achieve recommended blood concentration.
Oral (Children) Initial dose—0.15–0.2 mg/kg/day in 2 divided doses; titrate to achieve recommended blood concentration.
Intravenous (Adults and Children) Same as for kidney transplant.
Heart Transplanatation
Oral (Adults) Initial dose—0.075 mg/kg/day in 2 divided doses; titrate to achieve recommended blood concentration.
Intravenous (Adults) Initial dose—0.01 mg/kg/day as a continuous infusion; titrate to achieve recommended blood concentration.

Availability (generic available)

Capsules: 0.5 mg, 1 mg, 5 mg
Injection: 5 mg/mL

Nursing implications

Nursing assessment

  • Prevention of Organ Rejection: Monitor blood pressure closely during therapy. Hypertension is a common complication of tacrolimus therapy and should be treated.
    • Observe patients receiving IV tacrolimus for the development of anaphylaxis (rash, pruritus, laryngeal edema, wheezing) for at least 30 min and frequently thereafter. If signs develop, stop infusion and initiate treatment.
  • Lab Test Considerations: Tacrolimus blood level monitoring may be helpful in the evaluation of rejection and toxicity, dose adjustments, and assessment of compliance. For liver transplantation, most patients are stable when tacrolimus trough whole blood concentrations are maintained between 5–20 ng/mL. For kidney transplantation, during the first 3 mo, most patients maintained tacrolimus whole blood concentrations between 7–20 ng/mL and then between 5–15 ng/mL through 1 yr. For heart transplantation, from wk 1 to 3 mo, most patients maintained tacrolimus trough whole blood concentrations between 8–20 ng/mL and then between 6–18 ng/mL from 3–18 mo post-transplant.
    • Monitor serum creatinine, potassium, and glucose closely. ↑ serum creatinine and ↓ urine output may indicate nephrotoxicity. May also cause insulin-dependent post-transplant diabetes mellitus (incidence is higher in African American and Hispanic patients).
    • May also cause hyperuricemia, hypokalemia, hyperkalemia, hypomagnesemia, metabolic acidosis, metabolic alkalosis, hyperlipidemia, hyperphosphatemia, hypophosphatemia, hypocalcemia, and hyponatremia.
    • Monitor CBC. May cause anemia, leukocytosis, and thrombocytopenia.

Potential Nursing Diagnoses

Risk for infection (Adverse Reactions)

Implementation

  • Do not confuse Prograf with Prozac.
  • Therapy should be provided by clinicians and in facilities experienced in transplant management.
  • Therapy with tacrolimus should be started no sooner than 6 hr post-transplantation. Concurrent therapy with corticosteroids is recommended in the early postoperative period.
    • Tacrolimus should not be used concomitantly with cyclosporine. Tacrolimus or cyclosporine should be discontinued at least 24 hr before starting the other.
    • Oral therapy is preferred because of the risk of anaphylactic reactions with IV tacrolimus. IV therapy should be replaced with oral therapy as soon as possible.
    • Adults should be started at the lower end of the dose range. Pediatric: Children require higher doses to maintain blood trough concentrations of tacrolimus similar to adults.
  • Oral: Oral doses can be initiated 8–12 hr after discontinuation of IV doses. Maybe taken with or without food, but with or without food should be consistent, 12 hrs apart, at the same time each day.
  • Continuous Infusion: Dilute in 0.9% NaCl or D5W for a concentration of 0.004–0.02 mg/mL prior to use. May be stored in polyethylene or glass containers for 24 hr following dilution. Do not store in PVC containers.
  • Rate: Administer daily dose as a continuous infusion over 24 hr.
  • Y-Site Compatibility: alemtuzumab, alfentanil, amifostine, amikacin, aminocaproic acid, aminophylline, amiodarone, amphotericin B colloidal, amphotericin B lipid complex, amphotericin liposome,. anidulafungin., argatroban, atracurium, azithromycin, aztreonam, benztropine, bivalirudin, bleomycin, bumetanide, buprenorphine, busulfan, butorphanol, calcium acetate, calcium chloride, calcium gluconate, carboplatin, carmustine, caspofungin, cefazolin, cefperazone, cefotaxime, cefotetan, cefoxitin, ceftazidime, ceftriaxone, cefuroxime, chloramphenicol, chlorpromazine,. ciprofloxacin, cisatracurium, cisplatin, clindamycin, cyclophosphamide, cyclosporine, cytarabine, dactinomycin, daptomycin, dexamethasone sodium phosphate, dexmedetomidate, dexrazoxane, digoxin, diltiazem, diphenhydramine, dobutamine, docetaxel, dolasetron, dopamine, doripenem, doxacurium, doxorubicin, doxycycline, droperidol, enalaprilat, ephedrine, epinephrine, epirubicin, ertapenem, erythromycin lactobionate, esmolol, etoposide, etoposide phosphate, famotidine, fenoldopam, fentanyl, fluconazole, fludarabine, foscarnet, fosphenytoin, gemcitabine,. gentamicin, glycopyrrolate, granisetron, haloperidol, heparin, hetastarch, hydralazine, hydrocortisone sodium succinate, hydromorphone, idarubicin, ifosfamide, imipenem/cilastatin, insulin, irinotecan, isoproterenol, ketorolac, leucovorin, levofloxacin, levorphanol, lidocaine, linezolid, lorazepam, magnesioum sulfate, mannitol, mechlorethamine, meperidine, meropenem, mesna, metaraminol, methotrexate, methyldopate, methylprednisolone, metoclopramide, metoprolol, metronidazole, micafungin, midazolam, milrinone, mitoxantrone, morphine, multivitamins, mycophenolate, nafcilin, nalbuphine, naloxone, nesiritide, nicardipine,.norepinephrine, nitroglycerin, nitroprussidenorepinephrine, oxtreotide, ondansetron, oxacillin, oxytocin, paclitaxel, palosetron, pamidronate, pamcuronium, pemetrexed, penicillin G potassium, pentamidine, pentazocine, perphenazine, phentolamine, phenylephrine,. piperacillin/tazobactam, potassium acetate, potassium chloride, potassium phosphates, procainamide, prochlorperazine, promethazine, propranolol, quinupristin/dalfopristin, ranitidine, remifentanil, rocuronium, sodium acetate, sodium bicarbonate, sodium phosphates, streptozocin, succinylcholine, sufentanil, teniposide, theophylline, thiotepa, ticarcillin/clavulactam, tigecycline, tirofiban, tobramycin, tolazoline, trimethoprim/sulfamethoxazole, vancomycin, vasopressin, vecuronium, verapamil, vinCRIStine, vinorelbine, voriconazole, zidovudine, zolendronic acid
  • Y-Site Incompatibility: acyclovir, allopruinol, azathioprine, cefepeme, dantrolene, diazepam, diazoxide, esomeprezole, folic acid, ganciclovir, iron sucrose, levothyroxine, omeprazole, phenytoin, thiopental

Patient/Family Teaching

  • Instruct patient to take tacrolimus at the same time each day, as directed. Do not skip or double up on missed doses. Do not discontinue medication without advice of health care professional. Advise patient to read the Medication Guide prior to starting and with each Rx renewal; new information may be available.
    • Reinforce the need for lifelong therapy to prevent transplant rejection. Review symptoms of rejection for transplanted organ and stress need to notify health care professional immediately if they occur.
    • Advise patient to avoid grapefruit or grapefruit juice and eating raw oysters or other shellfish; make sure they are fully cooked before eating.
    • Advise patient to wear protective clothing and sunscreen to avoid photosensitivity reactions.
    • Instruct patient to avoid exposure to chicken pox, measles, mumps, and rubella. If exposed, see health care professional for prophylactic therapy.
    • Advise patient of the risk of taking tacrolimus during pregnancy.
    • Inform patient of the risk of lymphoma with tacrolimus therapy.
    • Emphasize the importance of repeated lab tests during tacrolimus therapy.

Evaluation/Desired Outcomes

  • Prevention of transplanted liver, kidney, or heart rejection.

Prograf

(prō′grăf′)
A trademark for the drug tacrolimus.
References in periodicals archive ?
According to the company, the primary endpoint of the study was a composite endpoint of treatment failure (biopsy-proven acute rejection or BPAR, graft failure, loss to follow up or death) that was evaluated after a 12-month treatment period to demonstrate the non-inferiority of Envarsus[R] compared to Prograf.
In conclusion, converting stable kidney transplant recipients from Prograf to an FDA and EMA approved generic tacrolimus is feasible and appears to be safe, but, nevertheless, it is suggested that close monitoring of patients and clinical monitoring of the graft function be implemented and maintained in time.
On admission, his immunosuppression regimen was mycophenolate mofetil (CellCept) 750 mg twice a day, tacrolimus (Prograf) 0.5 mg every 12 hours, prednisone 5 mg daily, and prophylactic sulfamethoxazole 800 mg/trimethoprim 160 mg three days a week.
The mycophenolate mofetil was discontinued, and the Prograf dosage was reduced to target FK506 troughs of 5-7.
Prograf is an antirejection medication used after an organ transplant to reduce the risk of organ rejection.
To keep his body from rejecting his new kidney, Mharick has been taking two maintenance medicines, Prograf (taken thrice a day) and Cellcept (once a day), which cost P220.50 and P133.75, respectively.
Veloxis Pharmaceuticals, A/S, Horsholm, Denmark, announced that one-daily Envarsus XR (tacrolimus extended-release tablets), an investigational new drug under review by the US Food and Drug Administration (FDA) for the review for the prevention of organ rejection in adult kidney transplant patients, demonstrated a lower treatment failure rate in African-Americans compared with twice-daily tacrolimus (Prograf).
The cells were treated with doxorubicin (Ebewe Pharma, Unterach am Attersee, Austria) and tacrolimus (FK506) (registered trademark Prograf, Astellas Pharma Inc., TYO: 4503, Japan) for 48 h.
Postoperative maintenance immunosuppression consisted of mycophenolate mofetil (CellCept), tacrolimus (Prograf) and prednisone.
The oral medication tacrolimus (Prograf) and new injectable medications used for treating arthritis, such as etanercept (Enbrel) or infliximab (Remicade), seem to be very effective for some individuals with psoriasis.
Boceprevir (Victrelis), a protease inhibitor approved for treating hepatitis C in 2011, interacts with cyclosporine, tacrolimus (Prograf), escitalopram (Lexapro), atorvastatin (Lipitor), and pravastatin (Pravachol), according to a statement from the Food and Drug Administration.
She initially received an immunosuppressive regimen of mycophenolate mofetil, prograf, and prednisone; mycophenolate mofetil was later discontinued.