Drug Interaction:
Immunosuppressant drugs include-
Azathioprine, Tacrolimus (FK 506 ), Mycophenolate Mofetil, Cyclosporine, Muromonab -CD3,
Interacting drugs- summary
+Tacrolimus -
Nephrotoxic agents/ Aminoglycosides / Amphotericin B / Cisplatin / Cyclosporine
potential for additive or synergistic impairment of renal function
Take care while administering tacrolimus with these drugs
Antifungals / Bromocriptine / Cal chnl blockrs/Cimetidine /Clarithromycin /Danazol / Diltiazem / Erythromycin /Methyl prednisolon / Metoclopramide
these agents may increase tacrolimus blood levels
Carbamazepine / Phenobarbital/ Phenytoin / Rifamycins
these agents may decrease tacrolimus blood levels
Itraconazole
coadmin has lead to increased tracrolimus plasma concentrations
Tacrolimus +
Vaccines
immunosuppressants may affect vaccination.
Indication:
ASTAGRAF XL. (tacrolimus extended-release capsules), for oral use Initial U.S. Approval: 2013
WARNING: MALIGNANCIES; SERIOUS INFECTIONS; AND
MORTALITY IN FEMALE LIVER TRANSPLANT RECIPIENTS
See full prescribing information for complete boxed warning
Only physicians experienced in immunosuppressive therapy and management
of organ transplant patients should prescribe ASTAGRAF XL (5.1)
Increased susceptibility to infection and the possible development of malignancies
may result from immunosuppression (5.2, 5.3, 5.6, 5.7)
Use in liver transplantation is not recommended due to increased mortality rate in
female liver transplant recipients (5.4)
RECENT MAJOR CHANGES
Warnings and Precautions,
Use with CYP3A4 Inhibitors and Inducers (5.14) 02//2014
Warnings and Precautions,
QT Prolongation (5.15) 02/2014
Warnings and Precautions,
Gastrointestinal Perforation (5.18) 02/2014
LIST OF DRUGS DURING 2004
Sr.No- 204
Name of the Drug- Tacrolimus Capsule (0.5mg/1mg/5mg)
Pharmacological Classification- For organ rejection
Date of Approval- 21-05-2004
Approved by U.S.FDA on 30-12-2004 (Ref- FDA approved List- 2004)
Approved by FDA on April 8, 1994
New Drugs Approved by (DCI) Drug Controller GENERAL - India For Marketing
(Ref- IDMA Publication)
Name of Drug Indication Date of Approval
1.Tacrolimus capsules 03-12-2012
0.25mg
For the prophylaxis of organ rejection in patients receiving Allogenic
Liver or Kidney transplant
2.Tacrolimus Capsule 21-05-2004
0.5mg/1mg/5mg
For organ rejection
3.Tacrolimus Capsule 3mg 24-04-2010
Addl.stgth
As approved
4.Tacrolimus Granules For Oral 26-11-2009
Suspnesion 0.2/1mg/ per sachet
Prophylaxis of transplant Rejection in Adult Kidney or Liver
Allograf rejection
5.Tacrolimus Ointment 10-03-2003
Imuno-modulator
6. Tacrolimus PR Caps 24-05-2010
0.5/1/5mg
For prophylaxis of Transplant Rejection in adult Kidney or Liver
Allograf rejection
Immunosuppressant drugs include-
Azathioprine, Tacrolimus (FK 506 ), Mycophenolate Mofetil, Cyclosporine, Muromonab -CD3,
Organ(liver) prophylaxis
INFORMATION UPDATE-
TOPICAL TACROLIMUS- USE AS LAST RESORT
Topical tacrolimus should not be used-
To treat atopic eczema
Even when atopic eczema is moderate to severe , tacrolimus should not be used as a
-first line of treatment . It should not be used before other treatements are tried
Tacrolimus may be considered to treat moderate or severe atopic eczema if the maximum
strength and potency of topical coticosteroids has been tried and has not worked, or where
there is a serious risk of important side effects from further use of topical corticisteroids.
European Medicines Evaluation Agency ( EMEA ) has recommended greater caution in order
to reduce potential risks of skin cancer and lymphoma. ( MIMS )
Adverse Reaction:
Principal adverse reactions are- tremor, headache, diarrhea, hypertension, nausea, and renal
dysfunction.
Others incude -
Abnormal dreams, agitation, anxiety, confusion, convulsion, depression, dizziness, emotional
stability, hallucinations, hypertonia, incordination, myoclonus nervousness, neuropathy,
psychosis, somnolence, thinking abnormal.
Special senses- abnormal vision, amblyopia, tinnitus
GI- Chlangitis, cholestatic jaundice, dyspepsia, dysphasia, flatulence, GI hemorrhage, GI peforation,hepatitis, ileus, increased appetite, jaundice, liver damage, oral moniliasis.
Cardiovascular- chest apin, abnormal ECG, hemorrhage, hypotension, tachycardia,
GU- hematuria, kidney failure
Metabolic/Nutrional- acidosis, alkaline phosphatase,increased alkalosis, bilirubinenima,
hypophosphatemia, hyponatreamia, AST increased, ALT decreased
Miscellaneous- arthalgia, generalized spasm., leg cramps, myalgia, myastenia, osteoporosis
Respiratory- asthma, bronchitis, cough increased, lung disorder, pulmonary edema, pharyngitis,
pneumonia, respiratory disorder, rhinitis, sinusitis, voice alteration
Dermatologic- alopecia, herpes simplex, hirsutism, skin disorder, sweating
Contra-Indications:
Hypersens to the drug
Special precautions:
Monitor regularly serum creatinine and potassium. Hyperetension is a common adverse effect
Hyperglycemia
Monitoring- Regularly assess serum creatinine and potassium. Perform routine monitoring of
metabolic and hematolgic systems as clinically warranted
Hypertension- is common adverse efect of tracolimus therap . Mild or moderate hypertension is more
frequently reported than severe hypertension. antihypertensive therapy may be required
Hyperglycemia- was associated with use of tracolimus in 29% to 47% of liver plant receipients and
may require treatment
Warnings-
Nephrotoxicity- tacrolimus can cause nephrotoxicity, particularly when used in high doses, particularly
when used in high doses.
Hyperkalemia- Mild to severe hyperkalemia has been noted in 10% to 44% of liver transplant
receipents treated with tacrolimus,which may require treatment. Monitor serum paotassium levels and
do not use potassium spaing diuretics therapy
Neurotoxicty- neurotoxicity including tremor, headache and otherchanges inmotor function status and
sensory function occured in about 55% of liver transplant recipients. Com and delirium also have been
associated withhigh plasma concentrations of tracolimus.
Lymphomas- because of the danger of oversuppression of the immune system,which can increase
susceptibility to infection, do not adminster tracolimus with other immunosuppressive agents except
adrenal corticosteroids.
The efficacy and safety of the use of tacromilus in combination with other immunosuppressive agents
has not been determined
Hypersentivity- a few patients receiving the injection have experienced anphylactic reactions.
Although the exact cause of these raections is not known , other drugs with castor oil derivatives have
been associated with anaphylaxis in small percentage of patients
Renal/function function impairment- use lower doses for patients for patients with renal insufficiency.
Use of tracolimus in liver transparent receipients experiencing post-transplant hepatic impairment
may be associated with increased risk of developing renal insufficiency related to high whole-blood
levels of tracolimus.
Monitor these patients closely and consider dosage adjustments. Use lower doses in these patients
Carcinogenesis/Fertility impairment- it has been reported that reduction or discontiuation of
immunosuppression may cause the lesions to regress.
Pregnancy- the use of tracolimus during pregnancy has associated with neonatal hyperkalemia
and renal dysfunction
Lactaction- since tacrolimus is excreted in breast milk, avoid nusring.
Children- pediatric patients generally require higher doses to maintain blood trough levels of
tacrolimus similar to adult patients
Dosages/ Overdosage Etc:
Approved by FDA on April 8, 1994
Indications:
Organ(liver) prophylaxis
Dosage:
Injection:
For IV infusion only
Overdosage- There is minimal experience with overdosage. In patients who have received inadvertant overdosage of tacrolimus, no adverse reactions different from those reported in patients receiving therapeutic doses have been described.
1. Follow general supportive treatment
2. Based on the poor aqueous solubility and extensive erythrocyte and plasm protein binding , it is anticipated that tacrolimus is not dialyzable to any significant extent.
Missed dose-
1. If you miss a dose of this medicine, take it as soon as possible.
2. However, if it is almost time for next dose, skip the missed dose and go back to your regular dosing schedule.
3. Do not double doses.
INDICATIONS AND USAGE
ASTAGRAF XL is a calcineurin-inhibitor immunosuppressant indicated for
the prophylaxis of organ rejection in patients receiving a kidney transplan
with mycophenolate mofetil (MMF) and corticosteroids, with or without
basiliximab induction
Limitations of use :
Not interchangeable with tacrolimus immediate-release capsules
Do not use simultaneously with cyclosporine
DOSAGE AND ADMINISTRATION
Recommended Initial Oral Dose and Observed Whole Blood Trough Concentrations
in Kidney Transplant Patients
Treatment Regimen Oral Dose Observed Whole Blood Trough Concentration
With basiliximab 0.15 mg/kg/day Day 1 to 60: 5-17 ng/mL
induction Month 3 to12: 4-12 ng/mL
Without induction Pre-operative: 0.1 mg/kg/day Day 1 to 60: 6-20 ng/mL
Post-operative: 0.2 mg/kg/day Month 3 to 12: 6-14 ng/mL
.
b Give first dose prior to or within 48 hours after transplant completion; may delay
therapy initiation until renal function has recovered
c Give preoperative dose within 12 hours prior to reperfusion, and first post-operative
dose within 12 hours after reperfusion but not less than 4 hours after pre-operative dose
Take once daily in the morning, preferably on an empty stomach; do not take with
an alcoholic beverage or grapefruit juice; do not chew, divide or crush capsules
Monitoring of whole blood tacrolimus trough concentrations is recommended
DOSAGE FORMS AND STRENGTHS
Capsules: 0.5 mg, 1 mg, 5 mg
Patient Information:
PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling (Medication Guide)
Administration
Advise patients to:
Inspect your ASTAGRAF XL medicine when you receive a new prescription and before
taking it.
If the appearance of the capsule is not the same as usual, or if dosage
instructions have changed, speak to your doctor or pharmacist as soon as possible
to make sure that you have the right medicine.
Take ASTAGRAF XL at the same time everyday to achieve consistent blood
concentrations.
Take ASTAGRAF XL in the morning, preferably at least 1 hour before or at least
2 hours after breakfast to achieve maximum possible blood concentrations of the drug.
Swallow capsule whole with liquid. Do not chew, divide or crush capsule.
Not take ASTAGRAF XL with an alcoholic beverage
Drug Interactions
Take a missed dose of ASTAGRAF XL as soon as the patient remembers but not
more than 14 hours after the scheduled time (i.e. for a missed 8AM dose, take by 10PM).
Beyond the 14-hour timeframe, the patient should wait until the usual scheduled time
the following morning to take the next scheduled dose.
Do not take 2 doses at the same time.
Development of Lymphoma and Other Malignancies
Inform patients they are at increased risk of developing lymphomas and other
malignancies, particularly of the skin, due to immunosuppression.
Advise patients to limit exposure to sunlight and ultraviolet (UV) light by wearing
protective clothing and use a sunscreen with a high protection factor
Increased Risk of Infection
Inform patients they are at increased risk of developing a variety of infections, including
opportunistic infections, due to immunosuppression and to contact their physician
if they develop any symptoms of infection .
New Onset Diabetes After Transplant
Inform patients that ASTAGRAF XL can cause diabetes mellitus and should be advised
to contact their physician if they develop frequent urination, increased thirst
or hunger .
Nephrotoxicity
Inform patients that ASTAGRAF XL can have toxic effects on the kidney that should
be monitored.
Advise patients to attend all visits and complete all blood tests ordered by their
medical team .
Neurotoxicity
Inform patients that they are at risk of developing adverse neurologic effects including
seizure, altered mental status, and tremor. Advise patients to contact their physician
should they develop vision changes, delirium, or tremors .
Hyperkalemia
Inform patients that ASTAGRAF XL can cause hyperkalemia. Monitoring of potassium
levels may be necessary, especially with concomitant use of other drugs known to
cause hyperkalemia .
Hypertension
Inform patients that ASTAGRAF XL can cause high blood pressure which may require
treatment with antihypertensive therapy .
Drug Interactions
Instruct patients to tell their health care providers when they start or stop taking any
concomitant medications, including prescription and non-prescription medicines,
herbal and dietary supplements. Some medications could alter tacrolimus
concentrations in the blood and thus may require the adjustment of the dosage of
ASTAGRAF XL .
Pregnant Women and Nursing Mothers
Instruct patients to tell their healthcare provider if they plan to become pregnant
or breast-feed their infant
Immunizations
Inform patients that ASTAGRAF XL can interfere with the usual response to
immunizations and that they should avoid live vaccines .
Product of Japan
Manufactured by:
Astellas Ireland Co., Limited
Killorglin, County Kerry, Ireland
Marketed by:
Astellas Pharma US, Inc.
Northbrook, IL 60062
Date: February 2014
Pharmacology/ Pharmacokinetics:
Pharmacology:
Tacrolimus ,previously known as FK 506., is a macrolide immunosuppressant produced by Sreptomyces tsukubaensis.
Tacromilus prolongs the survival of the host and transplanted graft in animal transplant models of liver, kidney,heart, bone marrow, small bowel and pancreas, lung and trachea, skin, cornea and limb.
Pharmacokinetics:
Absorption from GI tract after oral admin is variable. The absorption half-life in 16 liver transplant patients averaged 5.7hrs. Peak serum concentration is acheived in about 1.5 to 3.5hrs.
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1. Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. Tacrolimus
is transferred across the placenta. The use of tacrolimus during pregnancy in humans
has been associated with neonatal hyperkalemia and renal dysfunction.
ASTAGRAF XL should be used during pregnancy only if the potential benefit
to the mother justifies the potential risk to the fetus.
2. Nursing Mothers
Tacrolimus is present in breast milk. Because of the potential for serious adverse
drug reactions in nursing infants from ASTAGRAF XL, a decision should be made
whether to discontinue nursing or to discontinue the drug, taking into account the
importance of drug to the mother.
3. Pediatric Use
The safety and efficacy of ASTAGRAF XL in pediatric kidney transplant
patients < 16 years of age has not been established.
4. Geriatric Use
Clinical studies of ASTAGRAF XL did not include sufficient numbers of subjects
aged 65 and over to determine whether they respond differently from younger
subjects. Other reported clinical experience has not identified differences in
responses between elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, reflecting
the greater frequency of decreased hepatic, renal, or cardiac function and
of concomitant disease or other drug therapy.
5. Renal Impairment
The pharmacokinetics of tacrolimus in patients with renal impairment was similar
to that in healthy subjects with normal renal function. However, due to its potential
for nephrotoxicity, frequent monitoring of renal function is recommended; tacrolimus
dosage should be reduced if indicated ].
6. Hepatic Impairment
The mean clearance of tacrolimus was substantially lower in patients with severe
hepatic impairment (mean Child-Pugh score: >10) compared to healthy subjects
with normal hepatic function. Frequent monitoring of tacrolimus trough concentrations
is warranted in patients with hepatic impairment .
Manufacturer Details