Approved Drug Label (PDF)
5
Warnings and Precautions
5.15 Cannabidiol Drug Interactions
Newly added subsection:
When cannabidiol and ASTAGRAF XL are co-administered,
closely monitor for an increase in tacrolimus blood levels
and for adverse reactions suggestive of tacrolimus toxicity.
A dose reduction of ASTAGRAF XL should be considered as
needed when ASTAGRAF XL is co-administered with cannabidiol
[see Dosage and Administration (2.4) and Drug
Interactions (7.3)].
7
Drug Interactions
7.3 Cannabidiol
Newly added subsection:
The blood levels of tacrolimus may increase upon concomitant
use with cannabidiol. When cannabidiol and ASTAGRAF
XL are co-administered, closely monitor for an increase in
tacrolimus blood levels and for adverse reactions suggestive of
tacrolimus toxicity. A dose reduction of ASTAGRAF XL should
be considered as needed when ASTAGRAF XL is coadministered
with cannabidiol [see Dosage and Administration (2.4) and
Warnings and Precautions (5.15)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
Additions and revisions underlined:
Especially tell your healthcare
provider if you take:
. . .
cannabidiol (EPIDIOLEX)
. . .
Approved Drug Label (PDF)
5
Warnings and Precautions
5.6 Nephrotoxicity
due to ASTAGRAF XL and Drug Interactions
Additions and/or
revisions underlined:
ASTAGRAF XL, like other calcineurin-inhibitors, can cause
acute or chronic nephrotoxicity in transplant patients due to its
vasoconstrictive effect on renal vasculature, toxic tubulopathy and
tubular-interstitial effects. Acute renal impairment associated with tacrolimus
toxicity can result in high serum creatinine, hyperkalemia, decreased secretion
of urea and hyperuricemia, and is usually reversible. In patients with
elevated serum creatinine and tacrolimus whole blood trough concentrations
greater than the recommended range, consider dosage reduction or temporary
interruption of tacrolimus administration.
The risk for nephrotoxicity may increase when
ASTAGRAF XL is concomitantly administered with CYP3A inhibitors (by increasing
tacrolimus whole blood concentrations) or drugs associated with nephrotoxicity
(e.g., aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse
transcriptase inhibitors, protease inhibitors). When tacrolimus is used
concurrently with other known nephrotoxic drugs, monitor renal function and
tacrolimus blood concentrations, and adjust dose of both tacrolimus and/or
concomitant medications during concurrent use [see Adverse Reactions (6.1, 6.2) and Drug Interactions (7.2)].
5.14 Thrombotic
Microangiopathy (TMA) Including Hemolytic Uremic Syndrome and Thrombotic
Thrombocytopenic Purpura
Newly added subsection:
Cases of thrombotic microangiopathy (TMA), including
hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP),
have been reported in patients treated with ASTAGRAF XL TMA may have a
multifactorial etiology. Risk factors for TMA that can occur in transplant patients
include, for example, severe infections, graft-versus-host disease (GVHD),
Human Leukocyte Antigen (HLA) mismatch, the use of calcineurin inhibitors and
mammalian target of rapamycin (mTOR) inhibitors. These risk factors may, either
alone or combined, contribute to the risk of TMA.
In patients with signs and symptoms of TMA, consider
tacrolimus as a risk factor. Concurrent use of tacrolimus and mTOR inhibitors
may contribute to the risk of TMA.
6
Adverse Reactions
Addition of the
following to the bulleted line listing:
7
Drug Interactions
7.2 Effects of Other Drugs/Substances on ASTAGRAF XL
Addition of Caspofungin drug interaction to Table 5
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
Extensive changes;
please refer to label
PATIENT COUNSELING INFORMATION
17.9
Thrombotic Microangiopathy
Newly
added subsection:
Inform
patients that ASTAGRAF XL can cause blood clotting problems. The risk of this
occurring increases when patients take ASTAGRAF XL and sirolimus or everolimus
concomitantly, or when patients develop certain infections. Advise them to seek
medical attention promptly if they develop fever, petequiae or bruises, fatigue,
confusion, jaundice, oliguria [see Warnings and Precautions (5.14)].
Approved Drug Label (PDF)
5
Warnings and Precautions
Additions
and/or revisions underlined:
5.1
Lymphoma and Other Malignancies
… Examine patients for skin changes
and advise to avoid or limit exposure to sunlight and UV light by wearing
protective clothing and using a sunscreen with a high protection factor.
… The risk of PTLD appears greatest
in patients who are EBV seronegative, a population which includes many young
children. Monitor EBV serology during treatment.
5.4
Not Interchangeable with Other Tacrolimus Products – Medication Errors
… ASTAGRAF XL is not substitutable for
tacrolimus extended-release tablets, tacrolimus immediate-release capsules
or tacrolimus for oral suspension. Instruct patients and caregivers to
recognize the appearance of ASTAGRAF XL capsules and to confirm with the
healthcare provider if a different product is dispensed or if dosing
instructions have changed.
5.10
Risk of Rejection with Strong CYP3A Inducers and Risk of Serious Adverse
Reactions with Strong CYP3A Inhibitors
… when coadministering ASTAGRAF XL
with strong CYP3A inhibitors (e.g., including but not limited to
telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole,
clarithromycin) or strong CYP3A inducers (e.g., including but not limited to
rifampin, rifabutin).
6
Adverse Reactions
Addition
of the following bulleted line listing
Lymphoma
and Other Malignancies
Serious
Infections
Increased
Mortality in Female Liver Transplant Patients
New
Onset Diabetes after Transplant
Nephrotoxicity
due to ASTAGRAF XL and Drug Interactions
Neurotoxicity
Hyperkalemia
Hypertension
QT
Prolongation
Pure
Red Cell Aplasia
6.1
Clinical Trials Experience
Additions
and/or revisions underlined:
Table 2:
Percentage of Patients with Infections in Study 1a Through One Year
Post-Kidney Transplant
Table 3:
Percentage of Patients with NODAT Through One Year Post-Kidney
Transplant in Study 1a
Table 4:
Adverse Reactions (? 15%) in Kidney Transplant Patients Through One Year
Post-Transplant in Study 1a
Following the Vascular Disorders bullet, the
following information has been added:
Pediatrics
De Novo Pediatric Transplant Patients
A study
was conducted in 44 de novo pediatric transplant patients, (including 25 kidney
transplant patients; 13 randomized to Astagraf XL and 12 randomized to
Prograf), who were started on 0.3 mg/kg daily of tacrolimus product, given once
daily for Astagraf XL and divided into two doses for Prograf. Two kidney
transplant patients on Prograf discontinued the study (withdrawn consent,
sapovirus enteritis). Thirteen (13) pediatric kidney transplant patients
completed 52 weeks on ASTAGRAF XL. The most common adverse reactions were
diarrhea [7/13 (54%)], increased blood creatinine [6/13 (46%)], hypertension
[3/13 (23%)], cough [4/13 (31%)], and upper respiratory tract infection [4/13
(31%)].
Stable Pediatric Transplant Patients
Another
study was conducted in 81 stable pediatric allograft recipients (including 48
kidney transplant patients) 5 to 16 years of age converted 1:1 (mg:mg) from
Prograf to ASTAGRAF XL. Seventy-six (76) pediatric patients completed at least
one year of ASTAGRAF XL-based treatment. Treatment-related adverse reactions were
reported in 35%, including 13% serious adverse reactions. The most frequent
adverse reactions by system organ class were infections (55.7%), followed by
gastrointestinal disorders (27.8%), skin and subcutaneous tissue disorders
(21.5%), respiratory, thoracic and mediastinal disorders (20.3% each). The most
common adverse reactions were diarrhea (13.9%), headache (13.9%) and cough
(11.4%).
6.2 Postmarketing
Experience
… or
establish a causal relationship to drug exposure. These reactions have been
chosen for inclusion due to either their seriousness, frequency of reporting or
causal connection to ASTAGRAF XL:
Blood and Lymphatic System Disorders …
Musculoskeletal and Connective Tissue Disorders:
Rhabdomyolysis, myalgia, polyarthritis, pain in extremity including
Calcineurin-Inhibitor Induced Pain Syndrome (CIPS).
7
Drug Interactions
7.1 Mycophenolic Acid
Additions and/or revisions underlined:
When
ASTAGRAF XL is prescribed with a given dose of a mycophenolic acid (MPA)
product, exposure to MPA is higher with ASTAGRAF XL coadministration than with
cyclosporine coadministration with MPA …
8
Use in Specific Populations
8.1 Pregnancy
PLLR Conversion; extensive changes. Please refer to label for complete
information.
8.2 Lactation
PLLR Conversion; newly added information. Please refer to label for complete
information.
8.3 Females and
Males of Reproductive Technology
PLLR Conversion; newly added information. Please refer to label for complete
information.
8.4 Pediatric Use
Extensive information added. Please refer to label for complete
information.
8.8 Race
Addition of the following:
African-American
and Hispanic patients are at increased risk for new onset diabetes after
transplant. Monitor blood glucose concentrations and treat appropriately
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions
and/or revisions underlined:
Advise patients or caregivers
to:
17.3
Increased Risk of Infection
… if they develop any symptoms of
infection such as fever, sweats or chills, cough or flu-like symptoms,
muscle aches, or warm, red, painful areas of the skin.
17.8
Hypertension
… with anti-hypertensive therapy. Advise patients to monitor their blood
pressure.
17.9
Drug Interactions
… may require the adjustment of the
dosage of ASTAGRAF XL. Advise patients to avoid grapefruit, grapefruit juice
and alcoholic beverages.
Addition
of the following subsection:
17.10
Pregnancy, Lactation, and Infertility
Inform women of childbearing
potential that ASTAGRAF XL can harm the fetus. Instruct male and female
patients to discuss with their healthcare provider family planning options
including appropriate contraception. Also, discuss with pregnant patients the
risks and benefits of breastfeeding their infant.
Encourage female transplant patients
who become pregnant and male patients who have fathered a pregnancy, exposed to
immunosuppressants including tacrolimus, to enroll in the voluntary
Transplantation Pregnancy Registry International. To enroll or register,
patients can call the toll-free number 1-877-955-6877 or https://www.transplantpregnancyregistry.org/.
Based on animal studies, ASTAGRAF
XL may affect fertility in males and females.
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