FDA

Tacrolimus

Approved 10 Nov 2020OralCapsule

The FDA lists this product in 49 strengths and forms.

Indications

Tacrolimus capsules are a calcineurin-inhibitor immunosuppressant indicated for the prophylaxis of organ rejection in adult patients receiving allogeneic liver, kidney or heart transplants, and pediatric patients receiving allogeneic liver transplants in combination with other immunosuppressants. ( 1.1 )

1.1Prophylaxis of Organ Rejection in Kidney, Liver or Heart Transplant

Tacrolimus capsules are indicated for the prophylaxis of organ rejection, in adult patients receiving allogeneic kidney transplant [see Clinical Studies (14.1)] , liver transplant [see Clinical Studies (14.2)] , heart transplant [see Clinical Studies (14.3)] , and pediatric patients receiving allogeneic liver transplant [see Clinical Studies (14.2)] in combination with other immunosuppressants. Additional pediatric use information is approved for Astellas Pharma US, Inc.'s Prograf (tacrolimus) products.

However, due to Astellas Pharma US, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

Contraindications

Hypersensitivity to tacrolimus or HCO-60 (polyoxyl 60 hydrogenated castor oil). ( 4 ) Tacrolimus capsules are contraindicated in patients with a hypersensitivity to tacrolimus. Tacrolimus injection is contraindicated in patients with a hypersensitivity to HCO-60 (polyoxyl 60 hydrogenated castor oil). Hypersensitivity symptoms reported include dyspnea, rash, pruritus, and acute respiratory distress syndrome [see Adverse Reactions (6) ] .

Warnings and precautions

Not Interchangeable with Extended-Release Tacrolimus Products- Medication Errors: Instruct patients or caregivers to recognize the appearance of Tacrolimus capsules. ( 5.3 ) New Onset Diabetes After Transplant: Monitor blood glucose. ( 5.4 ) Nephrotoxicity (acute and/or chronic): Reduce the dose; use caution with other nephrotoxic drugs. ( 5.5 ) Neurotoxicity: Including risk of Posterior Reversible Encephalopathy Syndrome (PRES); monitor for neurologic abnormalities; reduce or discontinue tacrolimus capsules.

( 5.6 ) Hyperkalemia: Monitor serum potassium levels. Consider carefully before using with other agents also associated with hyperkalemia. ( 5.7 ) Hypertension: May require antihypertensive therapy. Monitor relevant drug-drug interactions. ( 5.8 ) Anaphylactic Reactions with IV formulation: Observe patients receiving tacrolimus injection for signs and symptoms of anaphylaxis. ( 5.9 ) Not recommended for use with sirolimus: Not recommended in liver and heart transplant due to increased risk of serious adverse reactions.

At a glance

Brand name: Tacrolimus
Route: Oral
Dosage form: Capsule
Applicant: Concord Biotech LTD
Status: Prescription
FDA approval: 10 Nov 2020
Application: ANDA213112-003

Indications

1.1Prophylaxis of Organ Rejection in Kidney, Liver or Heart Transplant

However, due to Astellas Pharma US, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

Contraindications

Warnings and precautions

Interactions

Mycophenolic Acid Products: Can increase MPA exposure after crossover from cyclosporine to tacrolimus; monitor for MPA-related adverse reactions and adjust MMF or MPA dose as needed. ( 7.1 ) Nelfinavir and Grapefruit Juice: Increased tacrolimus concentrations via CYP3A inhibition; avoid concomitant use. ( 7.2 ) CYP3A Inhibitors: Increased tacrolimus concentrations; monitor concentrations and adjust tacrolimus dose as needed.

( 5.11 , 7.2 ) CYP3A4 Inducers: Decreased tacrolimus concentrations; monitor concentrations and adjust tacrolimus dose as needed. ( 5.11 , 7.2 ) Therapeutic drug monitoring and dose reduction for tacrolimus should be considered when tacrolimus is co-administered with cannabidiol ( 5.17 , 7.3 ).

7.1Mycophenolic Acid

When tacrolimus is prescribed with a given dose of a mycophenolic acid (MPA) product, exposure to MPA is higher with tacrolimus co-administration than with cyclosporine co-administration with MPA, because cyclosporine interrupts the enterohepatic recirculation of MPA while tacrolimus does not. Monitor for MPA-associated adverse reactions and reduce the dose of concomitantly administered mycophenolic acid products as needed.

7.2Effects of Other Drugs on Tacrolimus Table

15 displays the effects of other drugs on Tacrolimus. Table 15. Effects of Other Drugs/Substances on Tacrolimus 1 1. Tacrolimus dosage adjustment recommendation based on observed effect of coadministered drug on tacrolimus exposures [see Clinical Pharmacology (12.3) ] , literature reports of altered tacrolimus exposures, or the other drug's known CYP3A inhibitor/inducer status. 2. High dose or double strength grapefruit juice is a strong CYP3A inhibitor; low dose or single strength grapefruit juice is a moderate CYP3A inhibitor. 3.

Strong CYP3A inhibitor/inducer, based on reported effect on exposures to tacrolimus along with supporting in vitro CYP3A inhibitor/inducer data, or based on drug- drug interaction studies with midazolam (sensitive CYP3A probe substrate). Drug/Substance Class or Name Drug Interaction Effect Recommendations Grapefruit or grapefruit juice 2 May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.6 , 5.11 , 5.12 )].

Avoid grapefruit or grapefruit juice. Strong CYP3A Inducers 3 : Antimycobacterials (e.g., rifampin, rifabutin), anticonvulsants (e.g., phenytoin, carbamazepine and phenobarbital), St John's Wort May decrease tacrolimus whole blood trough concentrations and increase the risk of rejection [see Warnings and Precautions (5.11 )]. Increase tacrolimus dose and monitor tacrolimus whole blood trough concentrations [ see Dosage and Administration (2.2 , 2.6 ) and Clinical Pharmacology (12.3) ].

Strong CYP3A Inhibitors 3 : Protease inhibitors (e.g, nelfinavir, telaprevir, boceprevir, ritonavir), azole antifungals (e.g., voriconazole, posaconazole, itraconazole, ketoconazole), antibiotics (e.g., clarithromycin, troleandomycin, chloramphenicol), nefazodone, letermovir, Schisandra sphenanthera extracts May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation).

A rapid, sharp rise in tacrolimus levels may occur early, despite an immediate reduction of tacrolimus dose [see Warnings and Precautions (5.6 , 5.11 , 5.12 )]. Reduce tacrolimus dose (for voriconazole and posaconazole, give one-third of the original dose) and adjust dose based on tacrolimus whole blood trough concentrations [ see Dosage and Administration (2.2 , 2.6 ) and Clinical Pharmacology (12.3) ]. Early and frequent monitoring of tacrolimus whole blood trough levels should start within 1-3 days and continue monitoring as necessary [see Warnings and Precautions (5.11)] .

Mild or Moderate CYP3A Inhibitors: Clotrimazole, antibiotics (e.g., erythromycin, fluconazole), calcium channel blockers (e.g., verapamil, diltiazem, nifedipine, nicardipine), amiodarone, danazol, ethinyl estradiol, cimetidine, lansoprazole and omeprazole May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.6 , 5.11 , 5.12 )].

Monitor tacrolimus whole blood trough concentrations and reduce tacrolimus dose if needed [ see Dosage and Administration (2.2 , 2.6 ) and Clinical Pharmacology (12.3) ]. Other drugs, such as: Magnesium and aluminum hydroxide antacids Metoclopramide May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.6 , 5.11 , 5.12 )].

Monitor tacrolimus whole blood trough concentrations and reduce tacrolimus dose if needed [ see Dosage and Administration (2.2 , 2.6 ) and Clinical Pharmacology (12.3) ]. Mild or Moderate CYP3A Inducers Methylprednisolone, prednisone May decrease tacrolimus whole blood trough concentrations. Monitor tacrolimus whole blood trough concentrations and adjust tacrolimus dose if needed [ see Dosage and Administration (2.2 , 2.6 ) ].

Caspofungin May decrease tacrolimus whole blood trough concentrations. Monitor tacrolimus whole blood trough concentrations and adjust Tacrolimus dose if needed [ see Dosage and Administration (2.2 , 2.6 ) ]. Direct Acting Antiviral (DAA) Therapy The pharmacokinetics of tacrolimus may be impacted by changes in liver function during DAA therapy, related to clearance of HCV virus. Close monitoring and potential dose adjustment of tacrolimus is warranted to ensure continued efficacy and safety [see Dosage and Administration (2.2, 2.6)].

7.3Cannabidiol

The blood levels of tacrolimus may increase upon concomitant use with cannabidiol. When cannabidiol and tacrolimus are co-administered, closely monitor for an increase in tacrolimus blood levels and for adverse reactions suggestive of tacrolimus toxicity. A dose reduction of tacrolimus should be considered as needed when tacrolimus is co-administered with cannabidiol [see Dosage and Administration ( 2.2 , 2.6 ) and Warnings and Precautions ( 5.17 )].

Adverse reactions

The most common adverse reactions (≥ 15%) were abnormal renal function, hypertension, diabetes mellitus, fever, CMV infection, tremor, hyperglycemia, leukopenia, infection, anemia, bronchitis, pericardial effusion, urinary tract infection, constipation, diarrhea, headache, abdominal pain, insomnia, paresthesia, peripheral edema, nausea, hyperkalemia, hypomagnesemia, and hyperlipemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Concord Biotech Limited at Telephone: 1-855-407-0586 or FDA at 1-800-FDA-1088 or www.fda.g ov/medwatch.

The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling: Lymphoma and Other Malignancies [see Warnings and Precautions (5.1) ] Serious Infections [ see Warnings and Precautions (5.2) ] New Onset Diabetes After Transplant [see Warnings and Precautions (5.4) ] Nephrotoxicity [see Warnings and Precautions (5.5) ] Neurotoxicity [see Warnings and Precautions (5.6) ] Hyperkalemia [see Warnings and Precautions (5.7) ] Hypertension [see Warnings and Precautions (5.8) ] Anaphylactic Reactions with Tacrolimus Injection [see Warnings and Precautions (5.9) ] Myocardial Hypertrophy [see Warnings and Precautions (5.13) ] Pure Red Cell Aplasia [see Warnings and Precautions (5.15) ] Thrombotic Microangiopathy, Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura [see Warnings and Precautions ( 5.16 )]

6.1Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In addition, the clinical trials were not designed to establish comparative differences across study arms with regards to the adverse reactions discussed below.

Kidney Transplantation The incidence of adverse reactions was determined in three randomized kidney transplant trials. One of the trials used azathioprine (AZA) and corticosteroids and two of the trials used mycophenolate mofetil (MMF) and corticosteroids concomitantly for maintenance immunosuppression. Tacrolimus-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in a trial where 205 patients received tacrolimus-based immunosuppression and 207 patients received cyclosporine-based immunosuppression.

The trial population had a mean age of 43 years (mean±SD was 43±13 years on tacrolimus and 44±12 years on cyclosporine arm), the distribution was 61% male, and the composition was White (58%), African- American (25%), Hispanic (12%), and Other (5%). The 12-month post-transplant information from this trial is presented below. The most common adverse reactions (≥30%) observed in tacrolimus-treated kidney transplant patients are: infection, tremor, hypertension, abnormal renal function, constipation, diarrhea, headache, abdominal pain, insomnia, nausea, hypomagnesemia, urinary tract infection, hypophosphatemia, peripheral edema, asthenia, pain, hyperlipidemia, hyperkalemia, and anemia.

Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 52% of kidney transplantation patients. Adverse reactions that occurred in ≥15% of kidney transplant patients treated with tacrolimus in conjunction with azathioprine are presented below: Table 4. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with Azathioprine (AZA) Tacrolimus/AZA (N = 205) Cyclosporine/AZA (N = 207) Nervous System Tremor 54% 34% Headache 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 50% 52% Chest Pain 19% 13% Urogenital Creatinine Increased 45% 42% Urinary Tract Infection 34% 35% Metabolic and Nutritional Hypophosphatemia 49% 53% Hypomagnesemia 34% 17% Hyperlipemia 31% 38% Hyperkalemia 31% 32% Diabetes Mellitus 24% 9% Hypokalemia 22% 25% Hyperglycemia 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% Pruritus 15% 7% Two trials were conducted for tacrolimus-based immunosuppression in conjunction with MMF and corticosteroids.

In the non-US trial (Study 1), the incidence of adverse reactions was based on 1195 kidney transplant patients that received tacrolimus (Group C, n=403), or one of two cyclosporine (CsA) regimens (Group A, n=384 and Group B, n=408) in combination with MMF and corticosteroids; all patients, except those in one of the two cyclosporine groups, also received induction with daclizumab. The trial population had a mean age of 46 years (range 17 to 76); the distribution was 65% male, and the composition was 93% Caucasian.

The 12-month post-transplant information from this trial is presented below. Adverse reactions that occurred in ≥10% of kidney transplant patients treated with tacrolimus in conjunction with MMF in Study 1 [Note: This trial was conducted entirely outside of the United States. Such trials often report a lower incidence of adverse reactions in comparison to U.S. trials] are presented below: Table 5. Kidney Transplantation: Adverse Reactions Occurring in ≥ 10% of Patients Treated with Tacrolimus in Conjunction with MMF (Study 1) Tacrolimus (Group C) (N = 403) Cyclosporine (Group A) (N = 384) Cyclosporine (Group B) (N = 408) Diarrhea 25% 16% 13% Urinary Tract Infection 24% 28% 24% Anemia 17% 19% 17% Hypertension 13% 14% 12% Leukopenia 13% 10% 10% Edema Peripheral 11% 12% 13% Hyperlipidemia 10% 15% 13% Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab, CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, MMF = mycophenolate mofetil In the U.S. trial (Study 2) with tacrolimus-based immunosuppression in conjunction with MMF and corticosteroids, 424 kidney transplant patients received tacrolimus (n=212) or cyclosporine (n=212) in combination with MMF 1 gram twice daily, basiliximab induction, and corticosteroids.

The trial population had a mean age of 48 years (range 17 to 77); the distribution was 63% male, and the composition was White (74%), African-American (20%), Asian (3%), and Other (3%). The 12-month post-transplant information from this trial is presented below. Adverse reactions that occurred in ≥15% of kidney transplant patients treated with tacrolimus in conjunction with MMF in Study 2 are presented below: Table 6.

Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with MMF (Study 2) Tacrolimus/MMF (N = 212) Cyclosporine/MMF (N = 212) Gastrointestinal Disorders Diarrhea 44% 26% Nausea 39% 47% Constipation 36% 41% Vomiting 26% 25% Dyspepsia 18% 15% Injury, Poisoning, and Procedural Complications Post-Procedural Pain 29% 27% Incision Site Complication 28% 23% Graft Dysfunction 24% 18% Metabolism and Nutrition Disorders Hypomagnesemia 28% 22% Hypophosphatemia 28% 21% Hyperkalemia 26% 19% Hyperglycemia 21% 15% Hyperlipidemia 18% 25% Hypokalemia 16% 18% Nervous System Disorders Tremor 34% 20% Headache 24% 25% Blood and Lymphatic System Disorders Anemia 30% 28% Leukopenia 16% 12% Miscellaneous Edema Peripheral 35% 46% Hypertension 32% 35% Insomnia 30% 21% Urinary Tract Infection 26% 22% Blood Creatinine Increased 23% 23% Less frequently observed adverse reactions in kidney transplantation patients are described under the subsection "Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies." Liver Transplantation There were two

Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA

Tacrolimus

Indications

1.1Prophylaxis of Organ Rejection in Kidney, Liver or Heart Transplant

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

Tacrolimus

Indications

1.1Prophylaxis of Organ Rejection in Kidney, Liver or Heart Transplant

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

5.1Lymphoma and Other Malignancies

5.2Serious Infections

5.3Not Interchangeable with Extended-Release Tacrolimus

5.4New Onset Diabetes After Transplant

5.6Neurotoxicity

5.7Hyperkalemia

5.8Hypertension

5.9Anaphylactic Reactions with Tacrolimus Injection

Interactions

7.1Mycophenolic Acid

7.2Effects of Other Drugs on Tacrolimus Table

7.3Cannabidiol

Adverse reactions

6.1Clinical Studies Experience

Composition

Strengths and forms

Official product information