Envarsus XR (Page 3 of 9)
6.2 Postmarketing Experience
The following adverse reactions have been reported from marketing experience with tacrolimus in the U.S. and outside the U.S. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following reactions have been included due to either their seriousness, frequency of reporting or strength of causal connection to ENVARSUS XR:
- Blood and Lymphatic System Disorders: Agranulocytosis, decreased blood fibrinogen, disseminated intravascular coagulation, hemolytic anemia, hemolytic uremic syndrome, leukopenia, febrile neutropenia, pancytopenia, prolonged activated partial thromboplastin time, pure red cell aplasia [see Warnings and Precautions (5.12)] , thrombocytopenic purpura, thrombotic thrombocytopenic purpura, thrombotic microangiopathy
- Cardiac Disorders: Atrial fibrillation, atrial flutter, cardiac arrhythmia, cardiac arrest, electrocardiogram T wave abnormal, flushing, myocardial hypertrophy, myocardial infarction, myocardial ischaemia, pericardial effusion, QT prolongation, supraventricular extrasystoles, supraventricular tachycardia, Torsade de Pointes, deep limb venous thrombosis, ventricular fibrillation
- Ear Disorders: Hearing loss including deafness
- Eye Disorders: Blindness, optic neuropathy, photophobia, optic atrophy
- Gastrointestinal Disorders: Abdominal pain, colitis, dysphagia, gastrointestinal perforation, impaired gastric emptying, intestinal obstruction, mouth ulceration, peritonitis, stomach ulcer
- Hepatobiliary Disorders: Bile duct stenosis, cholangitis, cirrhosis, fatty liver, hepatic cytolysis, hepatic failure, hepatic necrosis, hepatic steatosis, jaundice, hemorrhagic pancreatitis, necrotizing pancreatitis, venoocclusive liver disease, hepatitis (acute and chronic)
- Hypersensitivity Reactions: Hypersensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria
- Immune System Disorders: Graft versus host disease (acute and chronic)
- Metabolism and Nutrition Disorders: Glycosuria, increased amylase, pancreatitis
- Musculoskeletal and Connective Tissue Disorders: Myalgia, polyarthritis, rhabdomyolysis
- Neoplasms: Lymphoma including EBV-associated lymphoproliferative disorder, PTLD [see Warnings and Precautions (5.1)] ; leukemia
- Nervous System Disorders: Carpal tunnel syndrome, cerebral infarction, coma, dysarthria, flaccid paralysis, hemiparesis, mental disorder, mutism, nerve compression, posterior reversible encephalopathy syndrome (PRES) [see Warnings and Precautions (5.6)] , progressive multifocal leukoencephalopathy (PML) sometimes fatal [see Warnings and Precautions (5.2)] , quadriplegia, speech disorder, status epilepticus, syncope
- Renal and Urinary Disorder: Acute renal failure, hemorrhagic cystitis, hemolytic uremic syndrome, micturition disorder
- Respiratory, Thoracic and Mediastinal Disorders: Acute respiratory distress syndrome, interstitial lung disease, lung infiltration, pulmonary embolism, pulmonary hypertension, respiratory distress, respiratory failure
- Skin and Subcutaneous Tissue Disorders: Hyperpigmentation, photosensitivity, pruritus, rash
7 DRUG INTERACTIONS
7.1 Mycophenolic Acid
When ENVARSUS XR is prescribed with a given dose of mycophenolic acid (MPA) product, exposure to MPA is higher with ENVARSUS XR coadministration than with cyclosporine coadministration 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 MPA products as needed.
7.2 Effects of Other Drugs/Substances on ENVARSUS XR
| a ENVARSUS XR 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 statusb High dose or double strength grapefruit juice is a strong CYP3A inhibitor; low dose or single strength grapefruit juice is a moderate CYP3A inhibitorc Strong CYP3A inhibitor/inducer, based on reported effect on exposures to immediate-release tacrolimus along with supporting in vitro CYP3A inhibitor/inducer data, or based on drug-drug interaction studies with midazolam (sensitive CYP3A probe substrate) d A drug interaction study with voriconazole was conducted for ENVARSUS XR [see Clinical Pharmacology (12.3)]. No other drug-drug interaction studies were conducted with ENVARSUS XR. | ||||
| Drug/Substance Class or Name | Drug Interaction Effect | Recommendations | ||
| Grapefruit or grapefruit juiceb | 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, 5.9, 5.10)] | Avoid grapefruit or grapefruit juice | ||
| Alcohol | May modify the rate of tacrolimus release | Avoid alcoholic beverages | ||
| Strong CYP3A Inducersc, such as: 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 (5.9)] | Increase ENVARSUS XR dose and monitor tacrolimus whole blood trough concentrations [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)] | ||
| Strong CYP3A Inhibitorsc, , such as: Protease inhibitors (e.g., nelfinavir, telaprevir, boceprevir, ritonavir or ritonavir containing products, azole antifungals (e.g., voriconazole, posaconazole, itraconazole, ketoconazole), antibiotics (e.g., clarithromycin, troleandomycin, chloramphenicol), nefazodone, cobicistat | 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, 5.9, 5.10)] | Reduce ENVARSUS XR 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 (2.5) and Clinical Pharmacology (12.3)] | ||
| Mild or Moderate CYP3A Inhibitors, such as: antibiotics (e.g., erythromycin), calcium channel blockers (e.g., verapamil, diltiazem, nifedipine, nicardipine), amiodarone, danazol, ethinyl estradiol, cimetidine, lansoprazole and omeprazole, azole antifungals (e.g., clotrimazole, fluconazole, isavuconazole), imatinib, nilotinib, letermovir | 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, 5.9, 5.10)] | Monitor tacrolimus whole blood trough concentrations and reduce ENVARSUS XR dose if needed [see Dosage and Administration (2.5) 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 and 5.10)] | Monitor tacrolimus whole blood trough concentrations and reduce ENVARSUS XR dose if needed [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)] | ||
| Mild or Moderate CYP3A Inducers, such as: Methylprednisolone, prednisone | May decrease tacrolimus concentrations | Monitor tacrolimus whole blood trough concentrations and adjust ENVARSUS XR dose if needed [see Dosage and Administration (2.5)] | ||
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.
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