Dosage & Administration
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Tegsedi Prescribing Information
TEGSEDI causes reductions in platelet count that may result in sudden and unpredictable thrombocytopenia, which can be life-threatening. One clinical trial patient died from intracranial hemorrhage.
TEGSEDI is contraindicated in patients with a platelet count below 100 x 109/L
TEGSEDI is contraindicated in patients with:
- Platelet count below 100 x 109/L[see Warnings and Precautions ]
- History of acute glomerulonephritis caused by TEGSEDI[see Warnings and Precautions ]
- History of a hypersensitivity reaction to TEGSEDI[see Warnings and Precautions ].
- Platelet count less than 100 x 109/L
- History of acute glomerulonephritis caused by TEGSEDI
- Patients with a history of a hypersensitivity reaction to TEGSEDI
TEGSEDI can cause glomerulonephritis that may result in dialysis-dependent renal failure. In Study 1
Cases of glomerulonephritis were accompanied by nephrotic syndrome. Possible complications of nephrotic syndrome can include edema, hypercoagulability with venous or arterial thrombosis, and increased susceptibility to infection. TEGSEDI-treated patients who develop glomerulonephritis will require monitoring and treatment for nephrotic syndrome and its manifestations.
Accumulation of antisense oligonucleotides in proximal tubule cells of the kidney, sometimes leading to increased tubular proteinuria, has been described in nonclinical studies. Urine protein to creatinine ratio (UPCR) greater than 5 times the upper limit of normal occurred in 15% of TEGSEDI-treated patients, compared to 8% of patients on placebo. Increase from baseline in serum creatinine greater than 0.5 mg/dL occurred in 11% of TEGSEDI-treated patients, compared to 2% of patients on placebo.
Follow recommended monitoring and treatment recommendations for renal parameters
Use caution with nephrotoxic drugs and other drugs that may impair renal function. Because immunosuppressive treatment is necessary for the treatment of glomerulonephritis, avoid using TEGSEDI in patients for whom immunosuppressive treatment is not advised.
Prior to starting TEGSEDI, obtain a platelet count
Measure platelet count, serum creatinine, estimated glomerular filtration rate (eGFR), urine protein to creatinine ratio (UPCR), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin, and perform urinalysis prior to treatment with TEGSEDI and as directed following treatment initiation
Monitor platelet count, serum creatinine, estimated glomerular filtration rate (eGFR), urinalysis, urine protein to creatinine ratio (UPCR), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin during treatment with TEGSEDI, and for 8 weeks following discontinuation of treatment.
Platelet Count
Do not initiate TEGSEDI in patients with a platelet count less than 100 x 109/L. Monitor platelet count during the entire course of treatment with Tegsedi and for 8 weeks following discontinuation of treatment. Recommendations for platelet monitoring frequency and TEGSEDI dosing are specified in Table 1. If a patient develops signs or symptoms of thrombocytopenia, obtain a platelet count as soon as possible, and hold dosing until platelet count is confirmed. Recheck the platelet count as soon as possible if a platelet measurement is uninterpretable (e.g., clumped sample)
# Additional risk factors for bleeding include age >60 years, receiving anticoagulant or antiplatelet medicinal products, or prior history of major bleeding events.
†Patients who discontinue therapy with TEGSEDI because of platelet counts below 25 x109/L should not reinitiate therapy.
Twice weekly until 3 successive values above 75; then weekly monitoring.
Consider more frequent monitoring if additional risk factors for bleeding are present.#
Stop treatment. Do not restart TEGSEDI in patients with thrombocytopenia, unless there have been 3 successive values above 100 and the benefit of TEGSEDI outweighs the risk of thrombocytopenia and potential bleeding.
Corticosteroids recommended.
Consider discontinuation of any antiplatelet agents or anticoagulants.
Stop TEGSEDI.
Corticosteroids recommended.
Consider discontinuation of any antiplatelet agents or anticoagulants.
Renal Monitoring
TEGSEDI should generally not be initiated in patients with a urine protein to creatinine ratio (UPCR) of 1000 mg/g or higher. Monitor serum creatinine, estimated glomerular filtration rate (eGFR), urinalysis, and UPCR every 2 weeks during treatment with TEGSEDI. Hold TEGSEDI in patients who develop a UPCR of 1000 mg/g or higher, or estimated glomerular filtration rate (eGFR) below 45 mL/minute/1.73 m2, pending further evaluation of the cause.
If a dose is held, once eGFR increases to ≥45 mL/minute/1.73 m2, UPCR decreases to below 1000 mg/g, or the underlying cause of the decline in renal function is corrected, weekly dosing may be reinitiated. In the case of UPCR of 2000 mg/g or higher, perform further evaluation for acute glomerulonephritis, as clinically indicated. If acute glomerulonephritis is confirmed, TEGSEDI should be permanently discontinued.
Liver Tests
Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin monthly during treatment with TEGSEDI; monitor monthly for patients who have received a liver transplant
TEGSEDI causes reductions in platelet count at any time during treatment that may result in sudden and unpredictable thrombocytopenia that can be life-threatening. In Study 1
Three TEGSEDI-treated patients (3%) had sudden severe thrombocytopenia (platelet count below 25 x 109/L), which can have potentially fatal bleeding complications, including spontaneous intracranial or intrapulmonary hemorrhage. One patient in a clinical trial experienced a fatal intracranial hemorrhage.
In clinical trials, all 3 patients with severe thrombocytopenia had treatment-emergent antiplatelet IgG antibodies detected shortly before or at the time of the severe thrombocytopenia. In 2 patients, platelet clumping caused uninterpretable platelet measurements that delayed the diagnosis and treatment of severe thrombocytopenia. Platelet clumping can be caused by a reaction between antiplatelet antibodies and ethylenediaminetetraacetic acid (EDTA)
Monitoring and Dosing
Patients who are not able to adhere to the recommended laboratory monitoring or to the related treatment recommendations must not receive TEGSEDI. Do not initiate TEGSEDI in patients with a platelet count below 100 x 109/L. Follow recommended monitoring and treatment recommendations for platelet count
Concomitant Medications with Platelet Effects
When considering use of TEGSEDI concomitantly with antiplatelet drugs or anticoagulants, be aware of the risk of potential bleeding from thrombocytopenia with TEGSEDI, and consider discontinuation of these drugs in patients with a platelet count less than 50 x 109/L
Symptoms of Thrombocytopenia
Symptoms of thrombocytopenia can include unusual or prolonged bleeding (e.g., petechiae, easy bruising, hematoma, subconjunctival bleeding, gingival bleeding, epistaxis, hemoptysis, irregular or heavier than normal menstrual bleeding, hematemesis, hematuria, hematochezia, melena), neck stiffness or atypical severe headache. Patients and caregivers should be instructed to be vigilant for symptoms of thrombocytopenia and seek immediate medical help if they have concerns.
Severe Thrombocytopenia: Treatment with Glucocorticoids
Glucocorticoid therapy is strongly recommended in patients with a platelet count below 50 x 109/L, and in patients with suspected immune-mediated thrombocytopenia. Avoid using TEGSEDI in patients for whom glucocorticoid treatment is not advised.
If a patient develops signs or symptoms of thrombocytopenia, obtain a platelet count as soon as possible. The patient should not receive additional TEGSEDI unless a platelet count is determined to be interpretable and acceptable by a medical professional
TEGSEDI causes reductions in platelet count at any time during treatment that may result in sudden and unpredictable thrombocytopenia that can be life-threatening. In Study 1
Three TEGSEDI-treated patients (3%) had sudden severe thrombocytopenia (platelet count below 25 x 109/L), which can have potentially fatal bleeding complications, including spontaneous intracranial or intrapulmonary hemorrhage. One patient in a clinical trial experienced a fatal intracranial hemorrhage.
In clinical trials, all 3 patients with severe thrombocytopenia had treatment-emergent antiplatelet IgG antibodies detected shortly before or at the time of the severe thrombocytopenia. In 2 patients, platelet clumping caused uninterpretable platelet measurements that delayed the diagnosis and treatment of severe thrombocytopenia. Platelet clumping can be caused by a reaction between antiplatelet antibodies and ethylenediaminetetraacetic acid (EDTA)
Monitoring and Dosing
Patients who are not able to adhere to the recommended laboratory monitoring or to the related treatment recommendations must not receive TEGSEDI. Do not initiate TEGSEDI in patients with a platelet count below 100 x 109/L. Follow recommended monitoring and treatment recommendations for platelet count
Concomitant Medications with Platelet Effects
When considering use of TEGSEDI concomitantly with antiplatelet drugs or anticoagulants, be aware of the risk of potential bleeding from thrombocytopenia with TEGSEDI, and consider discontinuation of these drugs in patients with a platelet count less than 50 x 109/L
Symptoms of Thrombocytopenia
Symptoms of thrombocytopenia can include unusual or prolonged bleeding (e.g., petechiae, easy bruising, hematoma, subconjunctival bleeding, gingival bleeding, epistaxis, hemoptysis, irregular or heavier than normal menstrual bleeding, hematemesis, hematuria, hematochezia, melena), neck stiffness or atypical severe headache. Patients and caregivers should be instructed to be vigilant for symptoms of thrombocytopenia and seek immediate medical help if they have concerns.
Severe Thrombocytopenia: Treatment with Glucocorticoids
Glucocorticoid therapy is strongly recommended in patients with a platelet count below 50 x 109/L, and in patients with suspected immune-mediated thrombocytopenia. Avoid using TEGSEDI in patients for whom glucocorticoid treatment is not advised.
Following discontinuation of treatment for any reason, continue to monitor platelet count for 8 weeks, or longer if platelet counts are less than 100 x 109/L, to verify that platelet counts remain above 75 x 109/L
Monitor platelet count, serum creatinine, estimated glomerular filtration rate (eGFR), urinalysis, urine protein to creatinine ratio (UPCR), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin during treatment with TEGSEDI, and for 8 weeks following discontinuation of treatment.
Platelet Count
Do not initiate TEGSEDI in patients with a platelet count less than 100 x 109/L. Monitor platelet count during the entire course of treatment with Tegsedi and for 8 weeks following discontinuation of treatment. Recommendations for platelet monitoring frequency and TEGSEDI dosing are specified in Table 1. If a patient develops signs or symptoms of thrombocytopenia, obtain a platelet count as soon as possible, and hold dosing until platelet count is confirmed. Recheck the platelet count as soon as possible if a platelet measurement is uninterpretable (e.g., clumped sample)
# Additional risk factors for bleeding include age >60 years, receiving anticoagulant or antiplatelet medicinal products, or prior history of major bleeding events.
†Patients who discontinue therapy with TEGSEDI because of platelet counts below 25 x109/L should not reinitiate therapy.
Twice weekly until 3 successive values above 75; then weekly monitoring.
Consider more frequent monitoring if additional risk factors for bleeding are present.#
Stop treatment. Do not restart TEGSEDI in patients with thrombocytopenia, unless there have been 3 successive values above 100 and the benefit of TEGSEDI outweighs the risk of thrombocytopenia and potential bleeding.
Corticosteroids recommended.
Consider discontinuation of any antiplatelet agents or anticoagulants.
Stop TEGSEDI.
Corticosteroids recommended.
Consider discontinuation of any antiplatelet agents or anticoagulants.
Renal Monitoring
TEGSEDI should generally not be initiated in patients with a urine protein to creatinine ratio (UPCR) of 1000 mg/g or higher. Monitor serum creatinine, estimated glomerular filtration rate (eGFR), urinalysis, and UPCR every 2 weeks during treatment with TEGSEDI. Hold TEGSEDI in patients who develop a UPCR of 1000 mg/g or higher, or estimated glomerular filtration rate (eGFR) below 45 mL/minute/1.73 m2, pending further evaluation of the cause.
If a dose is held, once eGFR increases to ≥45 mL/minute/1.73 m2, UPCR decreases to below 1000 mg/g, or the underlying cause of the decline in renal function is corrected, weekly dosing may be reinitiated. In the case of UPCR of 2000 mg/g or higher, perform further evaluation for acute glomerulonephritis, as clinically indicated. If acute glomerulonephritis is confirmed, TEGSEDI should be permanently discontinued.
Liver Tests
Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin monthly during treatment with TEGSEDI; monitor monthly for patients who have received a liver transplant
TEGSEDI can cause glomerulonephritis that may require immunosuppressive treatment and may result in dialysis-dependent renal failure. One clinical trial patient who developed glomerulonephritis and did not receive immunosuppressive treatment remained dialysis-dependent. In clinical trials, cases of glomerulonephritis were accompanied by nephrotic syndrome, which can have manifestations of edema, hypercoagulability with venous or arterial thrombosis, and increased susceptibility to infection
TEGSEDI can cause glomerulonephritis that may result in dialysis-dependent renal failure. In Study 1
Cases of glomerulonephritis were accompanied by nephrotic syndrome. Possible complications of nephrotic syndrome can include edema, hypercoagulability with venous or arterial thrombosis, and increased susceptibility to infection. TEGSEDI-treated patients who develop glomerulonephritis will require monitoring and treatment for nephrotic syndrome and its manifestations.
Accumulation of antisense oligonucleotides in proximal tubule cells of the kidney, sometimes leading to increased tubular proteinuria, has been described in nonclinical studies. Urine protein to creatinine ratio (UPCR) greater than 5 times the upper limit of normal occurred in 15% of TEGSEDI-treated patients, compared to 8% of patients on placebo. Increase from baseline in serum creatinine greater than 0.5 mg/dL occurred in 11% of TEGSEDI-treated patients, compared to 2% of patients on placebo.
Follow recommended monitoring and treatment recommendations for renal parameters
Use caution with nephrotoxic drugs and other drugs that may impair renal function. Because immunosuppressive treatment is necessary for the treatment of glomerulonephritis, avoid using TEGSEDI in patients for whom immunosuppressive treatment is not advised.
TEGSEDI should generally not be initiated in patients with urinary protein to creatinine ratio (UPCR) of 1000 mg/g or higher
Monitor platelet count, serum creatinine, estimated glomerular filtration rate (eGFR), urinalysis, urine protein to creatinine ratio (UPCR), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin during treatment with TEGSEDI, and for 8 weeks following discontinuation of treatment.
Platelet Count
Do not initiate TEGSEDI in patients with a platelet count less than 100 x 109/L. Monitor platelet count during the entire course of treatment with Tegsedi and for 8 weeks following discontinuation of treatment. Recommendations for platelet monitoring frequency and TEGSEDI dosing are specified in Table 1. If a patient develops signs or symptoms of thrombocytopenia, obtain a platelet count as soon as possible, and hold dosing until platelet count is confirmed. Recheck the platelet count as soon as possible if a platelet measurement is uninterpretable (e.g., clumped sample)
# Additional risk factors for bleeding include age >60 years, receiving anticoagulant or antiplatelet medicinal products, or prior history of major bleeding events.
†Patients who discontinue therapy with TEGSEDI because of platelet counts below 25 x109/L should not reinitiate therapy.
Twice weekly until 3 successive values above 75; then weekly monitoring.
Consider more frequent monitoring if additional risk factors for bleeding are present.#
Stop treatment. Do not restart TEGSEDI in patients with thrombocytopenia, unless there have been 3 successive values above 100 and the benefit of TEGSEDI outweighs the risk of thrombocytopenia and potential bleeding.
Corticosteroids recommended.
Consider discontinuation of any antiplatelet agents or anticoagulants.
Stop TEGSEDI.
Corticosteroids recommended.
Consider discontinuation of any antiplatelet agents or anticoagulants.
Renal Monitoring
TEGSEDI should generally not be initiated in patients with a urine protein to creatinine ratio (UPCR) of 1000 mg/g or higher. Monitor serum creatinine, estimated glomerular filtration rate (eGFR), urinalysis, and UPCR every 2 weeks during treatment with TEGSEDI. Hold TEGSEDI in patients who develop a UPCR of 1000 mg/g or higher, or estimated glomerular filtration rate (eGFR) below 45 mL/minute/1.73 m2, pending further evaluation of the cause.
If a dose is held, once eGFR increases to ≥45 mL/minute/1.73 m2, UPCR decreases to below 1000 mg/g, or the underlying cause of the decline in renal function is corrected, weekly dosing may be reinitiated. In the case of UPCR of 2000 mg/g or higher, perform further evaluation for acute glomerulonephritis, as clinically indicated. If acute glomerulonephritis is confirmed, TEGSEDI should be permanently discontinued.
Liver Tests
Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin monthly during treatment with TEGSEDI; monitor monthly for patients who have received a liver transplant
TEGSEDI can cause glomerulonephritis that may result in dialysis-dependent renal failure. In Study 1
Cases of glomerulonephritis were accompanied by nephrotic syndrome. Possible complications of nephrotic syndrome can include edema, hypercoagulability with venous or arterial thrombosis, and increased susceptibility to infection. TEGSEDI-treated patients who develop glomerulonephritis will require monitoring and treatment for nephrotic syndrome and its manifestations.
Accumulation of antisense oligonucleotides in proximal tubule cells of the kidney, sometimes leading to increased tubular proteinuria, has been described in nonclinical studies. Urine protein to creatinine ratio (UPCR) greater than 5 times the upper limit of normal occurred in 15% of TEGSEDI-treated patients, compared to 8% of patients on placebo. Increase from baseline in serum creatinine greater than 0.5 mg/dL occurred in 11% of TEGSEDI-treated patients, compared to 2% of patients on placebo.
Follow recommended monitoring and treatment recommendations for renal parameters
Use caution with nephrotoxic drugs and other drugs that may impair renal function. Because immunosuppressive treatment is necessary for the treatment of glomerulonephritis, avoid using TEGSEDI in patients for whom immunosuppressive treatment is not advised.
Prior to starting TEGSEDI, measure the serum creatinine, estimated glomerular filtration rate (eGFR), urine protein to creatinine ratio (UPCR), and perform a urinalysis
Measure platelet count, serum creatinine, estimated glomerular filtration rate (eGFR), urine protein to creatinine ratio (UPCR), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin, and perform urinalysis prior to treatment with TEGSEDI and as directed following treatment initiation
If a dose is held, once eGFR increases to ≥45 mL/minute/1.73 m2, UPCR decreases to below 1000 mg/g, or the underlying cause of the decline in renal function is corrected, weekly dosing may be reinitiated. In patients with UPCR of 2000 mg/g or higher, perform further evaluation for acute glomerulonephritis, as clinically indicated. If acute glomerulonephritis is confirmed, TEGSEDI should be permanently discontinued
Monitor platelet count, serum creatinine, estimated glomerular filtration rate (eGFR), urinalysis, urine protein to creatinine ratio (UPCR), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin during treatment with TEGSEDI, and for 8 weeks following discontinuation of treatment.
Platelet Count
Do not initiate TEGSEDI in patients with a platelet count less than 100 x 109/L. Monitor platelet count during the entire course of treatment with Tegsedi and for 8 weeks following discontinuation of treatment. Recommendations for platelet monitoring frequency and TEGSEDI dosing are specified in Table 1. If a patient develops signs or symptoms of thrombocytopenia, obtain a platelet count as soon as possible, and hold dosing until platelet count is confirmed. Recheck the platelet count as soon as possible if a platelet measurement is uninterpretable (e.g., clumped sample)
# Additional risk factors for bleeding include age >60 years, receiving anticoagulant or antiplatelet medicinal products, or prior history of major bleeding events.
†Patients who discontinue therapy with TEGSEDI because of platelet counts below 25 x109/L should not reinitiate therapy.
Twice weekly until 3 successive values above 75; then weekly monitoring.
Consider more frequent monitoring if additional risk factors for bleeding are present.#
Stop treatment. Do not restart TEGSEDI in patients with thrombocytopenia, unless there have been 3 successive values above 100 and the benefit of TEGSEDI outweighs the risk of thrombocytopenia and potential bleeding.
Corticosteroids recommended.
Consider discontinuation of any antiplatelet agents or anticoagulants.
Stop TEGSEDI.
Corticosteroids recommended.
Consider discontinuation of any antiplatelet agents or anticoagulants.
Renal Monitoring
TEGSEDI should generally not be initiated in patients with a urine protein to creatinine ratio (UPCR) of 1000 mg/g or higher. Monitor serum creatinine, estimated glomerular filtration rate (eGFR), urinalysis, and UPCR every 2 weeks during treatment with TEGSEDI. Hold TEGSEDI in patients who develop a UPCR of 1000 mg/g or higher, or estimated glomerular filtration rate (eGFR) below 45 mL/minute/1.73 m2, pending further evaluation of the cause.
If a dose is held, once eGFR increases to ≥45 mL/minute/1.73 m2, UPCR decreases to below 1000 mg/g, or the underlying cause of the decline in renal function is corrected, weekly dosing may be reinitiated. In the case of UPCR of 2000 mg/g or higher, perform further evaluation for acute glomerulonephritis, as clinically indicated. If acute glomerulonephritis is confirmed, TEGSEDI should be permanently discontinued.
Liver Tests
Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin monthly during treatment with TEGSEDI; monitor monthly for patients who have received a liver transplant
TEGSEDI can cause glomerulonephritis that may result in dialysis-dependent renal failure. In Study 1
Cases of glomerulonephritis were accompanied by nephrotic syndrome. Possible complications of nephrotic syndrome can include edema, hypercoagulability with venous or arterial thrombosis, and increased susceptibility to infection. TEGSEDI-treated patients who develop glomerulonephritis will require monitoring and treatment for nephrotic syndrome and its manifestations.
Accumulation of antisense oligonucleotides in proximal tubule cells of the kidney, sometimes leading to increased tubular proteinuria, has been described in nonclinical studies. Urine protein to creatinine ratio (UPCR) greater than 5 times the upper limit of normal occurred in 15% of TEGSEDI-treated patients, compared to 8% of patients on placebo. Increase from baseline in serum creatinine greater than 0.5 mg/dL occurred in 11% of TEGSEDI-treated patients, compared to 2% of patients on placebo.
Follow recommended monitoring and treatment recommendations for renal parameters
Use caution with nephrotoxic drugs and other drugs that may impair renal function. Because immunosuppressive treatment is necessary for the treatment of glomerulonephritis, avoid using TEGSEDI in patients for whom immunosuppressive treatment is not advised.
Because of the risks of serious bleeding caused by severe thrombocytopenia and because of glomerulonephritis, both of which require frequent monitoring, TEGSEDI is available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy (REMS) called the TEGSEDI REMS Program
TEGSEDI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the TEGSEDI REMS Program, because of risks of serious bleeding caused by severe thrombocytopenia and because of glomerulonephritis
Important requirements of the TEGSEDI Prescribing Program include:
- Prescribers must be certified within the program by enrolling and completing training.
- Patients must enroll in the program and comply with ongoing monitoring requirements[see Warnings and Precautions and Dosage and Administration ]. Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive TEGSEDI.
Dosage and Administration (Monitor platelet count, serum creatinine, estimated glomerular filtration rate (eGFR), urinalysis, urine protein to creatinine ratio (UPCR), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin during treatment with TEGSEDI, and for 8 weeks following discontinuation of treatment. Platelet Count Do not initiate TEGSEDI in patients with a platelet count less than 100 x 109/L. Monitor platelet count during the entire course of treatment with Tegsedi and for 8 weeks following discontinuation of treatment. Recommendations for platelet monitoring frequency and TEGSEDI dosing are specified in Table 1. If a patient develops signs or symptoms of thrombocytopenia, obtain a platelet count as soon as possible, and hold dosing until platelet count is confirmed. Recheck the platelet count as soon as possible if a platelet measurement is uninterpretable (e.g., clumped sample) [see Warnings and Precautions ] .# Additional risk factors for bleeding include age >60 years, receiving anticoagulant or antiplatelet medicinal products, or prior history of major bleeding events. †Patients who discontinue therapy with TEGSEDI because of platelet counts below 25 x109/L should not reinitiate therapy. | ||
| Platelet count (x109/L) | Monitoring Frequency | Dosing |
| At least 100 | Weekly | Continue to dose weekly. |
| At least 75 to less than 100 | Weekly | Stop treatment. Do not restart unless platelet count is greater than 100. |
| At least 50 to less than 75 | Twice weekly until 3 successive values above 75; then weekly monitoring. | Stop treatment. Do not restart TEGSEDI in patients with thrombocytopenia, unless there have been 3 successive values above 100 and the benefit of TEGSEDI outweighs the risk of thrombocytopenia and potential bleeding. |
| At least 25 to less than 50* | Twice weekly until 3 successive values above 75; then weekly monitoring. Consider more frequent monitoring if additional risk factors for bleeding are present.# | Stop treatment. Do not restart TEGSEDI in patients with thrombocytopenia, unless there have been 3 successive values above 100 and the benefit of TEGSEDI outweighs the risk of thrombocytopenia and potential bleeding. Corticosteroids recommended. Consider discontinuation of any antiplatelet agents or anticoagulants. |
| Less than 25*† | Daily until 2 successive values above 25. Then monitor twice weekly until 3 successive values above 75. Then weekly monitoring until stable. | Stop TEGSEDI. Corticosteroids recommended. Consider discontinuation of any antiplatelet agents or anticoagulants. |
Renal Monitoring
TEGSEDI should generally not be initiated in patients with a urine protein to creatinine ratio (UPCR) of 1000 mg/g or higher. Monitor serum creatinine, estimated glomerular filtration rate (eGFR), urinalysis, and UPCR every 2 weeks during treatment with TEGSEDI. Hold TEGSEDI in patients who develop a UPCR of 1000 mg/g or higher, or estimated glomerular filtration rate (eGFR) below 45 mL/minute/1.73 m2, pending further evaluation of the cause.
If a dose is held, once eGFR increases to ≥45 mL/minute/1.73 m2, UPCR decreases to below 1000 mg/g, or the underlying cause of the decline in renal function is corrected, weekly dosing may be reinitiated. In the case of UPCR of 2000 mg/g or higher, perform further evaluation for acute glomerulonephritis, as clinically indicated. If acute glomerulonephritis is confirmed, TEGSEDI should be permanently discontinued.
Liver Tests
Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin monthly during treatment with TEGSEDI; monitor monthly for patients who have received a liver transplant
TEGSEDI causes reductions in platelet count at any time during treatment that may result in sudden and unpredictable thrombocytopenia that can be life-threatening. In Study 1
Three TEGSEDI-treated patients (3%) had sudden severe thrombocytopenia (platelet count below 25 x 109/L), which can have potentially fatal bleeding complications, including spontaneous intracranial or intrapulmonary hemorrhage. One patient in a clinical trial experienced a fatal intracranial hemorrhage.
In clinical trials, all 3 patients with severe thrombocytopenia had treatment-emergent antiplatelet IgG antibodies detected shortly before or at the time of the severe thrombocytopenia. In 2 patients, platelet clumping caused uninterpretable platelet measurements that delayed the diagnosis and treatment of severe thrombocytopenia. Platelet clumping can be caused by a reaction between antiplatelet antibodies and ethylenediaminetetraacetic acid (EDTA)
Monitoring and Dosing
Patients who are not able to adhere to the recommended laboratory monitoring or to the related treatment recommendations must not receive TEGSEDI. Do not initiate TEGSEDI in patients with a platelet count below 100 x 109/L. Follow recommended monitoring and treatment recommendations for platelet count
Concomitant Medications with Platelet Effects
When considering use of TEGSEDI concomitantly with antiplatelet drugs or anticoagulants, be aware of the risk of potential bleeding from thrombocytopenia with TEGSEDI, and consider discontinuation of these drugs in patients with a platelet count less than 50 x 109/L
Symptoms of Thrombocytopenia
Symptoms of thrombocytopenia can include unusual or prolonged bleeding (e.g., petechiae, easy bruising, hematoma, subconjunctival bleeding, gingival bleeding, epistaxis, hemoptysis, irregular or heavier than normal menstrual bleeding, hematemesis, hematuria, hematochezia, melena), neck stiffness or atypical severe headache. Patients and caregivers should be instructed to be vigilant for symptoms of thrombocytopenia and seek immediate medical help if they have concerns.
Severe Thrombocytopenia: Treatment with Glucocorticoids
Glucocorticoid therapy is strongly recommended in patients with a platelet count below 50 x 109/L, and in patients with suspected immune-mediated thrombocytopenia. Avoid using TEGSEDI in patients for whom glucocorticoid treatment is not advised.
The liver is a site of accumulation of antisense oligonucleotides. In clinical studies, 8% of TEGSEDI-treated patients had an increased alanine aminotransferase (ALT) at least 3 times the upper limit of normal (ULN), compared to 3% of patients on placebo; 3% of TEGSEDI-treated patients had an ALT at least 8 times the ULN, compared to no patient on placebo. One clinical study patient experienced an increased ALT more than 30 times the ULN. After a course of corticosteroids and discontinuation of TEGSEDI, the patient’s ALT returned to normal levels. Some patients had resolution of the liver laboratory abnormalities with continued use of TEGSEDI.
In clinical studies, demonstrated or possible cases of immune-mediated biliary disease occurred in TEGSEDI-treated patients. There was a single case of autoimmune hepatitis with primary biliary cirrhosis in a patient with a family history of primary biliary cirrhosis, as well as a single case of biliary obstruction of unclear etiology.
Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin at baseline and monthly during treatment with TEGSEDI. If a patient develops clinical signs or symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine), promptly measure serum transaminases and total bilirubin and interrupt treatment with TEGSEDI, as appropriate.
If a patient is suspected to have developed liver injury induced by TEGSEDI treatment, TEGSEDI should be discontinued.
In a clinical study, cases of liver transplant rejection were reported 2-4 months after starting TEGSEDI in patients whose liver allografts had previously been clinically stable (for over 10 years) prior to starting TEGSEDI. In these cases, the patients clinically improved and transaminase levels normalized after glucocorticoid administration and cessation of TEGSEDI.
In patients with a history of liver transplant, monitor ALT, AST, and total bilirubin monthly. Discontinue TEGSEDI in patients who develop signs of liver transplant rejection.
TEGSEDI is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.
- The recommended dosage is 284 mg administered by subcutaneous injection once weekly. ()
2.1 Dosing InformationThe recommended dose of TEGSEDI is 284 mg injected subcutaneously once weekly.
For consistency of dosing, patients should be instructed to give the injection on the same day every week.
If a dose is missed, patients should be instructed to take the missed dose as soon as possible, unless the next scheduled dose is within 2 days. In this situation, the patient should be directed to skip the missed dose and take the next scheduled dose on the scheduled day.
- Laboratory tests must be measured prior to treatment, continue to be monitored after treatment initiation, and for 8 weeks following discontinuation of treatment, as directed. (,
2.3 Assessment Prior to Initiating TEGSEDIMeasure platelet count, serum creatinine, estimated glomerular filtration rate (eGFR), urine protein to creatinine ratio (UPCR), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin, and perform urinalysis prior to treatment with TEGSEDI and as directed following treatment initiation
[see Dosage and Administration and Warnings and Precautions ].)2.4 Laboratory Testing and Monitoring to Assess Safety after Initiating TEGSEDIMonitor platelet count, serum creatinine, estimated glomerular filtration rate (eGFR), urinalysis, urine protein to creatinine ratio (UPCR), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin during treatment with TEGSEDI, and for 8 weeks following discontinuation of treatment.
Platelet Count
Do not initiate TEGSEDI in patients with a platelet count less than 100 x 109/L. Monitor platelet count during the entire course of treatment with Tegsedi and for 8 weeks following discontinuation of treatment. Recommendations for platelet monitoring frequency and TEGSEDI dosing are specified in Table 1. If a patient develops signs or symptoms of thrombocytopenia, obtain a platelet count as soon as possible, and hold dosing until platelet count is confirmed. Recheck the platelet count as soon as possible if a platelet measurement is uninterpretable (e.g., clumped sample)
[see Warnings and Precautions ].
# Additional risk factors for bleeding include age >60 years, receiving anticoagulant or antiplatelet medicinal products, or prior history of major bleeding events.
†Patients who discontinue therapy with TEGSEDI because of platelet counts below 25 x109/L should not reinitiate therapy.Platelet count (x109/L) Monitoring Frequency Dosing At least 100 Weekly Continue to dose weekly. At least 75 to less than 100 Weekly Stop treatment. Do not restart unless platelet count is greater than 100. At least 50 to less than 75 Twice weekly until 3 successive values above 75; then weekly monitoring. Stop treatment. Do not restart TEGSEDI in patients with thrombocytopenia, unless there have been 3 successive values above 100 and the benefit of TEGSEDI outweighs the risk of thrombocytopenia and potential bleeding. At least 25 to less than 50* Twice weekly until 3 successive values above 75; then weekly monitoring.
Consider more frequent monitoring if additional risk factors for bleeding are present.#
Stop treatment. Do not restart TEGSEDI in patients with thrombocytopenia, unless there have been 3 successive values above 100 and the benefit of TEGSEDI outweighs the risk of thrombocytopenia and potential bleeding.
Corticosteroids recommended.
Consider discontinuation of any antiplatelet agents or anticoagulants.
Less than 25*† Daily until 2 successive values above 25. Then monitor twice weekly until 3 successive values above 75. Then weekly monitoring until stable. Stop TEGSEDI.
Corticosteroids recommended.
Consider discontinuation of any antiplatelet agents or anticoagulants.
Renal Monitoring
TEGSEDI should generally not be initiated in patients with a urine protein to creatinine ratio (UPCR) of 1000 mg/g or higher. Monitor serum creatinine, estimated glomerular filtration rate (eGFR), urinalysis, and UPCR every 2 weeks during treatment with TEGSEDI. Hold TEGSEDI in patients who develop a UPCR of 1000 mg/g or higher, or estimated glomerular filtration rate (eGFR) below 45 mL/minute/1.73 m2, pending further evaluation of the cause.
If a dose is held, once eGFR increases to ≥45 mL/minute/1.73 m2, UPCR decreases to below 1000 mg/g, or the underlying cause of the decline in renal function is corrected, weekly dosing may be reinitiated. In the case of UPCR of 2000 mg/g or higher, perform further evaluation for acute glomerulonephritis, as clinically indicated. If acute glomerulonephritis is confirmed, TEGSEDI should be permanently discontinued.
Liver Tests
Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin monthly during treatment with TEGSEDI; monitor monthly for patients who have received a liver transplant
[see Warnings and Precautions ]. TEGSEDI should be discontinued in patients suspected of developing liver injury induced by TEGSEDI[see Warnings and Precautions ].
Injection: 284 mg/1.5 mL clear, colorless to pale yellow solution in a single-dose prefilled syringe.
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TEGSEDI during pregnancy. Health care providers are encouraged to register patients and pregnant women are encouraged to register themselves by calling: 1-877-465-7510, emailing: tegsedipregnancy@ubc.com, or visiting online at: www.tegsedipregnancystudy.com.
There are no data on the developmental risk associated with the use of TEGSEDI in pregnant women. TEGSEDI treatment leads to a decrease in serum vitamin A levels, and vitamin A supplementation is advised for patients taking TEGSEDI. Vitamin A is essential for normal embryofetal development; however, excessive levels of Vitamin A are associated with adverse developmental effects. The effects on the fetus of a reduction in maternal serum TTR caused by TEGSEDI and of vitamin A supplementation are unknown
The pharmacodynamic effects of TEGSEDI were evaluated in hATTR amyloidosis patients treated with 284 mg TEGSEDI via subcutaneous injection once weekly.
With repeat dosing, the mean percent decreases from baseline in serum TTR from Week 13 to Week 65 of treatment ranged from 68% to 74% (median range: 75% to 79%). Similar TTR reductions were observed regardless of TTR mutation, sex, age, or race.
Serum TTR is a carrier of retinol binding protein, which is involved in the transport of vitamin A in the blood. Mean reductions in serum retinol binding of 71%, and serum vitamin A of 63%, were observed at Week 65
Formal QTc studies have not been conducted with TEGSEDI. The potential for QTc prolongation with inotersen was evaluated in a randomized, placebo-controlled trial in healthy volunteers. No large changes in the mean QTc interval (>20 ms) were detected in the trial.
In the 66-week controlled efficacy trial, 5.4% of TEGSEDI-treated patients had evidence of QRS prolongation on their electrocardiograms (ECGs) to greater than 160 msec and greater than 25% above baseline, compared to and in 1.7% of patients on placebo.
TEGSEDI treatment leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance of vitamin A is advised for patients taking TEGSEDI. Higher doses than the recommended daily allowance of vitamin A should not be given to try to achieve normal serum vitamin A levels during treatment with TEGSEDI, as serum vitamin A levels do not reflect the total vitamin A in the body.
Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness).
In animal studies, subcutaneous administration of inotersen to pregnant rabbits resulted in premature delivery and reduced fetal body weight at the highest dose tested, which was associated with maternal toxicity. No adverse developmental effects were observed when inotersen or a pharmacologically-active surrogate was administered to pregnant mice.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.
Subcutaneous administration of inotersen (0, 3, 15, or 25 mg/kg) or a rodent-specific surrogate (15 mg/kg) to male and female mice every other day prior to and during mating and continuing in females throughout the period of organogenesis produced no adverse effects on embryofetal development.
Subcutaneous administration of inotersen (0, 2.5, 5, or 15 mg/kg) to pregnant rabbits every other day throughout the period of organogenesis resulted in premature delivery and reduced fetal body weight at the highest dose tested, which was associated with maternal toxicity (reduced body weight and food consumption).
Subcutaneous administration of inotersen (0, 2.9, 11.4, or 22.9 mg/kg) or a rodent-specific surrogate (11.4 mg/kg) to mice every other day throughout pregnancy and lactation produced no adverse effects on pre- or postnatal development.