Dosage & Administration
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Tegsedi Prescribing Information
Thrombocytopenia
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 [see Contraindications and Warnings and Precautions ].
Prior to starting TEGSEDI, obtain a platelet count [see Dosage and Administration ]. During treatment, monitor platelet counts weekly if values are 75 x 109/L or greater, and more frequently if values are less than 75 x 109/L [see Dosage and Administration and Warnings and Precautions ].
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 [see Warnings and Precautions ].
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 [see Dosage and Administration ].
Glomerulonephritis
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 [see Warnings and Precautions ].
TEGSEDI should generally not be initiated in patients with urinary protein to creatinine ratio (UPCR) of 1000 mg/g or higher [see Dosage and Administration and Warnings and Precautions ].
Prior to starting TEGSEDI, measure the serum creatinine, estimated glomerular filtration rate (eGFR), urine protein to creatinine ratio (UPCR), and perform a urinalysis [see Dosage and Administration ]. During treatment, monitor serum creatinine, eGFR urinalysis, and UPCR every two weeks. TEGSEDI should not be given to patients who develop a UPCR of 1000 mg/g or higher, or 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 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 [see Dosage and Administration and Warnings and Precautions ].
TEGSEDI REMS Program
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 [see Warnings and Precautions ].
TEGSEDI is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.
Dosing Information
The 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.
Administration
- TEGSEDI is intended for subcutaneous use only.
- The first injection administered by the patient or caregiver should be performed under the guidance of an appropriately qualified healthcare professional. Patients and/or caregivers should be trained in the subcutaneous administration of TEGSEDI in accordance with the Instructions for Use.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit [see How Supplied/Storage and Handling ].
- Sites for injection include the abdomen, upper thigh region, or outer area of the upper arm. It is important to rotate sites for injection.
- If injected in the upper arm, the injection should be administered by a person other than the patient.
- Injection should be avoided at the waistline and other sites where pressure or rubbing from clothing may occur.
- TEGSEDI should not be injected into areas of skin disease or injury.
- Tattoos and scars should also be avoided.
- TEGSEDI prefilled syringe should be allowed to reach room temperature prior to injection.
- Remove from refrigerated storage at least 30 minutes prior to use.
- Other warming methods should not be used.
- Use each prefilled syringe only once.
Assessment Prior to Initiating TEGSEDI
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 [see Dosage and Administration and Warnings and Precautions ].
Laboratory Testing and Monitoring to Assess Safety after Initiating TEGSEDI
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.
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 [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.
Pregnancy
Pregnancy Exposure Registry
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.
Risk Summary
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 [see Clinical Pharmacology , Warnings and Precautions ].
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.
Data
Animal Data
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.
Lactation
Risk Summary
There is no information regarding the presence of TEGSEDI in human milk, the effects on the breast-fed infant, or the effects on milk production. A study in lactating mice has shown excretion of inotersen in milk. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for TEGSEDI and any potential adverse effects on the breastfed infant from TEGSEDI or from the underlying maternal condition.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of TEGSEDI included 69 patients (45%) aged 65 and over. No differences in pharmacokinetics or effectiveness were observed between these patients and younger patients. Patients 65 years and older may be at increased risk of certain adverse reactions, such as congestive heart failure, chills, myalgia, and extremity pain.
Renal Impairment
No dose adjustment is necessary in patients with mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] ≥30 to <90 mL/min/1.73 m2) [see Clinical Pharmacology ]. TEGSEDI has not been studied in patients with severe renal impairment or end-stage renal disease.
Hepatic Impairment
No dose adjustment is necessary in patients with mild hepatic impairment [see Clinical Pharmacology ]. TEGSEDI has not been studied in patients with other degrees of hepatic impairment.
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 ].