Usual Adult Dose for Amyloidogenic Transthyretin Amyloidosis

284 mg subcutaneously once a week

Comments:

• If a dose is missed and it is not within 2 days of next scheduled dose, the dose should be administered as soon as possible; if the missed dose is within 2 days of next scheduled dose, skip the missed dose and take the next scheduled dose on the scheduled day.

Use: For the treatment of polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.

Renal Dose Adjustments

Mild to Moderate Renal Impairment (eGFR 30 mL/min/1.73 m2 or greater): No adjustment recommended
Severe Renal Impairment: Data not available

Urine Protein to Creatinine Ratio (UPCR) 1000 mg/g or higher: Do not initiate therapy

Routine renal monitoring should be performed: See Monitoring

• For patients who develop a UPCR of 1000 mg/g or higher or estimated glomerular filtration rate (eGFR) below 45 mL/minute/1.73 m2: Hold therapy and investigate for cause
• Weekly dosing may be reinitiated once eGFR increases to 45 mL/minute/1.73 m2 or higher and UPCR decreases to below 1000 mg/g, or the underlying cause of the decline in renal function is corrected
• For UPCR of 2000 mg/g or higher: Evaluate for acute glomerulonephritis; if acute glomerulonephritis is confirmed, this drug should be permanently discontinued

Liver Dose Adjustments

Mild Hepatic Impairment: No adjustment recommended
Moderate to Severe Hepatic Impairment: Data not available

Routine liver function monitoring should be performed: See Monitoring

If a patient develops clinical signs or symptoms suggestive of hepatic dysfunction, promptly measure serum transaminases and total bilirubin: Interrupt or discontinue treatment as appropriate

Dose Adjustments

Platelet Count: Monitoring and Treatment Recommendations:

• Platelet count 100 x 10(9)/L or greater: Continue weekly dosing; monitor platelet count weekly
• Platelet count 75 to less than 100 x 10(9)/L: Stop treatment and do not restart until platelet count is greater than 100 x 10(9)/L; monitor platelet count weekly
• Platelet count 50 x 10(9)/L to less than 75 x 10(9)/L: Stop treatment and do not restart unless 3 successive values are greater than 100 x 10(9)/L and the benefit of treatment outweighs the risk of thrombocytopenia and potential bleeding; monitor platelet count twice a week until 3 successive values are above 75 x 10(9)/L, then weekly
• Platelet count 25 to less than 50 x 10(9)/L: Stop treatment and do not restart unless 3 successive values are greater than 100 x 10(9)/L and the benefit of treatment outweighs the risk of thrombocytopenia and potential bleeding; corticosteroids are recommended, consider discontinuing any antiplatelet agents or anticoagulants; monitor platelet count twice a week until 3 successive values are above 75 x 10(9)/L, then weekly and consider more frequent monitoring if additional risk factors for bleeding are present
• Platelet count less than 25 x 10(9)/L: Discontinue therapy, corticosteroids are recommended, consider discontinuation of any antiplatelet agents or anticoagulants; monitor platelet count daily until 2 successive values are above 25 x 10(9)/L, then twice weekly until 3 successive values are above 75 x 10(9)/L, then weekly until stable

Patients who discontinue therapy due to platelet counts below 25 x 10(9)/L should not reinitiate therapy

Additional risk factors for bleeding include age greater than 60 years, concomitant use of anticoagulant or antiplatelet medicine and/or prior history of major bleeding events

If a patient develops signs or symptoms of thrombocytopenia, obtain a platelet count as soon as possible, and hold therapy until platelet count is confirmed as acceptable

Precautions

The US FDA requires a Risk Evaluation and Mitigation Strategy (REMS) for Tegsedi(R). It includes elements to assure safe use and an implementation system. For additional information: www.accessdata.fda.gov/scripts/cder/rems/index.cfm

US BOXED WARNINGS: THROMBOCYTOPENIA AND GLOMERULONEPHRITIS:
Thrombocytopenia: This drug causes reductions in platelet count that may result in sudden and unpredictable thrombocytopenia, which can be life-threatening; 1 clinical trial patient died from intracranial hemorrhage.

• Use is contraindicated in patients with a platelet count below 100 x 10(9)/L. Prior to starting therapy, obtain a platelet count; platelet counts should be monitored weekly if values are 75 x 10(9)/L and greater or more frequently if less than 75 x 10(9)/L.
• If a patient develops signs or symptoms of thrombocytopenia, obtain a platelet count as soon as possible; patient should not receive additional therapy unless the platelet counts is determined to be interpretable and acceptable by a medical professional.
• Following discontinuation for any reason, monitor platelet counts for 8 weeks; if platelet counts are less than 100 x 10(9)/L, continue monitoring to verify they increase to 75 X 100(9)/L or more.

Glomerulonephritis: This drug 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.

• This drug should generally not be initiated in patients with urinary protein to creatinine ratio (UPCR) of 1000 mg/g or higher.
• Prior to starting therapy, measure the serum creatinine, estimated glomerular filtration rate (eGFR), UPCR, and perform a urinalysis. During treatment, monitor serum creatinine, eGFR urinalysis, and UPCR every 2 weeks; this drug should not be given to patients who develop a UPCR of 1000 mg/g or higher, or eGFR below 45 mL/minute/1.73 m(2), pending further evaluation of cause. If a dose is held, once eGFR increases to 45 mL/minute/1.73 m(2) or more, 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. This drug should be permanently discontinued.
• This drug requires a REM because of the serious risks of serious bleeding caused by severe thrombocytopenia and because of glomerulonephritis, both of which require frequent monitoring.

CONTRAINDICATIONS:

• Platelet count below 100 x 10(9)/L
• History of acute glomerulonephritis cause by this drug
• History of a hypersensitivity reaction to this drug

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Dialysis

Data not available

Other Comments

Administration advice:

• For subcutaneous use only
• Administer once weekly on the same day each week
• First injection should be administered under the guidance of qualified healthcare professional
• Subcutaneous administration should be into the abdomen, upper thigh region, or outer area of upper arm; rotate sites
• Do not inject into areas of skin disease or injury; tattoos and scars should be avoided

MISSED DOSE: If a dose is missed and it is not within 2 days of next scheduled dose, the dose should be administered as soon as possible; if the missed dose is within 2 days of next scheduled dose, skip the missed dose and take the next scheduled dose on the scheduled day.

Storage requirements:

• Store at 2C to 8C (36F to 46F) in the original container; protect from direct light; do not freeze
• Stable at room temperature (up to 30C[86F]) in the original container for up to 6 weeks; discard if not used

Preparation techniques:

• Allow syringe to reach room temperature prior to injection
• Remove from refrigerator 30 minutes prior to use; other warming methods should not be used

General:

• This drug is only available through a REMS program because of the risks of serious bleeding caused by severe thrombocytopenia and because of glomerulonephritis; patients must be willing to comply with the ongoing monitoring requirements to ensure safe use.
• Uninterpretable platelet count due to a reaction between antiplatelet antibodies and ethylenediaminetetra-acetic acid (EDTA) may occur; if this occurs, perform a repeat platelet count as soon as possible using a different anticoagulant (e.g., sodium citrate, heparin) in the blood collection tube.
• Do not allow uninterpretable platelet measurements to delay the diagnosis and treatment of severe thrombocytopenia.

Monitoring:

• BASELINE: Measure platelet count, serum creatinine, eGFR, urine protein to creatinine ratio (UPCR), ALT, AST, and total bilirubin, and perform urinalysis prior to treatment.
• HEMATOLOGIC: Measure platelet count weekly and for 8 weeks following therapy; if platelet count is uninterpretable, hold dosing until an acceptable platelet count is confirmed. If platelet count is 50 to less than 75 x 10(9)/L, monitor platelet counts twice a week until 3 successive values are above 75 x 10(9)/L, then weekly; if platelet counts is 25 to less than 50 x 10(9)/L, monitor platelet counts twice a week until 3 successive values are above 75 x 10(9)/L, then weekly; if platelet counts is less than 25 x 10(9)/L, monitor platelet counts daily until 2 successive values above 25 x 10(9)/L, then twice a week until 3 successive values above 75 x 10(9)/L, then weekly until stable. If at any time, a patient develops signs or symptoms of thrombocytopenia, obtain a platelet count as soon as possible
• RENAL: Monitor serum creatinine, eGFR, urinalysis, and UPCR every 2 weeks during treatment; continue monitoring for 8 weeks following treatment
• HEPATIC: Monitor ALT, AST, and total bilirubin every 4 months during treatment

Patient advice:

• Patients should be instructed to read the US FDA-approved patient labeling (Medication Guide and Instructions for Use) each time the drug is dispensed.
• Patients should understand the importance of monitoring platelet counts, renal and hepatic values to ensure safe use of this drug.
• Patients should be instructed to seek prompt medical attention for signs and symptoms of thrombocytopenia, symptoms of stroke or any neurological reactions, symptoms suggestive of hepatic dysfunction, or any signs and symptoms of hypersensitivity.
• Patients should be instructed to take the recommended daily allowance of vitamin A, but not more; if they feel they are experiencing symptoms of vitamin A deficiency, such as night blindness, they should speak with their healthcare provider.
• Women of childbearing potential should speak to their healthcare provider if they are pregnant or plan to become pregnant; women should be advised of the potential risk to the fetus.

Frequently asked questions

• Onpattro vs Tegsedi - how do they compare?
• What is the Tegsedi REMS Program?