Version May 2024
Inotersen 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. Inotersen is contraindicated in patients with a platelet count below 100,000/mm3. Prior to starting inotersen, obtain a platelet count. During treatment, monitor platelet counts weekly if values are 75,000/mm3 or greater, and more frequently if values are less than 75,000/mm3. If a patient develops signs or symptoms of thrombocytopenia, obtain a platelet count as soon as possible. The patient should not receive additional inotersen unless a platelet count is determined to be interpretable and acceptable by a medical professional. Following discontinuation of treatment for any reason, continue to monitor platelet count for 8 weeks, or longer if platelet counts are less than 100,000/mm3, to verify that platelet counts remain above 75,000/mm3.
Inotersen 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. Inotersen should generally not be initiated in patients with urinary protein to creatinine ratio (UPCR) of 1,000 mg/g or higher. Prior to starting inotersen, 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. Inotersen should not be given to patients who develop a UPCR of 1,000 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 1,000 mg/g, or the underlying cause of the decline in renal function is corrected, weekly dosing may be reinitiated. In patients with UPCR of 2,000 mg/g or higher, perform further evaluation for acute glomerulonephritis, as clinically indicated. If acute glomerulonephritis is confirmed, inotersen should be permanently discontinued.
Because of the risks of serious bleeding caused by severe thrombocytopenia and because of glomerulonephritis, both of which require frequent monitoring, inotersen is available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy (REMS) called the TEGSEDI REMS Program.
Note: Prior to therapy initiation, assess platelet count, kidney function (serum creatinine, eGFR, urine protein to creatinine ratio, and urinalysis), and hepatic function (ALT, AST, and total bilirubin).
Polyneuropathy of hereditary transthyretin mediated amyloidosis: SUBQ: 284 mg once weekly.
Missed doses: If a dose is missed, administer the dose as soon as possible. If the next dose is scheduled within 2 days, skip the missed dose and administer the next scheduled dose on the scheduled day.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Kidney impairment prior to treatment initiation:
Urinary protein to creatinine ratio <1,000 mg/g:
eGFR ≥30 mL/minute/1.73 m2: No dosage adjustment necessary.
eGFR <30 mL/minute/1.73 m2 or end-stage kidney disease: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Urinary protein to creatinine ratio ≥1,000 mg/g: Therapy initiation is generally not recommended.
Nephrotoxicity or acute kidney injury during treatment:
eGFR <45 mL/minute/1.73 m2 or urine protein to creatinine ratio ≥1,000 mg/g: Interrupt therapy pending further evaluation of cause; continue to monitor kidney function. Once eGFR ≥45 mL/minute/1.73 m2 and urine protein to creatinine ratio <1,000 mg/g or underlying cause is corrected, may resume 284 mg once weekly.
Glomerulonephritis, acute, confirmed: Permanently discontinue therapy; monitor for and treat nephrotic syndrome and associated complications.
Hepatic impairment prior to treatment initiation:
Mild impairment: No dosage adjustment necessary.
Moderate to severe impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Hepatotoxicity during treatment:
Hepatic dysfunction, signs/symptoms (eg, nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, dark urine): Promptly assess ALT, AST, and total bilirubin; interrupt or discontinue therapy as clinically appropriate.
Liver transplant rejection, signs (eg, increased ALT, AST): Discontinue therapy.
Hypersensitivity reaction: Discontinue therapy; do not re-treat.
Thrombocytopenia:
Uninterpretable sample (eg, clumped): Repeat platelet count as soon as possible; hold therapy until interpretable sample is obtained.
Platelet count during therapy:
≥100,000/mm3: Continue 284 mg once weekly; monitor platelet count weekly
≥75,000 to <100,000/mm3: Discontinue treatment; monitor platelet count weekly; do not restart therapy until platelet count is >100,000/mm3 then resume 284 mg once weekly.
≥50,000 to <75,000 mm3: Discontinue treatment; monitor platelet count twice weekly until 3 successive values >75,000/mm3 then monitor weekly; do not restart therapy unless there have been 3 successive values >100,000/mm3 and the benefit of therapy outweighs the risk of thrombocytopenia and potential bleeding. If therapy restarted, resume 284 mg once weekly.
≥25,000 to <50,000/ mm3: Discontinue treatment; monitor platelet count twice weekly until 3 successive values >75,000/mm3 then monitor weekly; consider more frequent monitoring if additional risk factors for bleeding are present (>60 years of age, concomitant use of anticoagulant or antiplatelet agents, prior history of major bleeding); do not restart therapy unless there have been 3 successive values >100,000/mm3 and the benefit of therapy outweighs the risk of thrombocytopenia and potential bleeding. Treatment of thrombocytopenia with corticosteroids is recommended; consider discontinuation of antiplatelet or anticoagulant agents. If therapy restarted, resume 284 mg once weekly.
<25,000/mm3: Permanently discontinue therapy. Monitor platelet count daily until 2 successive values >25,000/mm3, then monitor twice weekly until 3 successive values >75,000/mm3, then monitor weekly until stable for a minimum of 8 weeks after drug discontinuation. Treatment of thrombocytopenia with corticosteroids is recommended and consider discontinuation of antiplatelet or anticoagulant agents.
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Cardiovascular: Peripheral edema (19%), cardiac arrhythmia (13%), presyncope (≤13%), syncope (≤13%)
Central nervous system: Headache (26%), fatigue (25%), chills (18%), paresthesia (10%)
Gastrointestinal: Nausea (31%), vomiting (15%).
Hematologic & oncologic: Thrombocytopenia (24%; severe thrombocytopenia: 3%), anemia (17%)
Immunologic: Antibody development (30%)
Local: Injection site reaction (49%)
Neuromuscular & skeletal: Myalgia (15%), arthralgia (13%)
Renal: Renal insufficiency (14%)
Miscellaneous: Fever (20%)
1% to 10%:
Cardiovascular: Orthostatic hypotension (8%)
Gastrointestinal: Decreased appetite (10%), xerostomia (5%)
Hematologic & oncologic: Bruise (7%), eosinophilia (5%)
Hepatic: Increased liver enzymes (9%)
Infection: Increased serum alanine aminotransferase (≥3 x ULN: 8%; ≥8 x ULN: 3%), bacterial infection (7%)
Renal: Glomerulonephritis (3%)
Respiratory: Dyspnea (9%), flu-like symptoms (8%)
Frequency not defined: Endocrine & metabolic: Vitamin A deficiency
<1%, postmarketing, and/or case reports: Autoimmune hepatitis, cerebrovascular accident, coronary artery dissection, hepatobiliary disease, hypersensitivity reaction, immune thrombocytopenia, lower back pain, paraplegia, speech disturbance, vasculitis (antineutrophil cytoplasmic autoantibody - positive systemic vasculitis), weight loss
Hypersensitivity to inotersen or any component of the formulation; platelet count <100,000/mm3; history of acute glomerulonephritis caused by inotersen
Canadian labeling: Additional contraindications (not in US labeling): Prior to therapy: urine protein to creatinine ratio ≥113 mg/mmol (1 g/g), eGFR <45 mL/minute/1.73 m2, severe liver impairment
Concerns related to adverse effects:
• Cerebrovascular: Stroke and cervicocephalic arterial dissection may occur, usually within 2 days of the first dose and in conjunction with symptoms of cytokine release (eg, muscular pain, weakness, nausea, vomiting) and an elevated C-reactive protein concentration of >100 mg/L. Instruct patients to notify their health care provider if symptoms of stroke or arterial dissection occur.
• Glomerulonephritis: May cause glomerulonephritis resulting in dialysis-dependent renal failure. Glomerulonephritis may be accompanied by nephrotic syndrome and associated complications (eg, edema, hypercoagulability with venous or arterial thrombosis, increased susceptibility to infection). Use caution in patients on concomitant nephrotoxic therapy and other agents that may impair renal function; avoid use in patients whom immunosuppressive therapy is not recommended since immunosuppressive therapy is typically used for treatment of glomerulonephritis.
• Hepatic effects: Abnormal LFTs, including increased ALT ≥3 times ULN, have been reported; liver laboratory abnormalities may resolve with continued use. Immune-mediated biliary disease may also occur.
• Hypersensitivity reactions: Hypersensitivity reactions have occurred. Symptoms may include headache, chest pain, hypertension, chills, flushing, dysphagia, palmar erythema, eosinophilia, involuntary choreiform movements, arthralgia, myalgia, and flu-like symptoms and typically occur within 2 hours of administration. Anti-inotersen antibodies were present in patients that developed hypersensitivity reactions during clinical trials.
• Inflammatory and immune effects: Serious inflammatory and immune adverse reactions have been reported, including immune thrombocytopenia, glomerulonephritis, and antineutrophil cytoplasmic autoantibody (ANCA)-positive systemic vasculitis.
• Neurologic effects: Rarely, serious neurologic effects associated with inflammatory and immune effects of inotersen have occurred, including paraparesis and impaired speech.
• Thrombocytopenia: Life-threatening thrombocytopenia may occur. Corticosteroid therapy is recommended in patients with platelet count <50,000/mm3 and in patients with suspected immune-mediated thrombocytopenia; avoid inotersen therapy in patients for whom corticosteroid therapy is not advised. Instruct patients to notify their health care provider if symptoms of thrombocytopenia occur.
• Vitamin A levels: A decrease in serum vitamin A has been reported with inotersen treatment. Supplement at the recommended daily allowance (RDA) of vitamin A during treatment. Do not administer doses higher than the RDA; serum vitamin A levels do not reflect the total vitamin A in the body. If ocular symptoms develop, such as night blindness, referral to an ophthalmologist is recommended.
Special populations:
• Liver transplant: Liver transplant rejection has been reported in clinically stable patients (>10 years post-transplant), usually 2 to 4 months after starting inotersen. LFTs normalized and clinical improvement occurred following discontinuation of inotersen and administration of corticosteroids.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Prefilled Syringe, Subcutaneous [preservative free]:
Tegsedi: 284 mg/1.5 mL (1.5 mL)
No
Solution Prefilled Syringe (Tegsedi Subcutaneous)
284 mg/1.5 mL (per mL): $7,488.26
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Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Prefilled Syringe, Subcutaneous:
Tegsedi: 284 mg/1.5 mL (1.5 mL)
SUBQ: Administer on the same day every week. Allow prefilled syringe to come to room temperature for ≥30 minutes prior to administration; other warming methods should not be used. May self-administer in the abdomen or upper thigh; administration in the upper arm should only be done by another person. Avoid administration at the waistline or other sites where pressure or rubbing from clothing may occur. Rotate injection sites with each injection. Do not administer into skin with disease or injury; avoid areas with tattoos and scars.
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/211172s010lbl.pdf#page=28, must be dispensed with this medication.
Polyneuropathy of hereditary transthyretin mediated amyloidosis: Treatment of the polyneuropathy of hereditary transthyretin mediated amyloidosis in adults
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): Inotersen may enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Anticoagulants: Inotersen may enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Females of reproductive potential and males with female partners of reproductive potential were required to use effective contraception during clinical trials of inotersen (Benson 2018).
Adverse events were observed in some animal reproduction studies.
Inotersen decreases serum vitamin A levels; appropriate concentrations of vitamin A are required for fetal development.
Data collection to monitor pregnancy and infant outcomes following exposure to inotersen is ongoing. Health care providers are encouraged to enroll females exposed to inotersen during pregnancy in the pregnancy registry (1-877-465-7510, [email protected], or www.tegsedipregnancystudy.com); patients may also enroll themselves.
It is not known if inotersen is present in breast milk.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.
Platelets: Monitor at baseline, at least weekly and as clinically appropriate throughout treatment, and for 8 weeks (or longer if platelet counts remain <100,000/mm3) following the discontinuation of treatment. Repeat platelet count as soon as possible if sample is uninterpretable (eg, clumped).
Serum creatinine, estimated glomerular filtration rate (eGFR), urine protein to creatinine ratio (UPCR), urinalysis: Monitor at baseline, every 2 weeks during treatment, and for 8 weeks following the discontinuation of treatment.
AST, ALT, total bilirubin: Monitor at baseline, every 4 months during treatment and as clinically appropriate throughout treatment, and for 8 weeks following the discontinuation of treatment. In liver transplant recipients, monitor at baseline, monthly during treatment, and for 8 weeks following the discontinuation of treatment.
Inotersen is an antisense oligonucleotide that causes degradation of mutant and wild type TTR mRNA through binding to the TTR mRNA, which results in a reduction of serum TTR protein and TTR protein deposits in tissues.
Absorption: Rapid
Distribution: Vdss: 293 L
Protein binding: >94%
Metabolism: Metabolized by nucleases to nucleotides of various lengths
Half-life elimination: 32.3 days (range: 29.4 to 35.5 days)
Time to peak: 2 to 4 hours (median)
Excretion: Urine (<1% as unchanged drug)
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