Source: FDA, National Drug Code (US) Revision Year: 2020
TEGSEDI is contraindicated in patients with:
TEGSEDI causes reductions in platelet count that may result in sudden and unpredictable thrombocytopenia that can be life-threatening. In Study 1 [see Clinical studies (14)], platelet counts below 100 × 109/L occurred in 25% of TEGSEDI-treated patients, compared with 2% of patients on placebo. Platelet counts below 75 × 109/L occurred in 14% of TEGSEDI-treated patients, compared to no patient on placebo. In Study 1 and its extension study, 39% of TEGSEDI-treated patients with a baseline platelet count below 200 x109/L had a nadir platelet count below 75 × 109/L, compared to 6% of patients with baseline platelet counts 200 x109/L or higher.
Three TEGSEDI-treated patients (3%) had sudden severe thrombocytopenia (platelet count below 25 × 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) [see Warnings and Precautions (5.8)].
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 × 109/L. Follow recommended monitoring and treatment recommendations for platelet count [see Dosage and Administration (2.4)]. If a patient develops signs or symptoms of thrombocytopenia, obtain a platelet count as soon as possible, and hold TEGSEDI dosing unless the platelet count is confirmed to be acceptable. Recheck the platelet count as soon as possible if a platelet measurement is uninterpretable (e.g., clumped sample) [see Warnings and Precautions (5.8)]. Hold TEGSEDI dosing until an acceptable platelet count is confirmed with an interpretable blood sample.
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 × 109/L [see Drug Interactions (7.1)].
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.
Glucocorticoid therapy is strongly recommended in patients with a platelet count below 50 × 109/L, and in patients with suspected immune-mediated thrombocytopenia. Avoid using TEGSEDI in patients for whom glucocorticoid treatment is not advised.
TEGSEDI can cause glomerulonephritis that may result in dialysis-dependent renal failure. In Study 1 [see Clinical studies (14)], glomerulonephritis occurred in three (3%) TEGSEDI-treated patients vs. no patient on placebo. In these patients, stopping TEGSEDI alone was not sufficient to resolve manifestations of glomerulonephritis, and treatment with an immunosuppressive medication was necessary. One patient did not receive immunosuppressive treatment and remained dialysis-dependent. If glomerulonephritis is suspected, pursue prompt diagnosis and initiate immunosuppressive treatment as soon as possible.
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 [see Dosage and Administration (2.4)]. TEGSEDI should generally not be initiated in patients with a UPCR of 1000 mg/g or greater. If acute glomerulonephritis is confirmed, TEGSEDI should be permanently discontinued [see Contraindications (4)].
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 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 [see Warnings and Precautions (5.1, 5.2)].
Important requirements of the TEGSEDI Prescribing Program include:
TEGSEDI may cause stroke and cervicocephalic arterial dissection. In clinical studies, 1 of 161 (0.6%) TEGSEDI-treated patients experienced carotid artery dissection and stroke. These events occurred within 2 days of the first TEGSEDI dose, a time when the patient also had symptoms of cytokine release (e.g., nausea, vomiting, muscular pain and weakness) and a high sensitivity C-reactive protein level greater than 100 mg/L.
Educate patients on the symptoms of stroke and central nervous system arterial dissection. Instruct patients to seek help as soon as possible if symptoms of stroke or arterial dissection occur.
Inflammatory and immune changes are an effect of some antisense oligonucleotide drugs, including TEGSEDI. In clinical studies, serious inflammatory and immune adverse reactions occurred in TEGSEDI-treated patients, including immune thrombocytopenia and glomerulonephritis, as well as a single case of antineutrophil cytoplasmic autoantibody (ANCA)-positive systemic vasculitis [see Warnings and Precautions (5.2) and (5.3)].
In clinical studies, neurologic serious adverse reactions consistent with inflammatory and immune effects occurred in TEGSEDI-treated patients, in addition to stroke and carotid artery dissection [see Warnings and Precautions (5.5)]. Two months after the first TEGSEDI dose, one patient developed a change in gait that progressed over 6 months to paraparesis, in the absence of radiologic evidence of spinal cord compression. Another patient developed progressive lumbar pain, weight loss, headache, vomiting, and impaired speech 7 months after starting TEGSEDI. Cerebrospinal fluid analysis findings included elevated protein, a lymphocyte-predominant pleocytosis, and testing that was negative for infection. The patient recovered after empiric therapy (high-dose steroids, antibiotics) and resumed TEGSEDI without recurrence of symptoms.
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 every four months 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 or discontinue treatment with TEGSEDI, as appropriate.
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 can cause hypersensitivity reactions. In clinical studies, 6 of 161 (4%) TEGSEDI-treated patients stopped treatment because of a hypersensitivity reaction. Antibodies to TEGSEDI were present when the reactions occurred. These reactions generally occurred within 2 hours of administration of TEGSEDI and included headache, chest pain, hypertension, chills, flushing, dysphagia, palmar erythema, eosinophilia, involuntary choreaform movements, arthralgia, myalgia, and flu-like symptoms.
If a hypersensitivity reaction occurs, discontinue administration of TEGSEDI, and initiate appropriate therapy. Do not use in patients who have a history of hypersensitivity reaction to TEGSEDI.
In Study 1 [see Clinical Studies (14)], 23% of TEGSEDI-treated patients had at least 1 uninterpretable platelet count caused by platelet clumping, compared to 13% of patients on placebo. In 2 cases of severe thrombocytopenia with platelet count below 25 × 109/L, one of which resulted in death, clumped platelet samples caused a delay in diagnosis and treatment. Both subjects had tested positive for treatment-emergent anti-platelet IgG antibodies detected shortly before, or at the time of the severe reduction in platelet count.
Although platelet clumping can have a variety of causes (e.g., incompletely mixed or inadequately anticoagulated samples), platelet clumping can be caused by a reaction between antiplatelet antibodies and ethylenediaminetetra-acetic acid (EDTA). In Study 1, 7 of the 9 (78%) TEGSEDI-treated patients with treatment-emergent positive antiplatelet antibody testing had at least 1 clumped platelet sample.
If there is suspicion of EDTA-mediated platelet clumping, perform a repeat platelet count using a different anticoagulant (e.g., sodium citrate, heparin) in the blood collection tube. Recheck the platelet count as soon as possible if a platelet measurement is uninterpretable. Hold TEGSEDI dosing until an acceptable platelet count is confirmed with an interpretable blood sample.
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).
The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of TEGSEDI cannot be directly compared to rates in clinical trials of other drugs and may not reflect the rates observed in practice.
A total of 112 adult patients with polyneuropathy caused by hereditary transthyretin-mediated amyloidosis (hATTR) received TEGSEDI in Study 1 and 60 patients received placebo. The, mean age of the study patients was 59 years (27 to 78 years of age). Of the TEGSEDI-treated patients, 69% were male and 94% were Caucasian, with a mean exposure of 385 days, and median exposure of 449 days. Baseline disease characteristics were largely similar in TEGSEDI-treated patients and patients in the placebo control group. Sixty-seven percent of patients were in Stage 1 of the disease at baseline, and 33% in Stage 2. Fifty-two percent of patients had Val30Met mutations in the TTR gene, with the remaining 48% comprised of 26 different other point mutations.
Table 2 presents common adverse reactions that occurred in at least 5% of TEGSEDI-treated patients and that occurred at least 5% more frequently or two times more frequently than on placebo.
The most common adverse reactions that occurred in at least 20% of TEGSEDI-treated patients and more frequently than on placebo were injection site reactions, nausea, headache, fatigue, thrombocytopenia, and fever. Serious adverse reactions were more frequent in TEGSEDI-treated patients (32%) than in patients on placebo (21%). The most common adverse reactions leading to discontinuation were thrombocytopenia and cachexia.
Table 2. Adverse Reactions Reported in At Least 5% TEGSEDI-Treated Patients and that Occurred At Least 5% More Frequently or At Least Two Times More Frequently than Placebo Patients (Study 1):
| TEGSEDI (N=112) % | Placebo (N=60) % | |
|---|---|---|
| Injection site reactions a | 49 | 10 |
| Nausea | 31 | 12 |
| Headache | 26 | 12 |
| Fatigue | 25 | 20 |
| Thrombocytopenia | 24 | 2 |
| Fever | 20 | 8 |
| Peripheral edema | 19 | 10 |
| Chills | 18 | 3 |
| Anemia | 17 | 3 |
| Vomiting | 15 | 5 |
| Myalgia | 15 | 10 |
| Decreased renal function | 14 | 5 |
| Arrhythmia b | 13 | 5 |
| Arthralgia | 13 | 8 |
| Pre-syncope or syncope | 13 | 5 |
| Decreased appetite | 10 | 0 |
| Paresthesia | 10 | 3 |
| Dyspnea | 9 | 3 |
| Elevated liver function test | 9 | 3 |
| Orthostasis | 8 | 2 |
| Influenza-like illness | 8 | 3 |
| Contusion | 7 | 2 |
| Bacterial infection c | 7 | 3 |
| Eosinophilia | 5 | 0 |
| Dry mouth | 5 | 2 |
a Includes bruising, erythema, hematoma, hemorrhage, induration, inflammation, mass, edema, pain, pruritus, rash, swelling, and urticaria.
b Includes arrhythmia, atrial fibrillation, atrial flutter, bradyarrhythmia, bradycardia, extrasystoles, sinus arrhythmia, sinus bradycardia, supraventricular extrasystoles, tachycardia, and ventricular extrasystoles.
c Includes bacteremia, cellulitis staphylococcal, clostridium difficile infection, conjunctivitis bacterial, cystitis Escherichia, Helicobacter gastritis, Helicobacter infection, Staphylococcal infection.
The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. In addition, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to TEGSEDI in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
In Study 1, 30% of TEGSEDI-treated patients tested positive for anti-drug antibodies (ADA) following 65 weeks of treatment [see Warnings and Precautions (5.7, 5.8)]. However, the assay measured only IgG isotypes and the existence of other isotypes may be possible. In many cases adverse reactions occurred in patients with ADA, although the available data are too limited to make definitive conclusions about the relationship.
Because of the risk of thrombocytopenia, caution should be used when using antiplatelet drugs (e.g., adenosine, clopidogrel, prasugrel, ticagrelor, or ticlopidine), including non-prescription products that affect platelets (e.g., aspirin, nonsteroidal anti-inflammatory drugs), or anticoagulants (e.g., heparin, warfarin), concomitantly with TEGSEDI [see Warnings and Precautions (5.1)].
Because of the risk of glomerulonephritis and renal toxicity, caution should be used when using nephrotoxic drugs and other drugs that may impair renal function concomitantly with TEGSEDI [see Warnings and Precautions (5.2)].
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 [see Clinical Pharmacology (12.2), Warnings and Precautions (5.9)].
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.
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.
Safety and effectiveness in pediatric patients have not been established.
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.
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 (12.3)]. TEGSEDI has not been studied in patients with severe renal impairment or end-stage renal disease.
No dose adjustment is necessary in patients with mild hepatic impairment [see Clinical Pharmacology (12.3)]. TEGSEDI has not been studied in patients with other degrees of hepatic impairment.
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