Inotersen is a parenteral transthyretin-directed antisense oligonucleotide indicated for the treatment of polyneuropathy due to hereditary transthyretin-mediated amyloidosis (hATTR) in adults. In a randomized, placebo-controlled trial, inotersen-treated patients with stage 1 or 2 hereditary transthyretin amyloidosis with polyneuropathy experienced significant improvements in the modified Neuropathy Impairment Score +7 (mNIS+7) and the Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) total score at week 66 after 15 months of treatment compared to patients who received placebo. The difference in the least-squares mean (95% CI) between the 2 groups was -19.7 (-26.4, -13; p less than 0.001) for mNIS+7 and -11.7 (-18.3, -5.1; p less than 0.001) for Norfolk QoL-DN. Improvements in these scores reflect gains in physiological outcomes (e.g., muscle strength, reflexes, sensation) and functional outcomes (e.g., walking, nutritional status, and performance of activities of daily living) with inotersen treatment. Serious adverse reactions including thrombocytopenia, glomerulonephritis, and kidney failure may occur. The choice of transthyretin silencing therapy (e.g., inotersen, patisiran) may depend on patient accessibility, dominant phenotype, adverse reaction profile and ease of administration. Prescribers, pharmacies, and patients must be registered with the Tegsedi REMS program. Patients must comply with blood tests to check platelet counts and kidney function, as well as routine urine testing. More information is available at www.TEGSEDIrems.com.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
-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 an urinalysis before treatment with inotersen.
-Do not initiate inotersen in patients with a platelet count less than 100,000 per microliter.
-Generally, do not initiate inotersen in patients with UPCR of 1,000 mg/g or more.
-Monitor platelet count weekly or more frequently depending on actual count. Monitor serum creatinine, eGFR, urinalysis, and UPCR every 2 weeks and ALT, AST, and total bilirubin monthly during inotersen treatment.
-Continue laboratory monitoring for 8 weeks after inotersen discontinuation.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if the solution looks cloudy, discolored, or has particles. Inotersen is a clear and colorless or pale yellow solution.
Subcutaneous Administration
-Inotersen is intended for patient self-administration. Administer the first injection under the guidance of an appropriately qualified healthcare professional. Provide proper training to patients and/or caregivers on how to prepare and administer inotersen, including aseptic technique.
-Administer the dose on the same day every week for consistency.
-Prior to administration, allow inotersen to sit at room temperature for at least 30 minutes. Do not warm using a heat source such as hot water or microwave.
-Clean injection site on the abdomen, upper thigh, or back of the upper arm with an alcohol wipe, and allow skin to dry. A person other than the patient should administer injections into the upper arm. Rotate injection sites.
-Avoid injection at sites where pressure or rubbing from clothing may occur. Do not inject into areas of skin disease or injury. Avoid tattoos and scars.
-If a dose is missed, give the next dose as soon as possible unless the next dose is scheduled within 2 days. In this situation, skip the missed dose and take the next scheduled dose on the scheduled day.
-Discard the prefilled syringe and cap in a FDA-cleared sharps disposal container. Do not discard in household trash.
-Storage: After removing from refrigerator, prefilled syringes may be stored in the original carton at room temperature up to 86 degrees F (30 degrees C) for up to 6 weeks. Protect from light.
Single-dose, Prefilled Syringe
-Pull needle cap straight off.
-Gently pinch and hold injection site skin.
-Insert the needle into skin at a 90-degree angle.
-Using slow and constant pressure, push the plunger all the way down until it stops moving. Hold the plunger fully down and wait 5 seconds.
-Slowly lift up on the plunger, and allow the safety spring to retract the needle inside the syringe.
In a placebo-controlled clinical trial, an injection site reaction was reported in 49% of inotersen-treated patients (n = 112) compared to 10% of patients who received placebo (n = 60). Reactions included bleeding, ecchymosis, erythema, hematoma, induration, inflammation, mass, edema, pain, pruritus, rash, swelling, and urticaria.
Inotersen causes reductions in platelet counts that may result in sudden and unpredictable thrombocytopenia that can be life-threatening. During a clinical trial, 3 inotersen-treated patients (3%) experienced sudden severe thrombocytopenia (platelet count below 25,000 per microliter), which can have fatal bleeding complications, including spontaneous intracranial or intrapulmonary hemorrhage. A single patient experienced a fatal intracranial hemorrhage. All 3 patients 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 diagnosis and treatment. Platelet clumping can be caused by a reaction between antiplatelet antibodies and ethylenediaminetetraacetic acid (EDTA). Platelet count below 100,000 per microliter was reported in 25% of inotersen-treated patients who received inotersen (n = 112) compared to 2% of patients who received placebo (n = 60). Platelet count below 75,000 per microliter occurred in 14% of inotersen-treated patients (vs. 0% placebo). In a clinical trial and its extension study, 39% of inotersen-treated patients with a baseline platelet count below 200,000 per microliter had a nadir platelet count below 75,000 per microliter, compared to 6% of patients with baseline platelet counts of 200,000 per microliter or more. If a patient develops signs or symptoms of thrombocytopenia, obtain a platelet count as soon as possible, and hold inotersen 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). 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 collection tube. Glucocorticoid therapy is strongly recommended in patients with a platelet count less than 50,000 per microliter and in all patients with suspected immune-mediated thrombocytopenia. In all patients, obtain a platelet count prior to starting inotersen treatment. Monitor platelet count weekly or more frequently if value is less than 75,000 per microliter. If inotersen is discontinued, continue to monitor platelet count for 8 weeks, or longer if platelet count is less than 100,000 per microliter, to verify that platelet counts remain more than 75,000 per microliter. Patients who are not able to adhere to the recommended laboratory monitoring or to the related treatment recommendations must not receive inotersen. Advise patients and caregivers to be vigilant for symptoms of thrombocytopenia and to seek immediate medical attention if they have concerns. 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. In a placebo-controlled trial, anemia also occurred more frequently in patients who received inotersen than in patients who received placebo (17% vs. 3%).
In a placebo-controlled trial, gastrointestinal adverse reactions that occurred more frequently in patients who received inotersen than in patients who received placebo include nausea (31% vs. 12%), vomiting (15% vs. 5%), decreased appetite (10% vs. 0%), and xerostomia (5% vs. 2%).
In a placebo-controlled trial, neurologic adverse reactions that occurred more frequently in patients who received inotersen than in patients who received placebo include headache (26% vs. 12%), pre-syncope or syncope (13% vs. 5%), and paresthesias (10% vs. 3%).
In a placebo-controlled trial, musculoskeletal adverse reactions that occurred more frequently in patients who received inotersen than in patients who received placebo include myalgia (15% vs. 10%) and arthralgia (13% vs. 8%).
In a placebo-controlled trial, arrhythmia occurred more frequently in patients who received inotersen than in patients who received placebo (13% vs. 5%). Specific arrhythmias included atrial fibrillation, atrial flutter, bradyarrhythmia, bradycardia, extrasystoles, sinus arrhythmia, sinus bradycardia, supraventricular extrasystoles, sinus tachycardia, and ventricular extrasystoles.
In a placebo-controlled trial, bacterial infection occurred more frequently in patients who received inotersen than in patients who received placebo (7% vs. 3%). Specific infections included bacteremia, staphylococcal cellulitis, Clostridium difficile infection, bacterial conjunctivitis, Escherichia cystitis, Helicobacter gastritis, Helicobacter infection, and staphylococcal infection. Influenza-like illness was reported in 8% of patients who received inotersen (vs. 3% placebo).
Inotersen can cause glomerulonephritis that may result in dialysis-dependent renal failure. In a placebo-controlled trial, glomerulonephritis was reported in 3% of patients who received inotersen (n = 112) compared to 0% of patients who received placebo (n = 60). If glomerulonephritis is suspected, promptly diagnose and initiate immunosuppressive treatment as soon as possible. If acute glomerulonephritis is confirmed, permanently discontinue inotersen. Inotersen treatment discontinuation alone did not resolve manifestations of glomerulonephritis, and treatment with an immunosuppressive medication was necessary. A single patient did not receive immunosuppressive treatment and remained dialysis-dependent. Cases of glomerulonephritis were accompanied by nephrotic syndrome. Possible complications of nephrotic syndrome include edema, hypercoagulability with venous or arterial thrombosis, and increased susceptibility to infection. Monitor inotersen-treated patients who develop glomerulonephritis for nephrotic syndrome and its manifestations. Decreased renal function was reported in 14% of patients who received inotersen compared to 5% of placebo-treated patients. Accumulation of antisense oligonucleotides in proximal tubular cells, sometimes leading to increased tubular proteinuria, has been observed in nonclinical studies. Urine protein to creatinine ratio (UPCR) of more than 5 times the upper limit of normal (ULN) occurred in 15% of inotersen-treated patients compared to 8% of patients given placebo. Increase from baseline in serum creatinine more than 0.5 mg/dL occurred in 11% of inotersen-treated patients compared to 2% of patients who received placebo. Monitor serum creatinine, estimated glomerular filtration rate (eGFR), UPCR, and perform urinalysis prior to treatment initiation, then every 2 weeks during therapy. If inotersen is discontinued, continue biweekly monitoring for 8 weeks. Other serious inflammatory and immune adverse reactions occurred in inotersen-treated patients, including a single case of antineutrophil cytoplasmic autoantibody (ANCA)-positive systemic vasculitis.
Inotersen can cause stroke and cervicocephalic arterial dissection. In a placebo-controlled trial, 1 of 161 (0.6%) of inotersen-treated patients experienced carotid artery dissection and stroke within 2 days of the first inotersen dose. Symptoms of cytokine release (e.g., nausea, vomiting, muscular pain and weakness) and a high sensitivity C-reactive protein concentration of more than 100 mg/L were present at the time of the event. Neurologic serious adverse reactions consistent with inflammatory and immune effects also occurred in inotersen-treated patients. A single patient developed a change in gait at 2 months after the first inotersen dose that progressed over 6 months to para-paresis, 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 inotersen treatment initiation. Cerebrospinal fluid analysis revealed elevated protein, a lymphocyte-predominant pleocytosis, and no infection. The patient recovered with empiric treatment (i.e., high-dose steroids, antibiotics) and resumed therapy with inotersen without recurrence of symptoms. Educate patients on the symptoms of stroke and central nervous system arterial dissection, and instruct them to seek help as soon as possible if symptoms of these or other serious neurologic adverse reactions occur.
In a placebo-controlled trial, general systemic adverse reactions that occurred more frequently in patients who received inotersen than in patients who received placebo include fatigue (25% vs. 20%), fever (20% vs. 8%), peripheral edema (19% vs. 10%), chills (18% vs. 3%), dyspnea (9% vs. 3%), orthostasis (8% vs. 2%), and contusion (7% vs. 2%).
The liver is a site of accumulation of antisense oligonucleotides. In a placebo-controlled trial, elevated hepatic enzymes were reported in 9% of patients who received inotersen (n = 112) compared to 3% of patients who received placebo (n = 60). Alanine aminotransferase (ALT) elevations of 8 times the upper limit of normal (ULN) or more occurred in 3% of inotersen-treated patients compared to 0% of patients who received placebo; ALT elevations of 3 times the ULN or more occurred in 8% of inotersen-treated patients compared to 3% of patients who received placebo. A single patient experienced an ALT increase more than 30 times the ULN, which normalized after treatment discontinuation and corticosteroid administration. Some patients experienced resolution of hepatic laboratory abnormalities with continued inotersen use. Cases of immune-mediated biliary disease occurred in patients who received inotersen. 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. Cases of organ transplant rejection were reported 2 to 4 months after inotersen initiation in patients whose liver allografts had been previously clinically stable for over 10 years. Transaminase concentrations normalized after treatment discontinuation and corticosteroid administration. Monitor ALT, aspartate aminotransferase (AST), and total bilirubin at baseline and monthly during treatment with inotersen. If a patient develops signs or symptoms of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, and/or dark urine), promptly measure serum transaminases and total bilirubin. Discontinue inotersen in patients suspected of developing hepatic injury induced by inotersen. Discontinue inotersen in patients who show signs of liver transplant rejection. Monitor ALT, AST, and total bilirubin for 8 weeks after inotersen discontinuation.
Hypersensitivity reactions to inotersen including headache, chest pain (unspecified), hypertension, chills, flushing, dysphagia, palmar erythema, eosinophilia, involuntary choreaform movements, arthralgia, myalgia, and flu-like symptoms have occurred, generally within 2 hours of administration. Eosinophilia was reported in 5% of patients who received inotersen (vs. 0% placebo). Discontinue inotersen if a hypersensitivity reaction occurs, and initiate appropriate therapy. In clinical trials, 6 of 161 (4%) of inotersen-treated patients discontinued treatment because of hypersensitivity reactions. Antibody formation to inotersen was present when hypersensitivity reactions occurred. After 65 weeks of treatment, antidrug antibodies to inotersen were detected in 30% of patients during a placebo-controlled trial.
Inotersen treatment leads to a decrease in serum vitamin A concentrations. Supplementation with the recommended daily allowance of vitamin A is advised for patients receiving inotersen. Do not give higher doses than the recommended daily allowance of vitamin A to try to normalize serum vitamin A concentrations, as serum concentrations do not reflect the total amount of vitamin A in the body. Refer patients to an ophthalmologist for evaluation if they develop ocular symptoms of vitamin A deficiency (e.g., night blindness).
Inotersen is contraindicated in patients with a history of a hypersensitivity reaction to inotersen. Hypersensitivity reactions to inotersen including headache, chest pain, hypertension, chills, flushing, dysphagia, palmar erythema, eosinophilia, involuntary choreaform movements, arthralgia, myalgia, and flu-like symptoms have occurred, generally within 2 hours of administration. Discontinue inotersen if a hypersensitivity reaction occurs, and initiate appropriate therapy.
Inotersen is contraindicated in patients with a platelet count less than 100,000 per microliter. Inotersen causes reductions in platelet counts that may result in sudden and unpredictable thrombocytopenia that can be life-threatening. Severe thrombocytopenia (platelet count less than 25,000 per microliter), which can have fatal bleeding complications, including spontaneous intracranial or intrapulmonary hemorrhage, may occur. If a patient develops signs or symptoms of thrombocytopenia, obtain a platelet count as soon as possible, and hold inotersen 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). Glucocorticoid therapy is strongly recommended in patients with a platelet count less than 50,000 per microliter and in all patients with suspected immune-mediated thrombocytopenia. Avoid using inotersen in patients for whom glucocorticoid therapy is not advised. In all patients, obtain a platelet count prior to starting inotersen treatment. Monitor platelet count weekly or more frequently if value is less than 75,000 per microliter. If inotersen is discontinued, continue to monitor platelet count for 8 weeks, or longer if platelet count is less than 100,000 per microliter, to verify that platelet counts remain more than 75,000 per microliter. Patients who are not able to adhere to the recommended laboratory monitoring or to the related treatment recommendations must not receive inotersen. Advise patients and caregivers to be vigilant for symptoms of thrombocytopenia and to seek immediate medical attention if they have concerns.
Inotersen is contraindicated in patients with a history of acute glomerulonephritis caused by inotersen. Monitor serum creatinine, estimated glomerular filtration rate (eGFR), urinalysis, and urine protein to creatinine ratio (UPCR) prior to treatment initiation, then every 2 weeks during therapy. Generally, do not initiate inotersen in patients with a UPCR of 1,000 mg/g or more. Inotersen can cause glomerulonephritis that may result in dialysis-dependent renal failure. If glomerulonephritis is suspected, promptly diagnose and initiate immunosuppressive treatment as soon as possible. Because immunosuppressive treatment is necessary for the treatment of glomerulonephritis, avoid using inotersen in patients who are not candidates for immunosuppressive therapy. If acute glomerulonephritis is confirmed, permanently discontinue inotersen. Cases of glomerulonephritis were accompanied by nephrotic syndrome. Inotersen-treated patients who develop glomerulonephritis will require monitoring and treatment for nephrotic syndrome and its manifestations. If inotersen is discontinued, continue biweekly monitoring for 8 weeks.
Supplementation with the recommended daily allowance of vitamin A is advised for patients receiving inotersen. Inotersen treatment leads to a decrease in serum vitamin A concentrations. Do not give higher doses than the recommended daily allowance of vitamin A to try to normalize serum vitamin A concentrations, as serum concentrations do not reflect the total amount of vitamin A in the body. Refer patients to an ophthalmologist for evaluation if they develop ocular symptoms of vitamin A deficiency (e.g., night blindness).
There are no data available on inotersen use during human pregnancy to inform a drug-associated risk of adverse developmental outcomes. Vitamin A supplementation is recommended for patients taking inotersen due to a decrease in serum vitamin A concentrations with treatment. Vitamin A is essential for normal embryofetal development; however, excessive vitamin A concentrations are associated with adverse developmental effects. The effects on the fetus from vitamin A supplementation or a reduction in maternal serum transthyretin (TTR) are unknown. In animal reproductive studies, premature delivery, reduced fetal weight, and maternal toxicity (reduced body weight and food consumption) were observed when inotersen 15 mg/kg subcutaneously every other day was administered to pregnant rabbits during organogenesis. No adverse effects on embryofetal or pre- or postnatal development were observed when inotersen was administered to pregnant mice. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to inotersen; information about the registry can be obtained at www.tegsedipregnancystudy.com or emailing [email protected] or by calling 1-877-465-7510.
There are no data on the presence of inotersen in human milk, the effects of inotersen on the breast-fed infant, or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for inotersen and any potential adverse effects on the breast-fed infant from inotersen or the underlying maternal condition.
-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 before treatment with inotersen.
-Do not initiate inotersen in patients with a platelet count less than 100,000 per microliter.
-Generally, do not initiate inotersen in patients with UPCR of 1,000 mg/g or more.
-Monitor platelet count weekly or more frequently depending on actual count. Monitor serum creatinine, eGFR, urinalysis, and UPCR every 2 weeks. Monitor ALT, AST, and total bilirubin monthly during inotersen treatment.
-Continue laboratory monitoring for 8 weeks after inotersen discontinuation.
For the treatment of hereditary transthyretin amyloidosis-associated polyneuropathy:
Subcutaneous dosage:
Adults: 284 mg subcutaneously once weekly. The choice of transthyretin silencing therapy (i.e., inotersen, patisiran) may depend on patient accessibility, dominant phenotype, adverse reaction profile, and ease of administration.
Therapeutic Drug Monitoring:
Monitoring and/or Treatment Recommendations For Treatment-Related Toxicity
Platelet Count
-Monitor platelet count weekly or more frequently depending on actual count as defined below.
-Platelet count 75,000 to 99,000 per microliter: Stop treatment. Do not restart unless platelet count is more than 100,000 per microliter. Monitor platelet count weekly.
-Platelet count 50,000 to 74,000 per microliter: Stop treatment. Do not restart unless platelet count is more than 100,000 per microliter for 3 successive measurements and the benefit of treatment outweighs the risk of thrombocytopenia and potential bleeding. Monitor platelet count twice weekly until 3 successive values more than 75,000 per microliter, then resume weekly monitoring.
-Platelet count 25,000 to 49,000 per microliter: Stop treatment. Do not restart unless platelet count is more than 100,000 per microliter for 3 successive measurements and the benefit of treatment outweighs the risk of thrombocytopenia and potential bleeding. Corticosteroids are recommended. Consider discontinuation of antiplatelet agents or anticoagulants. Monitor platelet count twice weekly until 3 successive values more than 75,000 per microliter, then resume weekly monitoring. Consider more frequent monitoring if additional risk factors for bleeding are present, including age older than 60 years, concomitant use of antiplatelet agents or anticoagulants, or prior history of major bleeding events.
-Platelet count less than 25,000 per microliter: Stop treatment. Corticosteroids are recommended. Consider discontinuation of antiplatelet agents or anticoagulants. Monitor platelet count daily until 2 successive values more than 25,000 per microliter followed by twice-weekly monitoring until 3 successive values more than 75,000 per microliter, then resume weekly monitoring until stable. Do not reinitiate inotersen. Continue laboratory monitoring for 8 weeks after inotersen discontinuation.
Renal Function
-Monitor serum creatinine, estimated glomerular filtration rate (eGFR), urinalysis, and urine protein to creatinine ratio (UPCR) every 2 weeks.
-UPCR 1,000 mg/g or more or eGFR less than 45 mL/minute/1.73 m2: Hold treatment. Resume weekly dosing when eGFR increases to 45 mL/minute/1.73 m2 or more, UPCR decreases to less than 1,000 mg/g, or the underlying cause of renal function decline is corrected.
-UPCR 2,000 mg/g or more: Hold treatment. Perform further evaluation for acute glomerulonephritis as clinically indicated. If glomerulonephritis is excluded, resume weekly dosing when eGFR increases to 45 mL/minute/1.73 m2 or more, UPCR decreases to less than 1,000 mg/g, or the underlying cause of renal function decline is corrected. Permanently discontinue inotersen if glomerulonephritis is confirmed. Continue laboratory monitoring for 8 weeks after inotersen discontinuation.
Liver Function
-Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin monthly. Discontinue inotersen in patients suspected of developing hepatic injury induced by inotersen. Discontinue inotersen in patients who show signs of liver transplant rejection. Monitor ALT, AST, and total bilirubin for 8 weeks after inotersen discontinuation.
Maximum Dosage Limits:
-Adults
284 mg/week subcutaneously.
-Geriatric
284 mg/week subcutaneously.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
No dose adjustment is necessary in patients with mild hepatic impairment (bilirubin of 1.5 times the upper limit of normal (ULN) or less and/or AST less than 1.9 times the ULN). Inotersen has not been studied in patients with moderate or severe hepatic impairment or in patients with prior liver transplant.
Patients with Renal Impairment Dosing
No dose adjustment is necessary in patients with mild to moderate renal impairment (estimated GFR 30 to 89 mL/minute/1.73 m2). Inotersen has not been studied in patients with severe renal impairment or end-stage renal disease.
*non-FDA-approved indication
Abciximab: (Moderate) Use caution with concomitant use of inotersen and platelet glycoprotein IIb/IIIa inhibitors due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of platelet glycoprotein IIb/IIIa inhibitors in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Use caution with concomitant use of inotersen and salicylates due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of salicylates in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Acetaminophen; Aspirin: (Moderate) Use caution with concomitant use of inotersen and salicylates due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of salicylates in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Use caution with concomitant use of inotersen and salicylates due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of salicylates in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Acetaminophen; Ibuprofen: (Moderate) Use caution with concomitant use of inotersen and nonsteroidal antiinflammatory drugs (NSAIDs) due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of NSAIDs in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Acyclovir: (Moderate) Use caution with concomitant use of inotersen and acyclovir due to the risk of glomerulonephritis and nephrotoxicity.
Adefovir: (Moderate) Use caution with concomitant use of inotersen and adefovir due to the risk of glomerulonephritis and nephrotoxicity.
Adenosine: (Moderate) Use caution with concomitant use of inotersen and adenosine due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of adenosine in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
ADP receptor antagonists: (Moderate) Use caution with concomitant use of inotersen and ADP receptor antagonists due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of ADP receptor antagonists in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Amikacin: (Moderate) Use caution with concomitant use of inotersen and aminoglycosides due to the risk of glomerulonephritis and nephrotoxicity.
Amiloride: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Aminoglycosides: (Moderate) Use caution with concomitant use of inotersen and aminoglycosides due to the risk of glomerulonephritis and nephrotoxicity.
Aminosalicylate sodium, Aminosalicylic acid: (Moderate) Use caution with concomitant use of inotersen and salicylates due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of salicylates in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Amlodipine; Celecoxib: (Moderate) Use caution with concomitant use of inotersen and nonsteroidal antiinflammatory drugs (NSAIDs) due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of NSAIDs in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Amphotericin B lipid complex (ABLC): (Moderate) Use caution with concomitant use of inotersen and amphotericin B due to the risk of glomerulonephritis and nephrotoxicity.
Amphotericin B liposomal (LAmB): (Moderate) Use caution with concomitant use of inotersen and amphotericin B due to the risk of glomerulonephritis and nephrotoxicity.
Amphotericin B: (Moderate) Use caution with concomitant use of inotersen and amphotericin B due to the risk of glomerulonephritis and nephrotoxicity.
Anagrelide: (Moderate) Use caution with concomitant use of inotersen and anagrelide due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of anagrelide in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Anticoagulants: (Moderate) Use caution with concomitant use of inotersen and anticoagulants due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of anticoagulants in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Antithrombin III: (Moderate) Use caution with concomitant use of inotersen and anticoagulants due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of anticoagulants in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Apixaban: (Moderate) Use caution with concomitant use of inotersen and anticoagulants due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of anticoagulants in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Argatroban: (Moderate) Use caution with concomitant use of inotersen and anticoagulants due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of anticoagulants in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Aspirin, ASA: (Moderate) Use caution with concomitant use of inotersen and salicylates due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of salicylates in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Use caution with concomitant use of inotersen and salicylates due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of salicylates in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Aspirin, ASA; Caffeine: (Moderate) Use caution with concomitant use of inotersen and salicylates due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of salicylates in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Use caution with concomitant use of inotersen and salicylates due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of salicylates in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Use caution with concomitant use of inotersen and salicylates due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of salicylates in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Use caution with concomitant use of inotersen and salicylates due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of salicylates in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Aspirin, ASA; Dipyridamole: (Moderate) Use caution with concomitant use of inotersen and dipyridamole due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of dipyridamole in a patient taking inotersen with a platelet count of less than 50,000 per microliter. (Moderate) Use caution with concomitant use of inotersen and salicylates due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of salicylates in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Aspirin, ASA; Omeprazole: (Moderate) Use caution with concomitant use of inotersen and salicylates due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of salicylates in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Aspirin, ASA; Oxycodone: (Moderate) Use caution with concomitant use of inotersen and salicylates due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of salicylates in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Atenolol; Chlorthalidone: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Azilsartan; Chlorthalidone: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Bacitracin: (Moderate) Use caution with concomitant use of inotersen and bacitracin due to the risk of glomerulonephritis and nephrotoxicity.
Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Use caution with concomitant use of inotersen and salicylates due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of salicylates in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Betrixaban: (Moderate) Use caution with concomitant use of inotersen and anticoagulants due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of anticoagulants in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Bismuth Subsalicylate: (Moderate) Use caution with concomitant use of inotersen and salicylates due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of salicylates in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Use caution with concomitant use of inotersen and salicylates due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of salicylates in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Bivalirudin: (Moderate) Use caution with concomitant use of inotersen and anticoagulants due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of anticoagulants in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Bumetanide: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Bupivacaine; Meloxicam: (Moderate) Use caution with concomitant use of inotersen and nonsteroidal antiinflammatory drugs (NSAIDs) due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of NSAIDs in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Use caution with concomitant use of inotersen and salicylates due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of salicylates in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Celecoxib: (Moderate) Use caution with concomitant use of inotersen and nonsteroidal antiinflammatory drugs (NSAIDs) due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of NSAIDs in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Celecoxib; Tramadol: (Moderate) Use caution with concomitant use of inotersen and nonsteroidal antiinflammatory drugs (NSAIDs) due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of NSAIDs in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Chlorothiazide: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Use caution with concomitant use of inotersen and nonsteroidal antiinflammatory drugs (NSAIDs) due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of NSAIDs in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Chlorthalidone: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Choline Salicylate; Magnesium Salicylate: (Moderate) Use caution with concomitant use of inotersen and salicylates due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of salicylates in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Cidofovir: (Moderate) Use caution with concomitant use of inotersen and cidofovir due to the risk of glomerulonephritis and nephrotoxicity.
Cilostazol: (Moderate) Use caution with concomitant use of inotersen and cilostazol due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of cilostazol in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Cisplatin: (Moderate) Use caution with concomitant use of inotersen and cisplatin due to the risk of glomerulonephritis and nephrotoxicity.
Clopidogrel: (Moderate) Use caution with concomitant use of inotersen and ADP receptor antagonists due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of ADP receptor antagonists in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Cyclosporine: (Moderate) Use caution with concomitant use of inotersen and cyclosporine due to the risk of glomerulonephritis and nephrotoxicity.
Dabigatran: (Moderate) Use caution with concomitant use of inotersen and anticoagulants due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of anticoagulants in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Dalteparin: (Moderate) Use caution with concomitant use of inotersen and anticoagulants due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of anticoagulants in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Diclofenac: (Moderate) Use caution with concomitant use of inotersen and nonsteroidal antiinflammatory drugs (NSAIDs) due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of NSAIDs in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Diclofenac; Misoprostol: (Moderate) Use caution with concomitant use of inotersen and nonsteroidal antiinflammatory drugs (NSAIDs) due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of NSAIDs in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Diflunisal: (Moderate) Use caution with concomitant use of inotersen and nonsteroidal antiinflammatory drugs (NSAIDs) due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of NSAIDs in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Diphenhydramine; Ibuprofen: (Moderate) Use caution with concomitant use of inotersen and nonsteroidal antiinflammatory drugs (NSAIDs) due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of NSAIDs in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Diphenhydramine; Naproxen: (Moderate) Use caution with concomitant use of inotersen and nonsteroidal antiinflammatory drugs (NSAIDs) due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of NSAIDs in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Dipyridamole: (Moderate) Use caution with concomitant use of inotersen and dipyridamole due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of dipyridamole in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Diuretics: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Edoxaban: (Moderate) Use caution with concomitant use of inotersen and anticoagulants due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of anticoagulants in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Enoxaparin: (Moderate) Use caution with concomitant use of inotersen and anticoagulants due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of anticoagulants in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Eptifibatide: (Moderate) Use caution with concomitant use of inotersen and platelet glycoprotein IIb/IIIa inhibitors due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of platelet glycoprotein IIb/IIIa inhibitors in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Ethacrynic Acid: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Etodolac: (Moderate) Use caution with concomitant use of inotersen and nonsteroidal antiinflammatory drugs (NSAIDs) due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of NSAIDs in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Fenoprofen: (Moderate) Use caution with concomitant use of inotersen and nonsteroidal antiinflammatory drugs (NSAIDs) due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of NSAIDs in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Flurbiprofen: (Moderate) Use caution with concomitant use of inotersen and nonsteroidal antiinflammatory drugs (NSAIDs) due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of NSAIDs in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Fondaparinux: (Moderate) Use caution with concomitant use of inotersen and anticoagulants due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of anticoagulants in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Foscarnet: (Moderate) Use caution with concomitant use of inotersen and foscarnet due to the risk of glomerulonephritis and nephrotoxicity.
Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Furosemide: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Ganciclovir: (Moderate) Use caution with concomitant use of inotersen and ganciclovir due to the risk of glomerulonephritis and nephrotoxicity.
Gentamicin: (Moderate) Use caution with concomitant use of inotersen and aminoglycosides due to the risk of glomerulonephritis and nephrotoxicity.
Heparin: (Moderate) Use caution with concomitant use of inotersen and anticoagulants due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of anticoagulants in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Hydrochlorothiazide, HCTZ: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Hydrocodone; Ibuprofen: (Moderate) Use caution with concomitant use of inotersen and nonsteroidal antiinflammatory drugs (NSAIDs) due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of NSAIDs in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Use caution with concomitant use of inotersen and salicylates due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of salicylates in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Ibuprofen: (Moderate) Use caution with concomitant use of inotersen and nonsteroidal antiinflammatory drugs (NSAIDs) due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of NSAIDs in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Ibuprofen; Famotidine: (Moderate) Use caution with concomitant use of inotersen and nonsteroidal antiinflammatory drugs (NSAIDs) due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of NSAIDs in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Ibuprofen; Oxycodone: (Moderate) Use caution with concomitant use of inotersen and nonsteroidal antiinflammatory drugs (NSAIDs) due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of NSAIDs in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Ibuprofen; Pseudoephedrine: (Moderate) Use caution with concomitant use of inotersen and nonsteroidal antiinflammatory drugs (NSAIDs) due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of NSAIDs in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Indapamide: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Indomethacin: (Moderate) Use caution with concomitant use of inotersen and nonsteroidal antiinflammatory drugs (NSAIDs) due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of NSAIDs in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Ketoprofen: (Moderate) Use caution with concomitant use of inotersen and nonsteroidal antiinflammatory drugs (NSAIDs) due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of NSAIDs in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Ketorolac: (Moderate) Use caution with concomitant use of inotersen and nonsteroidal antiinflammatory drugs (NSAIDs) due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of NSAIDs in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Magnesium Salicylate: (Moderate) Use caution with concomitant use of inotersen and salicylates due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of salicylates in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Meclofenamate Sodium: (Moderate) Use caution with concomitant use of inotersen and nonsteroidal antiinflammatory drugs (NSAIDs) due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of NSAIDs in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Mefenamic Acid: (Moderate) Use caution with concomitant use of inotersen and nonsteroidal antiinflammatory drugs (NSAIDs) due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of NSAIDs in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Meloxicam: (Moderate) Use caution with concomitant use of inotersen and nonsteroidal antiinflammatory drugs (NSAIDs) due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of NSAIDs in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Methenamine; Sodium Salicylate: (Moderate) Use caution with concomitant use of inotersen and salicylates due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of salicylates in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Metolazone: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Nabumetone: (Moderate) Use caution with concomitant use of inotersen and nonsteroidal antiinflammatory drugs (NSAIDs) due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of NSAIDs in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Naproxen: (Moderate) Use caution with concomitant use of inotersen and nonsteroidal antiinflammatory drugs (NSAIDs) due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of NSAIDs in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Naproxen; Esomeprazole: (Moderate) Use caution with concomitant use of inotersen and nonsteroidal antiinflammatory drugs (NSAIDs) due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of NSAIDs in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Naproxen; Pseudoephedrine: (Moderate) Use caution with concomitant use of inotersen and nonsteroidal antiinflammatory drugs (NSAIDs) due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of NSAIDs in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Nonsteroidal antiinflammatory drugs: (Moderate) Use caution with concomitant use of inotersen and nonsteroidal antiinflammatory drugs (NSAIDs) due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of NSAIDs in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Oxaprozin: (Moderate) Use caution with concomitant use of inotersen and nonsteroidal antiinflammatory drugs (NSAIDs) due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of NSAIDs in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Pamidronate: (Moderate) Use caution with concomitant use of inotersen and pamidronate due to the risk of glomerulonephritis and nephrotoxicity.
Paromomycin: (Moderate) Use caution with concomitant use of inotersen and aminoglycosides due to the risk of glomerulonephritis and nephrotoxicity.
Pentamidine: (Moderate) Use caution with concomitant use of inotersen and pentamidine due to the risk of glomerulonephritis and nephrotoxicity.
Pentosan: (Moderate) Use caution with concomitant use of inotersen and anticoagulants due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of anticoagulants in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Piroxicam: (Moderate) Use caution with concomitant use of inotersen and nonsteroidal antiinflammatory drugs (NSAIDs) due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of NSAIDs in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Platelet Glycoprotein IIb/IIIa Inhibitors: (Moderate) Use caution with concomitant use of inotersen and platelet glycoprotein IIb/IIIa inhibitors due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of platelet glycoprotein IIb/IIIa inhibitors in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Plazomicin: (Moderate) Use caution with concomitant use of inotersen and aminoglycosides due to the risk of glomerulonephritis and nephrotoxicity.
Prasugrel: (Moderate) Use caution with concomitant use of inotersen and ADP receptor antagonists due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of ADP receptor antagonists in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Rivaroxaban: (Moderate) Use caution with concomitant use of inotersen and anticoagulants due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of anticoagulants in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Salicylates: (Moderate) Use caution with concomitant use of inotersen and salicylates due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of salicylates in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Salsalate: (Moderate) Use caution with concomitant use of inotersen and salicylates due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of salicylates in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Spironolactone: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Streptomycin: (Moderate) Use caution with concomitant use of inotersen and aminoglycosides due to the risk of glomerulonephritis and nephrotoxicity.
Sulindac: (Moderate) Use caution with concomitant use of inotersen and nonsteroidal antiinflammatory drugs (NSAIDs) due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of NSAIDs in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Sumatriptan; Naproxen: (Moderate) Use caution with concomitant use of inotersen and nonsteroidal antiinflammatory drugs (NSAIDs) due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of NSAIDs in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Ticagrelor: (Moderate) Use caution with concomitant use of inotersen and ADP receptor antagonists due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of ADP receptor antagonists in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Tirofiban: (Moderate) Use caution with concomitant use of inotersen and platelet glycoprotein IIb/IIIa inhibitors due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of platelet glycoprotein IIb/IIIa inhibitors in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Tobramycin: (Moderate) Use caution with concomitant use of inotersen and aminoglycosides due to the risk of glomerulonephritis and nephrotoxicity.
Tolmetin: (Moderate) Use caution with concomitant use of inotersen and nonsteroidal antiinflammatory drugs (NSAIDs) due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of NSAIDs in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Torsemide: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Triamterene: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Triamterene; Hydrochlorothiazide, HCTZ: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Valacyclovir: (Moderate) Use caution with concomitant use of inotersen and valacyclovir due to the risk of glomerulonephritis and nephrotoxicity.
Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Use caution with concomitant use of inotersen and diuretics due to the risk of glomerulonephritis and nephrotoxicity.
Vancomycin: (Moderate) Use caution with concomitant use of inotersen and vancomycin due to the risk of glomerulonephritis and nephrotoxicity.
Vorapaxar: (Moderate) Use caution with concomitant use of inotersen and vorapaxar due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of vorapaxar in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Warfarin: (Moderate) Use caution with concomitant use of inotersen and anticoagulants due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of anticoagulants in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Zoledronic Acid: (Moderate) Use caution with concomitant use of inotersen and zoledronic acid due to the risk of glomerulonephritis and nephrotoxicity.
Inotersen is an antisense oligonucleotide inhibitor of human transthyretin (TTR) protein synthesis. Inotersen causes degradation of mutant and wild-type TTR messenger RNA (mRNA) through RNA interference. As a result, serum TTR protein and TTR protein tissue deposits are reduced.
Inotersen is administered subcutaneously. Plasma protein binding of inotersen is high, with more than 94% binding observed with human plasma proteins. The fraction bound is independent of drug concentration. Inotersen rapidly distributes to tissues, with the highest concentrations observed in the kidney and liver. Inotersen does not cross the blood-brain barrier. The mean steady-state apparent volume of distribution is 293 L (90% CI 268, 320). Inotersen is metabolized by nucleases to nucleotides of various lengths. Inotersen is mainly cleared through metabolism, and the mean total body clearance is 3.18 L/hour (90% CI 3.08, 3.29). Less than 1% of the administered inotersen dose is excreted unchanged into urine within 24 hours. The mean terminal elimination half-life of inotersen is 32.3 days (90% CI 29.4, 35.5).
Affected cytochrome P450 isoenzymes and drug transporters: none
Inotersen is not a substrate of cytochrome P450 isoenzymes. It does not induce or inhibit cytochrome P450 isoenzymes or transporters.
-Route-Specific Pharmacokinetics
Subcutaneous Route
Inotersen is absorbed rapidly into systemic circulation after subcutaneous administration, with a median Tmax of 2 to 4 hours. Systemic exposure to inotersen increases in a dose-proportional manner over the dose range of 150 to 400 mg. Steady-state is reached after approximately 3 months using the recommended dosage regimen of 284 mg once weekly. The estimated geometric mean steady-state peak concentrations (Cmax), trough concentrations, and AUC were 6.39 mcg/mL (90% CI 5.65, 7.2), 0.034 mcg/mL (90% CI 0.031, 0.038), and 90 mcg x hour/mL (90% CI 82.4, 97.4), respectively. Plasma Cmax and AUC do not exhibit accumulation at steady-state.
-Special Populations
Hepatic Impairment
Population pharmacokinetic analyses indicated no impact of mild hepatic impairment (bilirubin of 1.5 times the upper limit of normal (ULN) or less and/or AST less than 1.9 times the ULN) on inotersen exposure or transthyretin (TTR) protein reduction. Inotersen has not been studied in patients with moderate or severe hepatic impairment or in patients with prior liver transplant.
Renal Impairment
Population pharmacokinetic analyses indicated no impact of mild to moderate renal impairment (estimated GFR 30 to 89 mL/minute/1.73 m2) on inotersen exposure or transthyretin (TTR) protein reduction. Inotersen has not been studied in patients with severe renal impairment or end-stage renal disease.
Geriatric
Age had no impact on the steady-state pharmacokinetics of inotersen of transthyretin (TTR) protein reduction.
Gender Differences
Gender had no impact on the steady-state pharmacokinetics of inotersen of transthyretin (TTR) protein reduction.
Ethnic Differences
Race had no impact on the steady-state pharmacokinetics of inotersen of transthyretin (TTR) protein reduction.