TOCILIZUMAB Drug Interactions: What You Need to Know

INTERACTIONS

7.1 Concomitant Drugs for Treatment of Adult Indications In RA patients, population pharmacokinetic analyses did not detect any effect of methotrexate (MTX), non- steroidal anti-inflammatory drugs or corticosteroids on tocilizumab clearance. Concomitant administration of a single intravenous dose of 10 mg/kg tocilizumab with 10-25 mg MTX once weekly had no clinically significant effect on MTX exposure. Tocilizumab products have not been studied in combination with biological DMARDs such as TNF antagonists <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span> . In GCA patients, no effect of concomitant corticosteroid on tocilizumab exposure was observed.

7.2 Interactions with CYP450 Substrates Cytochrome P450s in the liver are down-regulated by infection and inflammation stimuli including cytokines such as IL-6. Inhibition of IL-6 signaling in RA patients treated with tocilizumab products may restore CYP450 activities to higher levels than those in the absence of tocilizumab products leading to increased metabolism of drugs that are CYP450 substrates. In vitro studies showed that tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Its effect on CYP2C8 or transporters is unknown. In vivo studies with omeprazole, metabolized by CYP2C19 and CYP3A4, and simvastatin, metabolized by CYP3A4, showed up to a 28% and 57% decrease in exposure one week following a single dose of tocilizumab, respectively. The effect of tocilizumab products on CYP enzymes may be clinically relevant for CYP450 substrates with narrow therapeutic index, where the dose is individually adjusted. Upon initiation or discontinuation of Tocilizumab-anoh, in patients being treated with these types of medicinal products, perform therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) and the individual dose of the medicinal product adjusted as needed. Exercise caution when coadministering Tocilizumab-anoh with CYP3A4 substrate drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives, lovastatin, atorvastatin, etc. The effect of tocilizumab products on CYP450 enzyme activity may persist for several weeks after stopping therapy <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

7.3 Live Vaccines Avoid use of live vaccines concurrently with Tocilizumab-anoh <span class="opacity-50 text-xs">[see Warnings and Precautions (5.9) ]</span> .

Tocilizumab-anoh is contraindicated in patients with known hypersensitivity to tocilizumab products [see Warnings and Precautions (5.6) ]. Known hypersensitivity to tocilizumab products. ( 4 )

AND PRECAUTIONS Serious Infections – do not administer Tocilizumab-anoh during an active infection, including localized infections. If a serious infection develops, interrupt Tocilizumab-anoh until the infection is controlled. ( 5.1 ) Gastrointestinal (GI) perforation—use with caution in patients who may be at increased risk. ( 5.2 ) Hepatotoxicity- Monitor patients for signs and symptoms of hepatic injury. Modify or discontinue Tocilizumab-anoh if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop. ( 2.8 , 5.3 ) Laboratory monitoring—recommended due to potential consequences of treatment-related changes in neutrophils, platelets, lipids, and liver function tests. ( 2.8 , 5.4 ) Hypersensitivity reactions, including anaphylaxis and death and serious cutaneous reactions including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) – discontinue Tocilizumab-anoh, treat promptly, and monitor until reaction resolves. ( 5.6 ) Live vaccines—Avoid use with Tocilizumab-anoh. ( 5.9 , 7.3 )

5.1 Serious Infections Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, protozoal, or other opportunistic pathogens have been reported in patients receiving immunosuppressive agents including tocilizumab products. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Among opportunistic infections, tuberculosis, cryptococcus, aspergillosis, candidiasis, and pneumocystosis were reported with tocilizumab products. Other serious infections, not reported in clinical studies, may also occur (e.g., histoplasmosis, coccidioidomycosis, listeriosis). Patients have presented with disseminated rather than localized disease, and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids which in addition to rheumatoid arthritis may predispose them to infections. Do not administer Tocilizumab-anoh in patients with an active infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating Tocilizumab-anoh in patients: with chronic or recurrent infection; who have been exposed to tuberculosis; with a history of serious or an opportunistic infection; who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or with underlying conditions that may predispose them to infection. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with Tocilizumab-anoh, as signs and symptoms of acute inflammation may be lessened due to suppression of the acute phase reactants <span class="opacity-50 text-xs">[see Dosage and Administration (2.10) , Adverse Reactions (6.1) , and Patient Counseling Information (17) ]</span> .

Hold

Tocilizumab-anoh if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with Tocilizumab-anoh should undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, initiate appropriate antimicrobial therapy, and closely monitor the patient. COVID-19 In patients with COVID-19, monitor for signs and symptoms of new infections during and after treatment with Tocilizumab-anoh. There is limited information regarding the use of tocilizumab products in patients with COVID-19 and concomitant active serious infections. The risks and benefits of treatment with Tocilizumab-anoh in COVID-19 patients with other concurrent infections should be considered.

Tuberculosis

Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating Tocilizumab-anoh. In patients with COVID-19, testing for latent infection is not necessary prior to initiating treatment with Tocilizumab-anoh. Consider anti-tuberculosis therapy prior to initiation of Tocilizumab-anoh in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti- tuberculosis therapy is appropriate for an individual patient. Closely monitor patients for the development of signs and symptoms of tuberculosis including patients who tested negative for latent tuberculosis infection prior to initiating therapy. The incidence of tuberculosis in worldwide clinical development programs is 0.1%. Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before initiating Tocilizumab-anoh.

Viral Reactivation

Viral reactivation has been reported with immunosuppressive biologic therapies and cases of herpes zoster exacerbation were observed in clinical studies with tocilizumab. No cases of Hepatitis B reactivation were observed in the trials; however patients who screened positive for hepatitis were excluded.

5.2 Gastrointestinal Perforations Events of gastrointestinal perforation have been reported in clinical trials, primarily as complications of diverticulitis in patients treated with tocilizumab.

Use

Tocilizumab-anoh with caution in patients who may be at increased risk for gastrointestinal perforation. Promptly evaluate patients presenting with fever, new onset abdominal symptoms, and a change in bowel habits for early identification of gastrointestinal perforation [see Adverse Reactions (6.1) ] .

5.3 Hepatotoxicity Serious cases of hepatic injury have been observed in patients taking intravenous or subcutaneous tocilizumab products. Some of these cases have resulted in liver transplant or death. Time to onset for cases ranged from months to years after treatment initiation with tocilizumab products. While most cases presented with marked elevations of transaminases (&gt; 5 times ULN), some cases presented with signs or symptoms of liver dysfunction and only mildly elevated transaminases. During randomized controlled studies, treatment with tocilizumab was associated with a higher incidence of transaminase elevations <span class="opacity-50 text-xs">[see Adverse Reactions (6.1 , 6.2 , 6.5 , 6.7) ]</span>. Increased frequency and magnitude of these elevations was observed when potentially hepatotoxic drugs (e.g., MTX) were used in combination with tocilizumab. For RA and GCA patients, obtain a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) before initiating Tocilizumab-anoh, every 4 to 8 weeks after start of therapy for the first 6 months of treatment and every 3 months thereafter. It is not recommended to initiate Tocilizumab-anoh treatment in RA or GCA patients with elevated transaminases ALT or AST greater than 1.5× ULN. In patients who develop elevated ALT or AST greater than 5× ULN, discontinue Tocilizumab-anoh. For recommended modifications based upon increase in transaminases see Dosage and Administration (2.10) . Patients hospitalized with COVID-19 may have elevated ALT or AST levels. Multi-organ failure with involvement of the liver is recognized as a complication of severe COVID-19. The decision to administer Tocilizumab-anoh should balance the potential benefit of treating COVID-19 against the potential risks of acute treatment with Tocilizumab-anoh. It is not recommended to initiate Tocilizumab-anoh treatment in COVID-19 patients with elevated ALT or AST above 10 × ULN. Monitor ALT and AST during treatment. Measure liver tests promptly in patients who report symptoms that may indicate liver injury, such as fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have abnormal liver tests (e.g., ALT greater than three times the upper limit of the reference range, serum total bilirubin greater than two times the upper limit of the reference range), Tocilizumab-anoh treatment should be interrupted and investigation done to establish the probable cause. Tocilizumab-anoh should only be restarted in patients with another explanation for the liver test abnormalities after normalization of the liver tests. A similar pattern of liver enzyme elevation is noted with tocilizumab products treatment in the PJIA and SJIA populations. Monitor liver test panel at the time of the second administration and thereafter every 4 to 8 weeks for PJIA and every 2 to 4 weeks for SJIA.

5.4 Changes in Laboratory Parameters Patients with Rheumatoid Arthritis, Giant Cell Arteritis and Coronavirus Disease 2019 Neutropenia Treatment with tocilizumab products was associated with a higher incidence of neutropenia. Infections have been uncommonly reported in association with treatment-related neutropenia in long-term extension studies and postmarketing clinical experience. -It is not recommended to initiate Tocilizumab-anoh treatment in RA and GCA patients with a low neutrophil count, i.e., absolute neutrophil count (ANC) less than 2000 per mm 3 . In patients who develop an absolute neutrophil count less than 500 per mm 3 treatment is not recommended.–Monitor neutrophils 4 to 8 weeks after start of therapy and every 3 months thereafter <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2) ]</span> . For recommended modifications based on ANC results see Dosage and Administration (2.10) .–It is not recommended to initiate Tocilizumab-anoh treatment in COVID-19 patients with an ANC less than 1000 per mm 3 . Neutrophils should be monitored.

Thrombocytopenia

Treatment with tocilizumab products was associated with a reduction in platelet counts. Treatment-related reduction in platelets was not associated with serious bleeding events in clinical trials [see Adverse Reactions (6.1 , 6.2) ] . – It is not recommended to initiate Tocilizumab-anoh treatment in RA and GCA patients with a platelet count below 100,000 per mm 3 . In patients who develop a platelet count less than 50,000 per mm 3 treatment is not recommended. – Monitor platelets 4 to 8 weeks after start of therapy and every 3 months thereafter. For recommended modifications based on platelet counts see Dosage and Administration (2.9) . – In COVID-19 patients with a platelet count less than 50,000 per mm 3 , treatment is not recommended. Platelets should be monitored.

Elevated Liver Enzymes

Refer to

5.3 Hepatotoxicity. For recommended modifications <span class="opacity-50 text-xs">[see Dosage and Administration (2.10) ]</span>

Lipid Abnormalities

Treatment with tocilizumab products was associated with increases in lipid parameters such as total cholesterol, triglycerides, LDL cholesterol, and/or HDL cholesterol [see Adverse Reactions (6.1 , 6.2) ] . – Assess lipid parameters approximately 4 to 8 weeks following initiation of Tocilizumab-anoh therapy. – Subsequently, manage patients according to clinical guidelines [e.g., National Cholesterol Educational Program (NCEP)] for the management of hyperlipidemia. Patients with Polyarticular and Systemic Juvenile Idiopathic Arthritis A similar pattern of liver enzyme elevation, low neutrophil count, low platelet count and lipid elevations is noted with tocilizumab products treatment in the PJIA and SJIA populations. Monitor neutrophils, platelets, ALT and AST at the time of the second administration and thereafter every 4 to 8 weeks for PJIA and every 2 to 4 weeks for SJIA. Monitor lipids as above for approved adult indications [see Dosage and Administration (2.10) ] .

5.5 Immunosuppression The impact of treatment with tocilizumab products on the development of malignancies is not known but malignancies were observed in clinical studies <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Tocilizumab-anoh is an immunosuppressant, and treatment with immunosuppressants may result in an increased risk of malignancies.

5.6 Hypersensitivity Reactions, Including Anaphylaxis Hypersensitivity reactions, including anaphylaxis, have been reported in association with tocilizumab products and anaphylactic events with a fatal outcome have been reported with intravenous infusion of tocilizumab products. Anaphylaxis and other hypersensitivity reactions that required treatment discontinuation were reported in 0.1% (3 out of 2644) of patients in the 6-month controlled trials of intravenous tocilizumab, 0.2% (8 out of 4009) of patients in the intravenous all-exposure RA population, 0.7% (8 out of 1068) in the subcutaneous 6-month controlled RA trials, and in 0.7% (10 out of 1465) of patients in the subcutaneous all- exposure population. In the SJIA controlled trial with intravenous tocilizumab, 1 out of 112 patients (0.9%) experienced hypersensitivity reactions that required treatment discontinuation. In the PJIA controlled trial with intravenous tocilizumab, 0 out of 188 patients (0%) in the tocilizumab all-exposure population experienced hypersensitivity reactions that required treatment discontinuation. Reactions that required treatment discontinuation included generalized erythema, rash, and urticaria. Injection site reactions were categorized separately [ s ee Adverse Reactions (6) ] . In the postmarketing setting, events of hypersensitivity reactions, including anaphylaxis and death have occurred in patients treated with a range of doses of intravenous tocilizumab products, with or without concomitant therapies. Events have occurred in patients who received premedication. Hypersensitivity, including anaphylaxis events, have occurred both with and without previous hypersensitivity reactions and as early as the first infusion of tocilizumab products <span class="opacity-50 text-xs">[see Adverse Reactions (6.10) ]</span> . In addition, serious cutaneous reactions, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported in patients with autoinflammatory conditions treated with tocilizumab products. Tocilizumab-anoh for intravenous use should only be infused by a healthcare professional with appropriate medical support to manage anaphylaxis.

For

Tocilizumab-anoh subcutaneous injection, advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction. If a hypersensitivity reaction occurs, immediately discontinue Tocilizumab-anoh, treat promptly and monitor until signs and symptoms resolve.

5.7 Demyelinating Disorders The impact of treatment with tocilizumab products on demyelinating disorders is not known, but multiple sclerosis and chronic inflammatory demyelinating polyneuropathy were reported rarely in RA clinical studies. Monitor patients for signs and symptoms potentially indicative of demyelinating disorders. Prescribers should exercise caution in considering the use of Tocilizumab-anoh in patients with preexisting or recent onset demyelinating disorders.

5.8 Active Hepatic Disease and Hepatic Impairment Treatment with Tocilizumab-anoh is not recommended in patients with active hepatic disease or hepatic impairment <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) , Use in Specific Populations (8.6) ]</span> .

5.9 Vaccinations Avoid use of live vaccines concurrently with Tocilizumab-anoh as clinical safety has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving tocilizumab products. No data are available on the effectiveness of vaccination in patients receiving tocilizumab products. Because IL-6 inhibition may interfere with the normal immune response to new antigens, it is recommended that all patients, particularly pediatric or elderly patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating Tocilizumab-anoh therapy. The interval between live vaccinations and initiation of Tocilizumab-anoh therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.