KESIMPTA

1 INDICATIONS AND USAGE KESIMPTA is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. KESIMPTA is a CD20-directed cytolytic antibody indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. ( 1 )

2 DOSAGE AND ADMINISTRATION Before initiating KESIMPTA, screen for Hepatitis B virus (HBV) and obtain serum quantitative immunoglobulins, aminotransferases, alkaline phosphatase, and bilirubin. ( 2.1 ) Administer KESIMPTA by subcutaneous injection only. ( 2.2 , 2.3 ) Initial Dosing: 20 mg administered at Weeks 0, 1, and 2. ( 2.2 ) Subsequent Dosing: 20 mg administered monthly starting at Week 4. ( 2.2 ) 2.1 Assessments Prior to First Dose of KESIMPTA Hepatitis B Virus Screening Prior to initiating KESIMPTA, perform Hepatitis B virus (HBV) screening. KESIMPTA is contraindicated in patients with active HBV confirmed by positive results for Hepatitis B surface antigen [HBsAg] and anti-HBV tests. For patients who are negative for HBsAg and positive for Hepatitis B core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment with KESIMPTA [see Warnings and Precautions (5.1)] . Serum Immunoglobulins Prior to initiating KESIMPTA, perform testing for quantitative serum immunoglobulins [see Warnings and Precautions (5.3)] . For patients with low serum immunoglobulins, consult immunology experts before initiating treatment with KESIMPTA. Vaccinations Because vaccination with live-attenuated or live vaccines is not recommended during treatment and after discontinuation until B-cell repletion, administer all immunizations according to immunization guidelines at least 4 weeks prior to initiation of KESIMPTA for live or live-attenuated vaccines, and whenever possible, at least 2 weeks prior to initiation of KESIMPTA for inactivated vaccines [see Warnings and Precautions (5.1)] . Liver Function Tests Prior to initiating KESIMPTA, obtain serum aminotransferases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), alkaline phosphatase, and bilirubin levels [see Warnings and Precautions (5.4)] . 2.2 Recommended Dosage The recommended dosage of KESIMPTA is: initial dosing of 20 mg by subcutaneous injection at Weeks 0, 1, and 2, followed by subsequent dosing of 20 mg by subcutaneous injection once monthly starting at Week 4. Missed Doses If an injection of KESIMPTA is missed, it should be administered as soon as possible without waiting until the next scheduled dose. Subsequent doses should be administered at the recommended intervals. 2.3 Administration Instructions Administer by subcutaneous injection only. KESIMPTA is intended for patient self-administration by subcutaneous injection. Administer KESIMPTA in the abdomen, thigh, or outer upper arm subcutaneously. Do not give injection into moles, scars, stretch marks, or areas where the skin is tender, bruised, red, scaly, or hard. The first injection of KESIMPTA should be performed under the guidance of a healthcare professional [see Warnings and Precautions (5.2)] . KESIMPTA Sensoready ® pens and syringes are for one-time use only and should be discarded after use. See Instructions for Use for complete administration instructions. 2.4 Preparation of KESIMPTA The KESIMPTA “Instructions for Use” for each presentation contains more detailed instructions on the preparation of KESIMPTA. Before administration, remove KESIMPTA Sensoready Pen or KESIMPTA prefilled syringe from the refrigerator and allow KESIMPTA to reach room temperature for about 15 to 30 minutes. DO NOT remove the needle cover while allowing the prefilled syringe to reach room temperature. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if the liquid contains visible particles or is cloudy.

5 WARNINGS AND PRECAUTIONS Infections: Serious, including life-threatening and fatal infections, have occurred in patients treated with anti-CD20 therapies. Delay KESIMPTA administration in patients with an active infection until the infection is resolved. Vaccination with live-attenuated or live vaccines is not recommended during treatment with KESIMPTA and after discontinuation, until B-cell repletion. ( 5.1 ) Injection-Related Reactions and Hypersensitivity Reactions: Management for injection-related reactions and hypersensitivity reactions depends on the type and severity of the reaction. ( 4 , 5.2 ) Reduction in Immunoglobulins: Monitor the level of immunoglobulins at the beginning, during, and after discontinuation of treatment with KESIMPTA until B-cell repletion. Consider discontinuing KESIMPTA if a patient develops a serious opportunistic infection or recurrent infections if immunoglobulin levels indicate immune compromise. ( 5.3 ) Liver Injury: Clinically significant liver injury has occurred. Obtain serum aminotransferases, alkaline phosphatase, and bilirubin levels before initiating KESIMPTA, and during treatment as clinically indicated. Discontinue KESIMPTA in patients with evidence of liver injury in the absence of an alternative etiology. ( 5.4 ) Fetal Risk: May cause fetal harm based on animal data. Advise females of reproductive potential of the potential risk to a fetus and to use an effective method of contraception during treatment and for 6 months after stopping KESIMPTA. ( 5.5 , 8.1 ) 5.1 Infections Serious, including life-threatening or fatal, bacterial, fungal, and new or reactivated viral infections have been observed during and following completion of treatment with anti-CD20 B-cell depleting therapies. In KESIMPTA Study 1 and Study 2 [see Clinical Studies (14)] , the overall rate of infections and serious infections in patients treated with KESIMPTA was similar to patients who were treated with teriflunomide (51.6% vs 52.7%, and 2.5% vs 1.8%, respectively). The most common infections reported by KESIMPTA-treated patients in the randomized clinical relapsing MS (RMS) trials included upper respiratory tract infection (39%) and urinary tract infection (10%). Delay KESIMPTA administration in patients with an active infection until the infection is resolved. Possible Increased Risk of Immunosuppressant Effects with Other Immunosuppressants When initiating KESIMPTA after an immunosuppressive therapy or initiating an immunosuppressive therapy after KESIMPTA, consider the potential for increased immunosuppressive effects [see Drug Interactions (7.1) and Clinical Pharmacology (12.2)] . KESIMPTA has not been studied in combination with other MS therapies. Hepatitis B Virus Reactivation There were no reports of HBV reactivation in patients with MS treated with KESIMPTA. However, HBV reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, has occurred in patients being treated with ofatumumab for chronic lymphocytic leukemia (CLL) (at higher intravenous doses than the recommended dose in MS but for a shorter duration of treatment) and in patients treated with other anti-CD20 antibodies. Infection KESIMPTA is contraindicated in patients with active hepatitis B disease. Fatal infections caused by HBV in patients who have not been previously infected have occurred in patients being treated with ofatumumab for CLL (at higher intravenous doses than the recommended dose in MS but for a shorter duration of treatment). HBV screening should be performed in all patients before initiation of treatment with KESIMPTA. At a minimum, screening should include Hepatitis B surface antigen (HBsAg) and Hepatitis B Core Antibody (HBcAb) testing. These can be complemented with other appropriate markers as per local guidelines. For patients who are negative for HBsAg and positive for HB core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult liver disease experts before starting and during tre…

4 CONTRAINDICATIONS KESIMPTA is contraindicated in patients with: Active HBV infection [see Warnings and Precautions (5.1)] . History of hypersensitivity to ofatumumab or life-threatening injection-related reaction to KESIMPTA. Hypersensitivity reactions have included anaphylaxis and angioedema [see Warnings and Precautions (5.2)] . Active HBV infection. ( 4 ) History of hypersensitivity to ofatumumab or life-threatening injection-related reaction to KESIMPTA. ( 4 )

7 DRUG INTERACTIONS 7.1 Immunosuppressive or Immune-Modulating Therapies Concomitant usage of KESIMPTA with immunosuppressant drugs, including systemic corticosteroids, may increase the risk of infection. Consider the risk of additive immune system effects when coadministering immunosuppressive therapies with KESIMPTA. When switching from therapies with immune effects, the duration and mechanism of action of these therapies should be taken into account because of potential additive immunosuppressive effects when initiating KESIMPTA.

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to KESIMPTA during pregnancy. Healthcare providers are encouraged to enroll pregnant patients, or pregnant women may register themselves in the MotherToBaby Pregnancy Study in Multiple Sclerosis by calling 1-877-311-8972, by sending an email to MotherToBaby@health.ucsd.edu, or by going to www.mothertobaby.org/join-study. Risk Summary There are no adequate data on the developmental risk associated with the use of KESIMPTA in pregnant women. Ofatumumab may cross the placenta and cause fetal B-cell depletion based on findings from animal studies. No teratogenicity was observed after intravenous administration of ofatumumab to pregnant monkeys during organogenesis. However, increased mortality, depletion of B-cell populations, and impaired immune function were observed in the offspring, in the absence of maternal toxicity, at plasma levels higher than that in humans ( see Data ). Although there are no data on ofatumumab, monoclonal antibodies can be actively transported across the placenta, and ofatumumab may cause immunosuppression in the in utero -exposed infant (see Clinical Considerations ). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Clinical Considerations Fetal/Neonatal adverse reactions Transport of endogenous IgG antibodies across the placenta is low in the first trimester and increases as pregnancy progresses and peaks during the third trimester. Transient peripheral B-cell depletion and lymphocytopenia have been observed in infants born to mothers exposed to other anti-CD20 antibodies during pregnancy. B-cell levels in infants following maternal exposure to KESIMPTA have not been adequately studied in clinical trials. The potential duration of B-cell depletion in infants exposed to ofatumumab in utero , and the impact of B-cell depletion on the safety and effectiveness of vaccines, are unknown. Avoid administering live vaccines to neonates and infants exposed to KESIMPTA in utero before confirming B-cell count is within normal range [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2)] . Data Animal Data In the embryo-fetal development (EFD) study, intravenous administration of ofatumumab (weekly doses of 0, 20, or 100 mg/kg) to pregnant monkeys during the period of organogenesis (gestation days 20 to 50) resulted in no adverse effects on embryofetal development; however, B-cell depletion was observed in fetuses at both doses when assessed on gestation day 100. Plasma exposure (C avg ) at the no-effect dose (100 mg/kg) for adverse effects on embryofetal development was greater than 5000 times that in humans at the recommended human maintenance dose of 20 mg. A no-effect dose for effects on B-cells was not identified; plasma exposure (C avg ) at the low-effect dose (20 mg/kg) was approximately 780 times that in humans at the recommended human maintenance dose (RHMD) of 20 mg/month. In the enhanced pre- and post-natal development (ePPND) study, intravenous administration of ofatumumab (5 weekly doses of 0, 10, and 100 mg/kg, followed by biweekly doses of 0, 3, and 20 mg/kg) to pregnant monkeys from gestation day 20 until birth resulted in no adverse effects on the development of the offspring. However, postnatal death, B-cell depletion, and impaired immune function were observed in the offspring at the high dose of 100/20 mg/kg. The deaths were considered secondary to B-cell depletion. Plasma exposure (C avg ) in dams at the no-effect dose (100/20 mg/kg) for adverse developmental effects was approximately 500 times that in humans at RHMD. A no-effect level for mortality and immune effects in offspring was not established because of the limited nu…

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail elsewhere in the labeling: Infections [see Warnings and Precautions (5.1)] Injection-Related Reactions and Hypersensitivity Reactions [see Warnings and Precautions (5.2)] Reduction in Immunoglobulins [see Warnings and Precautions (5.3)] Liver Injury [see Warnings and Precautions (5.4)] Most common adverse reactions (incidence greater than 10%) are upper respiratory tract infection, headache, injection-related reactions, and local injection site reactions. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Approximately 1500 patients with RMS received KESIMPTA in clinical studies. In Study 1 and Study 2, 1882 patients with RMS were randomized, 946 of whom were treated with KESIMPTA for a median duration of 85 weeks; 33% of patients receiving KESIMPTA were treated for up to 120 weeks [see Clinical Studies (14.1)] . The most common adverse reactions occurring in greater than 10% of patients treated with KESIMPTA and more frequently than in patients treated with teriflunomide were upper respiratory tract infections, injection-related reactions (systemic), headache, and injection-site reactions (local). The most common cause of discontinuation in patients treated with KESIMPTA was low immunoglobulin M (3.3%), defined in trial protocols as IgM at 10% below the lower limit of normal (LLN). Table 1 summarizes the adverse drug reactions that occurred in Study 1 and Study 2. Table 1: Adverse Reactions in Patients With RMS With an Incidence of at Least 5% With KESIMPTA and a Greater Incidence Than Teriflunomide (Pooled Study 1 and Study 2) a Includes the following: nasopharyngitis, upper respiratory tract infection, influenza, sinusitis, pharyngitis, rhinitis, viral upper respiratory infection, tonsillitis, acute sinusitis, pharyngotonsillitis, laryngitis, pharyngitis streptococcal, viral rhinitis, sinusitis bacterial, tonsillitis bacterial, viral pharyngitis, viral tonsillitis, chronic sinusitis, nasal herpes, tracheitis. Adverse reactions KESIMPTA 20 mg N = 946 % Teriflunomide 14 mg N = 936 % Upper respiratory tract infections a 39 38 Injection-related reactions (systemic) 21 15 Headache 13 12 Injection-site reactions (local) 11 6 Urinary tract infection 10 8 Back pain 8 6 Blood immunoglobulin M decreased 6 2 Injection-Related Reactions and Injection-Site Reactions The incidence of injection-related reactions (systemic) was highest with the first injection (14.4%), decreasing with subsequent injections (4.4% with second, less than 3% with third injection). Injection-related reactions were mostly (99.8%) mild to moderate in severity. Two (0.2%) patients treated with KESIMPTA reported serious injection-related reactions. There were no life-threatening injection-related reactions. Most frequently reported symptoms (2% or greater) included fever, headache, myalgia, chills, and fatigue. In addition to systemic injection-related reactions, local reactions at the administration site were very common. Local injection-site reactions were all mild to moderate in severity. The most frequently reported symptoms (2% or greater) included erythema, pain, itching, and swelling [see Warnings and Precautions (5.2)] . Laboratory Abnormalities Immunoglobulins In Study 1 and Study 2, a decrease in the mean level of IgM was observed in KESIMPTA-treated patients but was not associated with an increased risk of infections [see Warnings and Precautions (5.3)] . In 14.3% of patients in Study 1 and Study 2, treatment with KESIMPTA resulted in a decreas…