Kesimpta Drug Information

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.

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 and anti-HBV tests. For patients who are negative for HBsAg and positive for Hepatitis B core antibody or are carriers of HBV, consult liver disease experts before starting and during treatment with KESIMPTA . Serum Immunoglobulins Prior to initiating KESIMPTA, perform testing for quantitative serum immunoglobulins . 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 . Liver Function Tests Prior to initiating KESIMPTA, obtain serum aminotransferases (alanine aminotransferase and aspartate aminotransferase ), alkaline phosphatase, and bilirubin levels .

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.

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 . 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.

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.

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 . 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 . 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 . In 14.3% of patients in Study 1 and Study 2, treatment with KESIMPTA resulted in a decrease in a serum IgM that reached a value below 0.34 g/L. KESIMPTA was associated with a decrease of 4.3% in mean IgG levels after 48 weeks of treatment and an increase of 2.2% after 96 weeks.

Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medication, and the underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other ofatumumab products may be misleading.

Treatment-induced anti-drug antibodies (ADAs) were detected in 2 of 914 (0.2%) KESIMPTA-treated patients; no patients with treatment-enhancing or neutralizing ADAs were identified. There was no impact of positive ADA titers on pharmacokinetics, safety profile or B-cell kinetics in any patient; however, these data are not adequate to assess the impact of ADAs on the safety and efficacy of KESIMPTA.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of KESIMPTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System: Hypersensitivity reactions Hepatobiliary Disorders: Liver injury

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.

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 [email protected], 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 . 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 number of evaluable offspring at the low dose (10/3 mg/kg).

Pediatric Use Safety and effectiveness in pediatric patients have not been established.

is contraindicated in patients with: Active HBV infection . History of hypersensitivity to ofatumumab or life-threatening injection-related reaction to KESIMPTA. Hypersensitivity reactions have included anaphylaxis and angioedema . Active HBV infection. History of hypersensitivity to ofatumumab or life-threatening injection-related reaction to KESIMPTA.