Ofatumumab

Arzerra

100MG/5ML injectableÉtats-UnisCommercialiséAutorisé le 26 oct. 2009

Contenu en anglais

Indications

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 )

Contre-indications

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 )

Mises en garde et précautions d’emploi

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.

Indications

( 1 )

Contre-indications

( 4 )

Mises en garde et précautions d’emploi

Grossesse et allaitement

8.1Pregnancy 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 number of evaluable offspring at the low dose (10/3 mg/kg).

Effets indésirables

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.

6.1Clinical 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 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.

6.2 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.

6.3Postmarketing 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 [see Warnings and Precautions (5.2)] Hepatobiliary Disorders: Liver injury [see Warnings and Precautions (5.4)]

Arzerra

Indications

Contre-indications

Mises en garde et précautions d’emploi

Deux médicaments dans une même question ?

Arzerra

Indications

Contre-indications

Mises en garde et précautions d’emploi

Deux médicaments dans une même question ?

5.1Infections

5.2Injection-Related Reactions and Hypersensitivity Reactions

Interactions

7.1Immunosuppressive or Immune-Modulating Therapies

Grossesse et allaitement

8.1Pregnancy Pregnancy Exposure Registry

Effets indésirables

6.1Clinical Trials Experience

6.3Postmarketing Experience

Dans d’autres pays

Conditionnements

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