UPLIZNA (Page 2 of 5)

3 DOSAGE FORMS AND STRENGTHS

Injection: 100 mg/10 mL (10 mg/mL) clear to slightly opalescent, colorless to slightly yellow solution in a single-dose vial.

4 CONTRAINDICATIONS

UPLIZNA is contraindicated in patients with:

• A history of a life-threatening infusion reaction to UPLIZNA [see Warnings and Precautions ( 5.1)]
  
• Active hepatitis B infection [see Warnings and Precautions ( 5.2)]
  
• Active or untreated latent tuberculosis [see Warnings and Precautions ( 5.2)]

5 WARNINGS AND PRECAUTIONS

5.1 Infusion Reactions

UPLIZNA can cause infusion reactions, which can include headache, nausea, somnolence, dyspnea, fever, myalgia, rash, or other signs or symptoms. During the randomized clinical trial period, infusion reactions were observed with the first course of UPLIZNA in 9.3% of NMOSD patients. Infusion reactions were most common with the first infusion but were also observed during subsequent infusions.

Reducing the Risk of Infusion Reactions and Managing Infusion Reactions

Administer pre-medication with a corticosteroid, an antihistamine, and an anti-pyretic [see Dosage and Administration ( 2.2)] .

Management recommendations for infusion reactions depend on the type and severity of the reaction. For life-threatening infusion reactions, immediately and permanently stop UPLIZNA and administer appropriate supportive treatment. For less severe infusion reactions, management may involve temporarily stopping the infusion, reducing the infusion rate, and/or administering symptomatic treatment.

5.2 Infections

An increased risk of infections has been observed with other B-cell-depleting therapies. The most common infections reported by UPLIZNA-treated patients in the randomized and open-label clinical trial periods included urinary tract infection (20%), nasopharyngitis (13%), upper respiratory tract infection (8%), and influenza (7%). Delay UPLIZNA administration in patients with an active infection until the infection is resolved.

Possible Increased Risk of Immunosuppressant Effects with Other Immunosuppressants

UPLIZNA has not been studied in combination with other immunosuppressants. If combining UPLIZNA with another immunosuppressive therapy, consider the potential for increased immunosuppressive effects.

Hepatitis B Virus (HBV) Reactivation

Risk of HBV reactivation has been observed with other B-cell-depleting antibodies. There have been no cases of HBV reactivation in patients treated with UPLIZNA, but patients with chronic HBV infection were excluded from clinical trials. Perform HBV screening in all patients before initiation of treatment with UPLIZNA. Do not administer UPLIZNA to patients with active hepatitis. For patients who are chronic carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment.

Progressive Multifocal Leukoencephalopathy (PML)

PML is an opportunistic viral infection of the brain caused by the JC virus that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. Although no confirmed cases of PML were identified in UPLIZNA clinical trials, JC virus infection resulting in PML has been observed in patients treated with other B-cell-depleting antibodies and other therapies that affect immune competence. In UPLIZNA clinical trials one subject died following the development of new brain lesions for which a definitive diagnosis could not be established, though the differential diagnosis included an atypical NMOSD relapse, PML, or acute disseminated encephalomyelitis. At the first sign or symptom suggestive of PML, withhold UPLIZNA and perform an appropriate diagnostic evaluation. MRI findings may be apparent before clinical signs or symptoms. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.

Tuberculosis

Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating UPLIZNA. Consider anti-tuberculosis therapy prior to initiation of UPLIZNA in patients with a history of latent 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. Consult infectious disease experts regarding whether initiating anti-tuberculosis therapy is appropriate before starting treatment.

Vaccinations

Administer all immunizations according to immunization guidelines at least 4 weeks prior to initiation of UPLIZNA. The safety of immunization with live or live-attenuated vaccines following UPLIZNA therapy has not been studied, and vaccination with live-attenuated or live vaccines is not recommended during treatment and until B-cell repletion.

Vaccination of Infants Born to Mothers Treated with UPLIZNA During Pregnancy

In infants of mothers exposed to UPLIZNA during pregnancy, do not administer live or live-attenuated vaccines before confirming recovery of B-cell counts in the infant. Depletion of B-cells in these exposed infants may increase the risks from live or live-attenuated vaccines. Non-live vaccines, as indicated, may be administered prior to recovery from B-cell and immunoglobulin level depletion, but consultation with a qualified specialist should be considered to assess whether a protective immune response was mounted [see Use in Specific Populations ( 8.1)].

5.3 Reduction in Immunoglobulins

There may be a progressive and prolonged hypogammaglobulinemia or decline in the levels of total and individual immunoglobulins such as immunoglobulins G and M (IgG and IgM) with continued UPLIZNA treatment [see Adverse Reactions ( 6.1)] . Monitor the levels of quantitative serum immunoglobulins during treatment with UPLIZNA, especially in patients with opportunistic or recurrent infections, and until B-cell repletion after discontinuation of therapy. Consider discontinuing UPLIZNA therapy if a patient with low immunoglobulin G or M develops a serious opportunistic infection or recurrent infections, or if prolonged hypogammaglobulinemia requires treatment with intravenous immunoglobulins.

5.4 Fetal Risk

Based on animal data, UPLIZNA can cause fetal harm due to B-cell lymphopenia and reduce antibody response in offspring exposed to UPLIZNA even after B-cell repletion. Transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other B-cell depleting antibodies during pregnancy. Advise females of reproductive potential to use effective contraception while receiving UPLIZNA and for at least 6 months after the last dose [see Use in Specific Populations ( 8.1)].

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Infusion Reactions [see Warnings and Precautions ( 5.1)]
  
• Infections [see Warnings and Precautions ( 5.2)]
• Reduction in Immunoglobulins [see Warnings and Precautions ( 5.3)]

6.1 Clinical Trial 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 practice.

The safety of UPLIZNA was evaluated in Study 1, in which 161 patients were exposed to UPLIZNA at the recommended dosage regimen during the randomized, controlled treatment period; during which 52 patients received placebo [see Dosage and Administration ( 2.1) and Clinical Studies ( 14)]. Subsequently, 198 patients were exposed to UPLIZNA during an open-label treatment period.

Two-hundred and eight patients in the randomized and open-label treatment periods had a total of 324 person-years of exposure to UPLIZNA, including 165 patients with exposure for at least 6 months and 128 with exposure for one year or more.

Table 3 lists adverse reactions that occurred in at least 5% of patients treated with UPLIZNA and at a greater incidence than in patients who received placebo in Study 1. The most common adverse reactions (incidence of at least 10% in patients treated with UPLIZNA and at a greater incidence than placebo) were urinary tract infection and arthralgia.

Table 3 Adverse Reactions in Patients with NMOSD with an Incidence of at Least 5% with UPLIZNA and a Greater Incidence than Placebo in Study 1

Adverse Reactions	UPLIZNA N = 161 %	Placebo N = 52 %
Urinary tract infection	11	10
Arthralgia	10	4
Headache	8	8
Back pain	7	4

Across both the randomized and open-label treatment in Study 1, the most common adverse reactions (greater than 10%) were urinary tract infection (20%), nasopharyngitis (13%), infusion reaction (12%), arthralgia (11%), and headache (10%).

Laboratory Abnormalities

Decreased Immunoglobulins

At the end of the 6.5-month randomized, controlled period, relative to baseline, the total immunoglobulin level was reduced approximately 8% from baseline for patients treated with UPLIZNA as compared to an increase of 6% in patients treated with placebo. The mean decreases from baseline in immunoglobulin G (IgG) and immunoglobulin M (IgM) were approximately 4% and 32%, respectively, in patients treated with UPLIZNA, whereas IgG was increased by 6% and IgM was increased by approximately 13% in placebo-treated patients. The proportion of patients treated with UPLIZNA who had IgG levels below the lower limit of normal at year 1 was 6.6% and at year 2 was 13%. The proportion of patients treated with UPLIZNA who had IgM levels below the lower limit of normal at year 1 was 31% and at year 2 was 42%.

Decreased Neutrophil Counts

Neutrophil counts between 1.0-1.5 x10⁹ /L were observed in 6.9% of UPLIZNA-treated patients versus 1.9% of patients who received placebo. Neutrophil counts between 0.5-1.0 x10⁹ /L were observed in 1.9% of patients treated with UPLIZNA compared to no patients who received placebo. At the end of the 6.5-month randomized, controlled period, the proportion of patients with a neutrophil count below the limit of normal was 12% for patients treated with UPLIZNA compared to 4.2% for patients who received placebo.

Decreased Lymphocyte Counts

A reduction in lymphocyte counts was observed more frequently in patients treated with UPLIZNA compared to those who received placebo. At the end of the 6.5-month randomized, controlled period, the proportion of patients with a lymphocyte count below the limit of normal was 5.3% for patients treated with UPLIZNA compared to 4.2% for patients who received placebo.