Uplinza

2.1 Assessments Prior to First Dose of UPLIZNA

Hepatitis B Virus Screening

Prior to initiating UPLIZNA, perform Hepatitis B virus (HBV) screening. UPLIZNA is contraindicated in patients with active HBV confirmed by positive results for surface antigen [HBsAg] and anti-HBV tests. 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 treatment with UPLIZNA [see Contraindications ( 4) and Warnings and Precautions ( 5.2)].

Serum Immunoglobulins

Prior to initiating UPLIZNA, perform testing for quantitative serum immunoglobulins. For patients with low serum immunoglobulins, consult immunology experts before initiating treatment with UPLIZNA [see Warnings and Precautions ( 5.3)].

Tuberculosis Screening

Prior to initiating UPLIZNA, evaluate for active tuberculosis and test for latent infection. For patients with active tuberculosis or positive tuberculosis screening without a history of appropriate treatment, consult infectious disease experts before initiating treatment with UPLIZNA [see Contraindications ( 4) and Warnings and Precautions ( 5.2)].

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 UPLIZNA for live or live-attenuated vaccines [see Warnings and Precautions ( 5.2) and Clinical Pharmacology ( 12.2)].

2.2 Assessment and Premedication Before Every Infusion

Infection Assessment

Prior to every infusion of UPLIZNA, determine whether there is an active infection. In case of active infection, delay infusion of UPLIZNA until the infection resolves [see Warnings and Precautions ( 5.2)].

Premedication

Table 1 shows premedication to administer prior to each infusion of UPLIZNA to reduce the frequency and severity of infusion reactions [see Warnings and Precautions ( 5.2)].

2.3 Recommended Dosage and Administration

UPLIZNA is administered as an intravenous infusion (see Table 2). The recommended dosage is:

• Initial dose: 300 mg intravenous infusion followed 2 weeks later by a second 300 mg intravenous infusion. 
  
• Subsequent doses (starting 6 months from the first infusion): single 300 mg intravenous infusion every 6 months.

Administration

UPLIZNA must be diluted prior to administration [see Dosage and Administration ( 2.4)].

Prior to the start of the intravenous infusion, the prepared infusion solution should be at room temperature.

Administer UPLIZNA under the close supervision of an experienced healthcare professional with access to appropriate medical support to manage potential severe reactions such as serious infusion reactions [see Warnings and Precautions ( 5.1)]. 

Administer the prepared solution intravenously via an infusion pump at an increasing rate to completion, approximately 90 minutes, according to the schedule in Table 2. Administer through an intravenous line containing a sterile, low-protein binding 0.2 or 0.22 micron in-line filter. 

Monitor the patient closely for infusion reactions during and for at least one hour after the completion of the infusion.

2.4 Preparation and Storage of Infusion Solution

Preparation

Visually inspect UPLIZNA solution for particulate matter and discoloration [see Dosage Forms and Strengths ( 3)]. If the solution is cloudy, discolored, or it contains discrete particulate matter, do not use and contact the manufacturer (1-866-479-6742). Do not shake the vial.

• Obtain an intravenous bag containing 250 mL of 0.9% Sodium Chloride Injection, USP. Do not use other diluents to dilute UPLIZNA.
  
• Withdraw 10 mL of UPLIZNA from each of the 3 vials contained in the carton and transfer a total of 30 mL into the 250 mL intravenous bag. Mix diluted solution by gentle inversion. Do not shake the solution.
  
• Discard the unused portion remaining in the vials.

Storage of Infusion Solution

UPLIZNA does not contain a preservative.

Administer the prepared infusion solution immediately. If not administered immediately, store the infusion solution for a maximum of 24 hours in the refrigerator between 2°C to 8°C (36°F to 46°F) or 4 hours at room temperature between 20°C to 25°C (68°F to 77°F) prior to the start of the infusion.

8.1 Pregnancy

Risk Summary

UPLIZNA is a humanized IgG1 monoclonal antibody and immunoglobulins are known to cross the placental barrier. There are no adequate data on the developmental risk associated with the use of UPLIZNA in pregnant women. However, transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other B-cell depleting antibodies during pregnancy. B-cell levels in infants following maternal exposure to UPLIZNA have not been studied in clinical trials. The potential duration of B-cell depletion in such infants, and the impact of B-cell depletion on vaccine safety and effectiveness, is unknown [see Warnings and Precautions ( 5.2)].

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.

Data

Animal Data

Intravenous administration of inebilizumab-cdon (0, 3, or 30 mg/kg/week) to human CD19 transgenic (huCD19 Tg) male and female mice prior to and during mating and continuing in females through gestation day 15 resulted in no adverse effects on embryofetal development; however, there was a marked reduction in B cells in fetal blood and liver at both doses tested. These results demonstrate that inebilizumab-cdon crosses the placenta and depletes B cells in the fetus.

Intravenous administration of inebilizumab-cdon (0, 3, or 30 mg/kg) to huCD19 Tg mice every three days throughout organogenesis and lactation resulted in depletion of B cells and persistent reductions in immune function (even following repletion of B cells and lasting into adulthood) in offspring at both doses tested. At the end of the lactation period, plasma inebilizumab-cdon levels in offspring were only slightly lower than those in maternal plasma. A no-effect level for immunotoxicity in the offspring was not identified.

8.2 Lactation

Risk Summary

There are no data on the presence of inebilizumab-cdon in human milk, the effects on a breastfed infant, or the effects on milk production. Human IgG is excreted in human milk, and the potential for absorption of UPLIZNA to lead to B-cell depletion in the breastfed infant is unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for UPLIZNA and any potential adverse effects on the breastfed infant from UPLIZNA or from the underlying maternal condition.

8.3 Females of Reproductive Potential

Contraception

Women of childbearing potential should use contraception while receiving UPLIZNA and for 6 months after the last infusion of UPLIZNA [see Clinical Pharmacology ( 12.3)].

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of UPLIZNA did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

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)].

6.1 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.

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.

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 medications, and 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 inebilizumab products may be misleading.

In Study 1, treatment-emergent antibodies (those that appeared or significantly increased from baseline after administration of UPLIZNA), were detected in 5.6% patients receiving UPLIZNA. Although these data do not demonstrate an impact of anti-inebilizumab-cdon antibody development on the efficacy or safety of UPLIZNA in these patients, the available data are too limited to make definitive conclusions.

7.1 Immunosuppressive or Immune-Modulating Therapies

Concomitant usage of UPLIZNA with immunosuppressant drugs, including systemic corticosteroids, may increase the risk of infection. Consider the risk of additive immune system effects when co-administering immunosuppressive therapies with UPLIZNA.

12.1 Mechanism of Action

The precise mechanism by which inebilizumab-cdon exerts its therapeutic effects in NMOSD is unknown but is presumed to involve binding to CD19, a cell surface antigen presents on pre-B and mature B lymphocytes. Following cell surface binding to B lymphocytes, inebilizumab-cdon results in antibody-dependent cellular cytolysis.

12.2 Pharmacodynamics

Pharmacodynamics of UPLIZNA were assessed with an assay for CD20+ B cells, since UPLIZNA can interfere with the CD19+ B cell assay. Treatment with UPLIZNA reduces CD20+ B cell counts in blood by 8 days after infusion. In Study 1 [see Clinical Studies ( 14)], CD20+ B-cell counts were reduced below the lower limit of normal by 4 weeks in 100% of patients treated with UPLIZNA and remained below the lower limit of normal in 94% of patients for 28 weeks after initiation of treatment.

12.3 Pharmacokinetics

The pharmacokinetics of inebilizumab-cdon in NMOSD patients following intravenous administration of UPLIZNA was biphasic with a mean terminal half-life of 18 days. The mean maximum concentration was 108 μg/mL (300 mg, second dose on Day 15), and the cumulative AUC of the 26-week treatment period in which NMOSD patients received two intravenous administrations 2 week apart was 2980 µg•d/mL.

Distribution

Based on population pharmacokinetic analysis, the estimated typical central and peripheral volume of distribution of inebilizumab-cdon was 2.95L and 2.57L, respectively.

Metabolism

Inebilizumab-cdon is a humanized IgG1 monoclonal antibody that is degraded by proteolytic enzymes widely distributed in the body.

Elimination

The results of population pharmacokinetic analysis indicated that the estimated inebilizumab-cdon systemic clearance of the first-order elimination pathway was 0.19 L/day. At low exposure levels, inebilizumab-cdon was likely subject to the receptor (CD19)-mediated clearance, which decreased with time presumably because of the depletion of B-cells by UPLIZNA treatment.

Specific Populations

Gender, Race, Geriatric Use

A population pharmacokinetic analysis indicated that there was no significant effect of gender, race, and age on inebilizumab-cdon clearance.

Renal/Hepatic Impairment

No formal clinical studies have been conducted to investigate the effect of renal impairment or hepatic impairment on inebilizumab-cdon pharmacokinetic parameters.

Drug Interaction Studies

Cytochrome P450 enzymes and transporters are not involved in the clearance of inebilizumab-cdon; therefore, the potential risk of interactions between UPLIZNA and concomitant medications that are substrates, inducers, or inhibitors of cytochrome P450 enzymes and transporters is low.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

No studies have been conducted to assess the carcinogenic potential of inebilizumab-cdon.

Mutagenesis

No studies have been conducted to assess the genotoxic potential of inebilizumab-cdon.

Impairment of Fertility

Intravenous administration of inebilizumab-cdon (0, 3, or 30 mg/kg/week) to human CD19 transgenic male and female mice prior to and during mating and continuing in females through gestation day 15 resulted in reduced fertility at both doses tested. A no-effect dose for adverse effects on fertility was not identified.