U.S. FDA APPROVED  DRUGS DURING 2020

Sr.No-  23

 CONTRAINDICATIONS

UPLIZNA is contraindicated in patients with:                                                                    • A history of a life-threatening infusion reaction to UPLIZNA                                           • Active hepatitis B infection                                                                                            • Active or untreated latent tuberculosis 

WARNINGS AND PRECAUTIONS

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 

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.

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 openlabel 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 liveattenuated 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 

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 

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.

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 openlabel 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 5 Reference ID: 4623153 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 liveattenuated 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)]. 6 Reference ID: 4623153 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

 PATIENT COUNSELING INFORMATION

Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide).

Infusion Reactions -                                                                                                    Inform patients about the signs and symptoms of infusion reactions and advise them to contact their healthcare provider immediately if they observe signs or symptoms of infusion reactions 

Infections-                                                                                                                    Advise patients to contact their healthcare provider for any signs of infection during treatment or after the last dose. Signs include fever, chills, constant cough, or dysuria [

Advise patients that UPLIZNA may cause reactivation of hepatitis B infection and that monitoring will be required if they are at risk 

Advise patients that PML has happened with drugs that are similar to UPLIZNA and may happen with UPLIZNA.

Inform the patient that PML is characterized by a progression of deficits and usually leads to death or severe disability over weeks or months.

Instruct the patient of the importance of contacting their healthcare provider if they develop any symptoms suggestive of PML.

Inform the patient that typical symptoms associated with PML are diverse, progress over 153 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 

Vaccinations-                                                                                                            Advise patients to complete any required vaccinations at least 4 weeks prior to initiati- on of UPLIZNA. Administration of live-attenuated or live vaccines is not recommended during UPLIZNA treatment and until B-cell recovery 

Pregnancy -                                                                                                           Instruct patients that if they are pregnant or plan to become pregnant while taking UPLIZNA, they should inform their healthcare provider.

Advise females of reproductive potential that they should use effective contraception during treatment and for 6 months after UPLIZNA therapy 

Manufactured by: Viela Bio, Inc., 1 Medimmune Way, Gaithersburg, MD 20878 USA U.S. License No. xxxxxxx

 CLINICAL PHARMACOLOGY

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.

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.  

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 inebilizumabcdon 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 inebilizumabcdon; 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.

 USE IN SPECIFIC POPULATIONS

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.

The potential duration of B-cell depletion in such infants, and the impact of B-cell depletion on vaccine safety and effectiveness, is unknown 

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. 

2. Lactation Risk Summary

There are no data on the presence of ineblizumab-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.

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 

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

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.