DRUG INTERACTIONS-

Etrasimod is primarily metabolized by CYP2C8, CYP2C9, and CYP3A4.

Because of the potential additive effect on heart rate, VELSIPITY may increase the risk of QT prolongation and Torsades de Pointes with concomitant use of Class Ia and Class III anti-arrhythmic drugs and QT prolonging drugs.

Prevention or Management Seek the advice of a cardiologist before initiating VELSIPITY treatment with Class Ia (e.g., quinidine, procainamide), Class III anti-arrhythmic drugs (e.g., amiodarone, sotalol), or other drugs that prolong the QT interval.

Beta-Blockers or Calcium Channel Blockers Clinical Impact A transient decrease in heart rate and AV conduction delays may occur when initiating VELSIPITY

 Concomitant use of VELSIPITY in patients receiving stable beta blocker treatment did not result in additive effects on heart rate reduction].

BRIEF SUMMARY

ZILUCOPLAN- (Oct 2023)

Indn- to treat generalized gravis in adults who are anti-acert; chloine                                         receptor (AChR) antibody positive      

Comp-  Tablets: 2 mg of etrasimod  • The recommended dosage is 2 mg orally once daily. 

ADR-   Most common adverse reactions (incidence =5%) are: headache, elevated liver tests, and dizziness. 

CI-    • Infections: May increase the risk of infections. Obtain a complete blood count (CBC) before initiation of treatment.

Monitor for infection during treatment and for 5 weeks after discontinuation. Consider interruption of treatment if a serious infection develops. Avoid use of live attenuated vaccines during and for up to 5 weeks after treatment.

Pat Inform 

 Risk of Infections Inform patients that they may be more likely to get infections, some of which could be life-threatening, when taking VELSIPITY and for 5 weeks after stopping it, and that they should contact their healthcare provider if they develop symptoms of infection

 Inform patients that prior or concomitant use of drugs that suppress the immune system may increase the risk of infection.

Advise patients that some vaccines containing live virus (live attenuated vaccines) should be avoided during treatment with VELSIPITY.

=================================================================

U.S.  APPROVED DRUGS DURING 2023                                       

Serial No 42

Name-          ZILBRYSQ

Active ingedient-        Zilucoplan                      

Indication              to treat generalized gravis in adults who are anti-acert; chloine                                         receptor (AChR) antibody positive                                                                                          

Date  of approval       10/12/2023 

HIGHLIGHTS OF PRESCRIBING INFORMATION-

These highlights do not include all the information needed to use VELSIPITY safely and effectively.

See full prescribing information for VELSIPITY. VELSIPITY™ (etrasimod) tablets, for oral use

Initial U.S. Approval: 2023

INDICATIONS AND USAGE-

 VELSIPITY is a sphingosine 1-phosphate receptor modulator indicated for the treatment of moderately to severely active ulcerative colitis in adults.

ADVERSE REACTIONS-

 Most common adverse reactions (incidence =5%) are: headache, elevated liver tests, and dizziness. 

CONTRAINDICATIONS-

 • In the last 6 months, experienced myocardial infarction, unstable angina pectoris, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, or Class III or IV heart failure.

 • History or presence of Mobitz type II second-degree or third-degree atrioventricular (AV) block, sick sinus syndrome, or sino-atrial block, unless the patient has a functioning pacemaker.

WARNINGS AND PRECAUTIONS-

 • Infections: May increase the risk of infections. Obtain a complete blood count (CBC) before initiation of treatment.

Monitor for infection during treatment and for 5 weeks after discontinuation. Consider interruption of treatment if a serious infection develops. Avoid use of live attenuated vaccines during and for up to 5 weeks after treatment.

 • Bradyarrhythmia and Atrioventricular Conduction Delays: May result in a transient decrease in heart rate and AV conduction delays.

Obtain an electrocardiogram (ECG) to assess for preexisting cardiac conduction abnormalities before starting treatment. Consider cardiology consultation for conduction abnormalities or concomitant use with other drugs that decrease heart rate.

 • Liver Injury: Elevations of aminotransferases may occur. Obtain transaminase and bilirubin levels before initiating VELSIPITY. Discontinue if significant liver injury is confirmed. 

• Macular Edema: May increase the risk of macular edema. Obtain a baseline evaluation of the fundus, including the macula, near the start of treatment with VELSIPITY. Periodically conduct an evaluation of the fundus, including the macula, while on therapy and any time there is a change in vision. Consider discontinuing VELSIPITY if macular edema develops.

 • Increased Blood Pressure: Monitor blood pressure during treatment.

 • Fetal Risk: May cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for one week after stopping VELSIPITY.

 • Malignancies: Obtain a skin examination prior to or shortly after the start of treatment and periodically during treatment, especially if risk factors. Promptly evaluate suspicious skin lesions.

 • Posterior Reversible Encephalopathy Syndrome (PRES): If symptoms develop, obtain a physical and neurological exam, and consider MRI.

 • Respiratory Effects: May cause a decline in pulmonary function. Assess pulmonary function (e.g., spirometry) if clinically indicated.

 • Unintended Additive Immune System Effects from Prior Treatment with Immunosuppressive or Immune-Modulating Drugs: Consider the half-life and mode of action of prior therapies.

 • Immune System Effects After Stopping VELSIPITY: If using concomitant immunosuppressants, monitor patients for infectious complications for up to 5 weeks after the last dose of VELSIPITY.

DOSAGE AND ADMINISTRATION-

 • Assessments are required prior to initiating VELSIPITY.

 • The recommended dosage is 2 mg orally once daily. 

DOSAGE FORMS AND STRENGTHS-

Tablets: 2 mg of etrasimod 

PATIENT COUNSELING INFORMATION-

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Risk of Infections Inform patients that they may be more likely to get infections, some of which could be life-threatening, when taking VELSIPITY and for 5 weeks after stopping it, and that they should contact their healthcare provider if they develop symptoms of infection

 Inform patients that prior or concomitant use of drugs that suppress the immune system may increase the risk of infection.

Advise patients that some vaccines containing live virus (live attenuated vaccines) should be avoided during treatment with VELSIPITY.

Advise patients that if immunizations are planned, they should be administered at least 4 weeks prior to initiation of VELSIPITY. Inform patients that the use of live attenuated vaccines should be avoided during and for 5 weeks after treatment with VELSIPITY.

Cardiac Effects-                                                                                                                Advise patients that initiation of VELSIPITY treatment may result in transient decrease in heart rate 

Liver Injury-                                                                                                                   Inform patients that VELSIPITY may increase liver enzymes.

Advise patients that they should contact their healthcare provider if they have any unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine

 Macular Edema-                                                                                                        Advise patients that VELSIPITY may cause macular edema, and that they should obtain an eye exam near the start of treatment with VELSIPITY, have their eyes monitored periodically by an eye care professional while receiving therapy, and contact their healthcare provider if they experience any changes in their vision while taking VELSIPITY

 Fetal Risk -                                                                                                             VELSIPITY may cause fetal harm. Advise females to immediately inform their healthcare provider of a known or suspected pregnancy

 Advise females of reproductive potential to use effective contraception during treatment with VELSIPITY and for one week after stopping VELSIPITY

 Pregnancy and Pregnancy Registry-                                                                             Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to VELSIPITY during pregnancy

Malignancies-                                                                                                                      Advise patients to limit exposure to sunlight and ultraviolet (UV) light, wear protective clothing, and use a sunscreen with a high protection factor. If a suspicious skin lesion is observed, patients should immediately report it to their healthcare provider

 Posterior Reversible Encephalopathy Syndrome-                                                            Advise patients to immediately report to their healthcare provider any symptoms involving sudden onset of severe headache, altered mental status, visual disturbances, or seizure.

Inform patients that delayed treatment could lead to permanent neurological consequences

 Respiratory Effects-                                                                                                 Advise patients that they should contact their healthcare provider if they experience new onset or worsening dyspnea

 Immune System Effects after Stopping VELSIPITY-                                                      Advise patients that VELSIPITY continues to have effects, such as lowering effects on peripheral lymphocyte count, for up to 5 weeks after the last dose, and to monitor for signs and symptoms of infection during that time

 This product’s labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com.

For Medical Information about VELSIPITY, please visit www.pfizermedinfo.com or call 1-800-438-1985. LAB-1528-0.

CLINICAL PHARMACOLOGY

1. Mechanism of Action-                                                                                           Etrasimod is a sphingosine 1-phosphate (S1P) receptor modulator that binds with high affinity to S1P receptors 1, 4, and 5 (S1P1,4,5).

Etrasimod has minimal activity on S1P3 (25-fold lower than Cmax at the recommended dose) and no activity on S1P2. Etrasimod partially and reversibly blocks the capacity of lymphocytes to egress from lymphoid organs, reducing the number of lymphocytes in peripheral blood.

The mechanism by which etrasimod exerts therapeutic effects in UC is unknown but may involve the reduction of lymphocyte migration into the intestines.

2. Pharmacodynamics-                                                                                              Reduction in Blood Lymphocyte Counts VELSIPITY causes a reduction in peripheral blood lymphocyte count

 In UC-1 and UC-2, mean lymphocyte counts decreased to approximately 50% of baseline at 2 weeks (approximate mean blood lymphocyte counts 0.9 x 109 /L) and the lower lymphocyte counts were maintained during treatment with VELSIPITY.

Cardiac Electrophysiology-                                                                                               At 2 times the maximum recommended dose, etrasimod does not cause clinically significant QTc interval prolongation.

Pulmonary Function Reductions in absolute FEV1 were observed in subjects treated with VELSIPITY .

Drug Interaction Studies-                                                                                                No clinically significant differences in heart rate reduction were observed when etrasimod was used concomitantly with stable beta blocker treatment. The effect of concomitant use of etrasimod with a calcium channel blocker on heart rate reduction is unknown .

3. Pharmacokinetics-                                                                                               Etrasimod mean (SD) steady state maximum plasma concentration (Cmax) was 113 (27.5) ng/mL and area under the time concentration curve at the dosing interval (AUCtau) was 2162 (488) ng*h/mL at the recommended dosage.

Etrasimod Cmax and AUC are approximately dose proportional from 0.7 mg to 2 mg (0.35 times up to the recommended dosage). Etrasimod steady state is reached within 7 days with an accumulation of approximately 2- to 3-fold compared to the first dose.

Absorption-                                                                                                                      The median (range) time to reach etrasimod Cmax (Tmax) is approximately 4 hours (range 2 to 8 hours) after oral administration.

Effect of Food-                                                                                                                 No clinically significant differences in the pharmacokinetics of etrasimod were observed following administration of VELSIPITY with a high-fat meal (800 to 1000 calories)

Distribution-                                                                                                                    The mean apparent volume of distribution of etrasimod is 66 (24) L. Etrasimod plasma protein binding is 97.9%.

Elimination-                                                                                                                    The mean plasma elimination half-life (t1/2) of etrasimod is approximately 30 hours with an apparent steady state oral clearance of approximately 1 L/h after oral administration.

Metabolism-                                                                                                                  Etrasimod is metabolized by oxidation and dehydrogenation mediated primarily by CYP2C8, CYP2C9, and CYP3A4, with a minor contribution by CYP2C19 and CYP2J2. Etrasimod also undergoes conjugation primarily mediated by UGTs, with a minor contribution by sulfotransferases. Unchanged etrasimod is the main circulating component in plasma.

Excretion-                                                                                                                    Approximately 82% of total radioactive etrasimod dose was recovered in the feces and 5% in the urine within 336 hours. Approximately 11% of administered radioactive dose was excreted as unchanged etrasimod in feces and none was excreted unchanged in urine. 

Specific Populations-                                                                                                      No clinically significant differences in the pharmacokinetics of etrasimod were observed based on age (>65 years), sex, body weight, race, ethnicity, disease (healthy subjects vs. subjects with ulcerative colitis), and severe renal impairment (eGFR =29 mL/min).

Patients with Hepatic Impairment-                                                                            Etrasimod AUC increased by 13% in subjects with mild (Child-Pugh A), 29% in moderate (Child-Pugh B), and 57% in severe (Child-Pugh C) hepatic impairment, respectively, compared with subjects with normal liver function.

No clinically significant difference in the unbound etrasimod AUC was observed

Drug Interaction Studies-                                                                                         Clinical Studies Combined moderate CYP2C9 and CYP3A4 inhibitors: Concomitant use of etrasimod with steady-state fluconazole (moderate CYP2C9 and CYP3A4 inhibitor) increased etrasimod AUC by 84%

 Combined CYP3A4 (strong), CYP2C8 (moderate) and CYP2C9 (moderate) inducers: Concomitant use of etrasimod with rifampin (strong CYP3A4, moderate CYP2C8, and CYP2C9 inducer) decreased etrasimod AUC by 49% 

Oral Contraceptives:                                                                                                       No clinically significant differences in the pharmacokinetics and pharmacodynamics of oral contraceptive containing 30 mcg ethinyl estradiol and 150 mcg levonorgestrel were observed when used concomitantly with etrasimod.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy-                                                                                                           Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in females exposed to VELSIPITY during pregnancy.

Risk Summary-                                                                                                            Based on findings from animal studies, VELSIPITY may cause fetal harm when administered to a pregnant woman. Available data from reports of pregnancies from the clinical development program with VELSIPITY are insufficient to identify a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes.

The background risk of major birth defects and miscarriage for the indicated population is unknown

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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-                                                                                                                       There are no data on the presence of etrasimod in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. When etrasimod was orally administered to female rats during pregnancy and lactation, etrasimod was detected in the plasma of the offspring, suggesting excretion of etrasimod in milk.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for VELSIPITY and any potential adverse effects on the breastfed infant from VELSIPITY or from the underlying maternal condition.

3. Females and Males of Reproductive Potential-                                                          Based on animal data, VELSIPITY may cause fetal harm when administered to pregnant women 

Contraception Females-                                                                                              Before initiation of VELSIPITY treatment, females of reproductive potential should be counseled on the potential for a serious risk to the fetus and the need for effective contraception during treatment with VELSIPITY and for one week following the last dose 

4. Pediatric Use-                                                                                                             The safety and effectiveness of VELSIPITY in pediatric patients have not been established.

5 Geriatric Use-                                                                                                                   Of the 577 VELSIPITY-treated subjects in the three clinical trials (UC-1, UC-2, and UC-3), 30 subjects (5%) were 65 years of age and older, while 3 subjects (<1%) were 75 years of age and older.

6. Hepatic Impairment-                                                                                           Etrasimod undergoes extensive hepatic metabolism. Exposure to etrasimod was similar in subjects with mild and moderate hepatic impairment (Child-Pugh A and B) compared to subjects with normal hepatic function; however, etrasimod exposure was increased in subjects with severe hepatic impairment (Child Pugh C) compared to subjects with normal hepatic function

7 CYP2C9 Poor Metabolizers- Increased exposure of etrasimod in patients who are CYP2C9 poor metabolizers is expected with concomitant use of moderate to strong inhibitors of CYP2C8 or CYP3A4. Concomitant use of VELSIPITY is not recommended in these patients