41/23. Etrasimod- (VELSIPITY)- (Oct 2023)- to treat moderately to severely active ulcerative colitis in adults
Drug Name:41/23. Etrasimod- (VELSIPITY)- (Oct 2023)- to treat moderately to severely active ulcerative colitis in adults
List Of Brands:
Indication Type Description:
Indication
Adverse Reaction
Contra-Indications
Dosages/ Overdosage Etc
Patient Information
Pharmacology/ Pharmacokinetics
Pregnancy and lactation
Indication:
BRIEF SUMMARY
ETRASIMOD- (Oct 2023)
Indn- To treat moderately to severely active ulcerative coloitis in adults
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
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U.S. APPROVED DRUGS DURING 2023
Serial 41
Name - VELSIPITY
Drug name- Etrasimod
Indication- To treat moderately to severely active ulcerative coloitis in adults
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.
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
---------------------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. (4, 5.2) • 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.
(4, 5.2) ---------------------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. (5.1) • 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. (2.1, 5.2, 7) • Liver Injury: Elevations of aminotransferases may occur. Obtain transaminase and bilirubin levels before initiating VELSIPITY. D
Adverse Reaction:
ADVERSE REACTIONS-
Most common adverse reactions (incidence =5%) are: headache, elevated liver tests, and dizziness.
Contra-Indications:
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.
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.
Dosages/ Overdosage Etc:
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 Information:
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- VEL SIPITY 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 [see Warnings and Precautions (5.9)].
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.
Pharmacology/ Pharmacokinetics:
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 intestine
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.
Dose-response relationship analysis indicates there is a dose-dependent reduction in blood lymphocyte counts. After discontinuing VELSIPITY 2 mg once daily, the median time for peripheral blood lymphocytes to return to the normal range was 2.6 weeks, with approximately 90% of subjects in the normal range within 4.7 weeks.
Reduction in Heart Rate and AV Conduction Delays- VELSIPITY may result in a transient decrease in heart rate and AV conduction upon treatment initiation [see Warnings and Precautions (5.2)]. In UC-1 and UC-2, the mean (SD) decrease in heart rate was 7.2 (8.98) bpm at 2 to 3 hours after the first dose of VELSIPITY on Day 1
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 [see Warnings and Precautions (5.9)].
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 [see Use in Specific Populations (8.6)].
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.
Other Drugs: Itraconazole (a P-gp and strong CYP3A inhibitor) increased etrasimod AUC by 32%. Gemfibrozil (an inhibitor of OATP1B1 and OAT3 and a strong inhibitor of CYP2C8) increased etrasimod AUC by 36%. These effects are unlikely to be clinically significant.
In Vitro Studies- Based on in vitro studies, etrasimod is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, nor an inducer of CYP1A2, CYP2B6, and CYP3A4 at clinically relevant concentrations. Etrasimod is not an inhibitor of UGT1A3, UGT1A4, UGT1A9, UGT2B7, or UGT2B17 in vitro. Etrasimod is not a substrate or an inhibitor of P-gp, BCRP, BSEP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, and MATE2-K transporters.
Pregnancy and lactation:
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. Pregnant females exposed to VELSIPITY and healthcare providers are encouraged to contact the pregnancy registry by calling 1-800-616-3791.
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.
There are risks to the mother and the fetus associated with increased disease activity in women with inflammatory bowel disease during pregnancy (see Clinical Considerations). In animal reproduction studies, administration of etrasimod during organogenesis produced adverse effects on development, including embryolethality and fetal malformations, in both rats and rabbits at maternal exposures 5 and 6 times, respectively, the exposure at the maximum recommended human dose (MRHD).
Administration of VELSIPITY to pregnant rats during organogenesis through lactation resulted in decreased pup growth and viability at maternal exposures 5 times the exposure at the MRHD, as well as impaired reproductive performance in first generation offspring, including decreased implantations and increased pre-implantation loss at maternal exposures 24 times the exposure at the MRHD
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.
Clinical Considerations- Disease-Associated Maternal and/or Embryo/Fetal Risk Published data suggest that the risk of adverse pregnancy outcomes in women with inflammatory bowel disease is associated with increased disease activity.
Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.
2 Lactation Risk Summary - 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 [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1)]
4 Pediatric Use- The safety and effectiveness of VELSIPITY in pediatric patients have not been established.
5.Geriatric use- 30 subjects (5%) were 65 years of age and older, while 3 subjects (<1%) were 75 years of age and older. Clinical studies of VELSIPITY did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger adult subjects.
The pharmacokinetics of etrasimod are similar in subjects 65 years of age and older compared to younger adult subjects [see Clinical Pharmacology (12.3)].
6.Hepatic use- use 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
Use of VELSIPITY in patients with severe hepatic impairment is not recommended. No dosage adjustment is needed in patients with mild to moderate hepatic impairment.
7. Other use- 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