11/20. Ozanimod- (EPOSIA)- @- (Mar -2020)- TO Treat Relapsing Form of Multiple Sclerosis
Drug Name:11/20. Ozanimod- (EPOSIA)- @- (Mar -2020)- TO Treat Relapsing Form of Multiple Sclerosis
List Of Brands:
Indication Type Description:
Drug Interaction
Indication
Adverse Reaction
Contra-Indications
Dosages/ Overdosage Etc
Patient Information
Pharmacology/ Pharmacokinetics
Pregnancy and lactation
Drug Interaction:
DRUG INTERACTIONS
• Vaccines: Avoid use of live attenuated vaccines during and for up to 3 months after treatment with ZEPOSIA
• Strong CYP2C8 Inhibitors: Co-administration is not recommended
• BCRP Inhibitors: Co-administration is not recommended
• Strong CYP2C8 Inducers: Co-administration should be avoided
Indication:
U.S. FDA APPROVED DRUGS DURING 2020
Sr.No- 11
Adverse Reaction:
ADVERSE REACTIONS
Most common adverse reactions (incidence =4%): Upper respiratory infection, hepatic transaminase elevation, orthostatic hypotension, urinary tract infection, back pain, and hypertension.
Contra-Indications:
Dosages/ Overdosage Etc:
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 ZEPOSIA and for 3 months 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 ZEPOSIA. If immunizations are planned, administer at least 1 month prior to initiation of ZEPOSIA.
Avoid the use of live attenuated vaccines during and for 3 months after treatment with ZEPOSIA.
Patients without a healthcare professional-confirmed history of chickenpox or without documentation of a full course of vaccination against VZV should be tested for antibodies to VZV before initiating ZEPOSIA.
Cardiac Effects-
Advise patients that initiation of ZEPOSIA treatment may result in a transient decrease in heart rate. Inform patients that to reduce this effect, dose titration is required.
Advise patients that the dose titration is also required if a dose is missed for 1 day or more during the first 14 days of treatment.
Liver Injury Inform patients that ZEPOSIA 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.
Pregnancy and Fetal Risk-
Inform patients that, based on animal studies, ZEPOSIA may cause fetal harm.
Discuss with women of childbearing age whether they are pregnant, might be pregnant, or are trying to become pregnant.
Advise women of childbearing potential of the need for effective contraception during treatment with ZEPOSIA and for 3 months after stopping ZEPOSIA.
Advise a female patient to immediately inform her healthcare provider if she is pregnant or planning to become pregnant.
Respiratory Effects- Advise patients that they should contact their healthcare provider if they experience new onset or worsening dyspnea
Macular Edema- Advise patients that ZEPOSIA may cause macular edema, and that they should contact their healthcare provider if they experience any changes in their vision.
Inform patient with diabetes mellitus or a history of uveitis that their risk of macular edema maybe increased
Posterior Reversible Encephalopathy Syndrome- Advise patients to immediately report to their healthcare provide 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
Severe Increase in Disability After Stopping ZEPOSIA- Inform patients that severe increase in disability has been reported after discontinuation of a S1P receptor modulator like ZEPOSIA.
Advise patients to contact their physician if they develop worsening symptoms of MS following discontinuation of ZEPOSIA
Immune System Effects- After Stopping ZEPOSIA- Advise patients that ZEPOSIA continues to have effects, such as lowering effects on peripheral lymphocyte count, for up to 3 months after the last dose
Manufactured for: Celgene Corporation Summit, NJ 07901 ZEPOSIA® is a registered trademark of Celgene Corporation. Patent: www.celgene.com/therapies © 2019-2020 Celgene Corporation. All Rights Reserved. ZEPPI/ZEPMG.001
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
1. Mechanism of Action- Ozanimod is a sphingosine 1-phosphate (S1P) receptor modulator that binds with high affinity to S1P receptors 1 and 5. Ozanimod blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood.
2. Pharmacodynamics- Reduction in Blood Lymphocyte Counts In active-controlled MS clinical trials, mean lymphocyte counts decreased to approximately 45% of baseline at 3 months (approximate mean blood lymphocyte counts 0.8 x 109 /L), and low lymphocyte counts were maintained during treatment with ZEPOSIA
After discontinuing ZEPOSIA 0.92 mg, the median time for peripheral blood lymphocytes to return to the normal range was 30 days, with approximately 90% of patients in the normal range within 3 months.
Reduction in Heart Rate-
ZEPOSIA may cause a transient decrease in heart rate on initiation of dosing.
An up-titration schedule of ZEPOSIA 0.23 mg followed by doses of 0.46 mg, and 0.92 mg attenuates the magnitude of heart rate reductions
Drug Interaction Studies- Sympathomimetic Agents- No clinically significant differences in heart rate or blood pressure was observed when ZEPOSIA 1.84 mg daily (two times the recommended dosage) for 28 days was co-administered with a single dose of 60 mg pseudoephedrine (a sympathomimetic agent) compared to pseudoephedrine alone.
Beta Blocker or Calcium Channel Blocker- The effect of co-administration of the maintenance dosage of ZEPOSIA, propranolol, or diltiazem, or administration with both a beta blocker and a calcium channel blocker taken together has not been studied.
Pulmonary Function- Dose-dependent reductions in FEV1 and FVC were observed in patients treated with ZEPOSIA
Cardiac Electrophysiology- Following a 14-day titration regimen of once daily doses of ozanimod 0.23 mg for 4 days, 0.46 mg for 3 days, 0.92 mg for 3 days, and 1.84 mg (2 times the maximum approved recommended dose) for 4 days in healthy subjects, ZEPOSIA did not prolong the QTc interval to any clinically relevant extent [see Warnings and Precautions (5.2)].
3. Pharmacokinetics- The steady state exposure parameters of ozanimod and its major active metabolite, CC112273 are summarized.
Exposure Parameters of Ozanimod and its Major Metabolite - Parameters Ozanimod CC112273 Cmax,ss 0.244 ng/mL (31.8%) 6.98 ng/mL (42.7%) AUCtau,ss 4.46 ng*h/mL (31.8%) 143.77 ng*h/mL (39.2%)
Dose Proportionality -The Cmax and AUC increases proportionally over the ozanimod dose range from 0.46 mg to 0.92 mg.
Time to Steady State 102 hours (28.2%)b 45 days (45%) Accumulation Ratio 2.40 (21.1%) b 16 (101%) a Mean [coefficient of variation (CV%)] following ozanimod 0.92 mg once daily dose in relapsing MS patients, unless otherwise specified. b In healthy subjects.
Cmax,ss = maximum observed plasma concentration at steady state, AUCtau,ss = area under the plasma concentration-time curve during a dosage interval at steady state
Absorption- The Tmax of ozanimod is approximately 6-8 hours.
Effect of Food - No clinically significant differences in the Cmax and AUC of ozanimod were observed following administration of ZEPOSIA with a high-fat, high-calorie meal.
Distribution- The mean (CV%) apparent volume of distribution of ozanimod (Vz/F) is 5590 L (27%). Human plasma proteins binding of ozanimod, CC112273 and CC1084037 is approximately 98.2%, 99.8%, and 99.3%, respectively.
Elimination- The mean (CV%) plasma half-life (t1/2) of ozanimod is approximately 21 hours (15%). The mean (CV%) effective half-life (t1/2) of CC112273 and its direct interconverting metabolite CC1084037 was approximately 11 days (104%) in relapsing MS patients.
The mean (CV%) apparent oral clearance for ozanimod was approximately 192 L/h (37%).
Metabolism- Ozanimod is metabolized by multiple enzymes to form circulating major active metabolites (e.g., CC112273 and CC1084037) and minor active metabolites (e.g., RP101988, RP101075, and RP101509) with similar activity and selectivity for S1P1 and S1P5.
Approximately 94% of circulating total active drug exposure is represented by ozanimod (6%), CC112273 (73%), and CC1084037 (15%), in humans.
Excretion- Following a single oral dose of radiolabeled ozanimod 0.92 mg, approximately 26% of the radioactivity was recovered in urine and 37 % in feces, primarily composed of inactive metabolites.
Specific Populations- No clinically significant differences in the pharmacokinetics of ozanimod and CC112273 were observed based on sex.
The effect of age (65 years of age and older) or hepatic impairment on the pharmacokinetics of ozanimod is unknown
Racial or Ethnic Groups- In a dedicated Japanese PK bridging study, following repeated dosing of 0.96 mg ZEPOSIA, ozanimod exposures (Cmax and AUCtau) were unchanged and CC112273 exposures (Cmax and AUCtau) were approximately 28% and 43% higher, respectively, in Japanese subjects (N=10) compared to Caucasian subjects (N=12). These differences are not considered clinically meaningful.
Patients with Renal Impairment- In a dedicated renal impairment trial, following a single oral dose of 0.23 mg ZEPOSIA, exposures (AUClast) for ozanimod and CC112273 were approximately 27% higher and 23% lower, respectively, in subjects with end stage renal disease (N=8) compared to subjects with normal renal function (N=8).
Based on this trial, renal impairment has no clinically important effects on pharmacokinetics of ozanimod or CC112273.
Smokers Population- PK analyses showed that CC112273 steady-state exposure (AUC) was approximately 50% lower in smokers than in nonsmokers. The clinical impact of smoking on ozanimod treatment for patients with RMS is not known.
Drug Interaction Studies- Clinical Studies- Strong CYP3A and P-gp Inhibitors No clinically significant differences in the pharmacokinetics of ozanimod and its major active metabolites CC112273 and CC1084037 were observed when co-administered with itraconazole (P-gp and strong CYP3A inhibitor).
Strong CYP2C8 Inhibitors- Co-administration of ozanimod with gemfibrozil (a strong CYP2C8 inhibitor) increased exposure (AUC) of active metabolites CC112273 and CC1084037 by approximately 47% and 69%, respectively.
No clinically significant differences in the AUC of ozanimod were observed when co-administered with gemfibrozil
BCRP Inhibitor- Co-administration of ozanimod with cyclosporine (BCRP inhibitor) had no effect on ozanimod exposure, but doubled the exposure of the minor active metabolites, RP101988 and RP101075 (the direct precursor of the major active metabolite CC112273).
Coadministration of ozanimod with BCRP inhibitors may also increase exposure of CC112273 and CC1084037
Strong CYP2C8 Inducers- Co-administration of rifampin (a strong inducer of CYP3A and P-gp, and a moderate inducer of CYP2C8) 600 mg once daily at steady state and a single dose of ZEPOSIA 0.92 mg reduced the exposure (AUC) for ozanimod, CC112273, and CC1084037 by approximately 24%, 60%, and 55%, respectively.
The effect on CC112273 and CC1084037 is primarily caused by induction of CYP2C8 [see Drug Interactions (7.6)].
Monoamine Oxidase Inhibitors- No clinical studies evaluating the drug interaction potential of ozanimod with MAO inhibitors have been conducted
Oral Contraceptives- No clinically significant differences in the pharmacokinetic of oral contraceptive containing ethinyl estradiol and norethindrone were observed when co-administered with ozanimod.
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1. Pregnancy Risk Summary- There are no adequate data on the developmental risk associated with the use of ZEPOSIA in pregnant women. In animal studies, administration of ozanimod during pregnancy produced adverse effects on development, including embryolethality, an increase in fetal malformations, and neurobehavioral changes, in the absence of maternal toxicity.
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.
The background risk of major birth defects and miscarriage for the indicated population is unknown.
2 Lactation Risk Summary
There are no data on the presence of ozanimod in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Following oral administration of ozanimod, ozanimod and/or metabolites were detected in the milk of lactating rat at levels higher than those in maternal plasma.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZEPOSIA and any potential adverse effects on the breastfed infant from ZEPOSIA or from the underlying maternal condition.
3. Females and Males of Reproductive Potential- Contraception- Before initiation of ZEPOSIA treatment, women of childbearing potential should be counseled on the potential for a serious risk to the fetus and the need for contraception during treatment with ZEPOSIA
Because of the time it takes to eliminate the drug from the body after stopping treatment, the potential risk to the fetus may persist and women of childbearing age should also use effective contraception for 3 months after stopping ZEPOSIA.
4. Pediatric Use- Safety and effectiveness in pediatric patients have not been established.
5. Geriatric Use- Clinical studies of ZEPOSIA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
6. Hepatic Impairment- The effect of hepatic impairment on the pharmacokinetics of the ozanimod major active metabolites is unknown.
Use of ZEPOSIA in patients with hepatic impairment is not recommended.