伊曲莫德(Etrasimod)的详细说明书：作用与功效,用法用量,副作用,注意事项等

Etrasimod is a sphingosine 1-phosphate (S1P) receptor modulator that exerts a therapeutic effect by reversibly isolating lymphocytes in lymphoid tissue and reducing the number of peripheral blood lymphocytes.

Indications for Etrasimod

It is suitable for the treatment of moderately to severely active ulcerative colitis in adults.

Usage and Dosage of Etramod (Etrasimod)

1. Assessment, medication and vaccination before taking Etrasimod for the first time

Before starting treatment with Etrasimod, the following assessments need to be performed:

(1) Complete blood count

Obtain a complete blood count, including lymphocyte count, recently (i.e. within the past 6 months or after stopping previous UC treatment).

(2). Cardiac evaluation

Obtain an electrocardiogram to determine whether there are pre-existing cardiac conduction abnormalities. Patients with certain pre-existing conditions should seek the advice of a cardiologist.

(3) Liver function test

Obtain recent (i.e., within the past 6 months) transaminase and bilirubin levels.

(4), Ophthalmic evaluation

At the beginning of itrimod treatment, obtain a baseline evaluation of the fundus, including the macula.

(5) Skin examination

Carry out a skin examination before starting or shortly after starting isramod treatment. If suspicious skin lesions are observed, prompt evaluation should be performed.

(6) Vaccination

For patients who do not have a history of chickenpox confirmed by medical professionals, or who have not completed the full course of varicella-zoster virus vaccination records, a VZV antibody test should be performed before starting itrimod treatment; it is recommended that patients with negative antibodies be vaccinated with VZV vaccine before starting itrimod treatment.

If a live attenuated vaccine is required, it should be given at least 4 weeks before starting treatment with istrimod.

Update vaccinations according to current immunization guidelines before initiating treatment with istrimod.

2. Recommended dose

The recommended dose is 2 mg, taken orally once a day.

3. How to take the medicine

Swallow the tablet whole, with or without food.

4. Treatment of missed doses

If you miss a dose, you should take the missed dose at the next scheduled time; do not double the next dose.

The pictures are from public channels (such as the official website of the FDA, the official website of the original drug manufacturer, etc.) and are for reference only.

Contraindications of Etrasimod

Etrasimod is contraindicated in the following patients:

1. Patients who have had myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization within the past 6 months, or patients with New York Heart Association class III or IV heart failure.

2. Patients with or existing Mohs type II second or third degree atrioventricular block, sick sinus syndrome or sinoatrial block, unless the patient is equipped with a normal functioning pacemaker.

Precautions for Etrasimod

1. Risk of infection

Etrasimod will cause the peripheral blood lymphocyte count to drop to approximately 45% of the baseline value on average (at week 52). This is due to the reversible retention of lymphocytes in lymphoid tissue. Therefore, itrimod may increase susceptibility to infection. Life-threatening and rare fatal infections have been reported with other sphingosine-1-phosphate receptor modulators.

Before initiating treatment, obtain a recent (i.e., within 6 months or after stopping previous UC treatment) complete blood count, including lymphocyte count.

In patients with active infection, delay initiation of itrimod therapy until the infection has resolved.

If the patient develops a serious infection, consider interrupting treatment with istrimod.

Because residual pharmacodynamic effects (such as a reduction in peripheral lymphocyte counts) may remain for up to 5 weeks after discontinuation of the drug, vigilance for infection should continue during this period.

2. Progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy is an opportunistic viral infection of the brain caused by JC virus. It usually occurs in patients with low immune function and usually leads to death or severe disability. Typical symptoms associated with PML are diverse and progress over days to weeks, including progressive weakness or clumsiness in one limb, visual impairment, and changes in thinking, memory, and orientation leading to confusion and personality changes.

If PML is confirmed, treatment with istrimod should be discontinued.

3. Herpes virus infection

Herpes simplex virus encephalitis, varicella-zoster virus meningitis and local herpes virus infection have been reported in patients treated with S1P receptor modulators. Patients who do not have a history of varicella confirmed by a medical professional or who do not have a documented history of varicella-zoster virus vaccination should undergo VZV antibody testing before initiating treatment with istrimod.

4. Cryptococcal infection

Fatal cryptococcal meningitis and disseminated cryptococcal infection have been reported in patients treated with S1P receptor modulators. Physicians should remain alert to clinical symptoms or signs of CM. Patients who develop symptoms or signs consistent with cryptococcal infection should receive prompt diagnostic evaluation and treatment. Treatment with istrimod should be withheld until cryptococcal infection is ruled out. If CM is diagnosed, appropriate treatment should be initiated.

5. Previous and concurrent use of anti-tumor, immunomodulatory, or non-corticosteroid immunosuppressive treatments

The combined use of itrimod with anti-tumor, immunomodulatory, or non-corticosteroid immunosuppressive treatments has not been studied. Avoid concurrent use of these therapies during and for several weeks after istrimod administration due to the risk of additive immunosuppressive effects.

6. Vaccination

For patients who do not have a history of chickenpox confirmed by a medical professional or who have not completed the full course of varicella-zoster virus vaccination records, a VZV antibody test should be performed before starting isramod treatment. It is recommended that anti-antibody-negative patients complete the full course of VZV vaccination before starting itrimod treatment, and thereafter delay the start of itrimod treatment for 4 weeks to allow the vaccination to take full effect.

If live attenuated vaccines are required, they should be vaccinated at least 4 weeks before starting treatment with istrimod. Avoid using live attenuated vaccines during treatment with istrimod and within 5 weeks after treatment.

7. Decreased heart rate

Starting treatment with istrimod may cause a temporary decrease in heart rate, and a few subjects may experience symptoms such as dizziness, which resolve spontaneously without intervention.

8. Liver injury

Obtain transaminase and bilirubin levels for patients with symptoms suggestive of liver dysfunction (such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine). If significant hepatic injury is confirmed, discontinue itrimod.

9. Macular edema

At the time of starting itrimod treatment, obtain a baseline assessment of the fundus, including the macula. Perform periodic fundus evaluations, including the macula, during treatment and any time vision changes occur.

10. Posterior reversible encephalopathy syndrome

If a patient develops any neurological or psychiatric symptoms/signs (e.g., cognitive deficits, behavioral changes, cortical visual impairment, or any other neurocortical symptoms/signs), any symptoms/signs suggestive of increased intracranial pressure, or accelerated neurological deterioration, the physician should immediately order a comprehensive physical and neurological examination and should consider performing an MRI examination.

Adverse reactions of Etrasimod

If you have the following side effects during medication, please seek medical attention immediately: bladder pain, bloody or turbid urine, blurred vision, burning or stinging skin, dark urine, difficulty urinating, burning, pain, dizziness, frequent urination, headache, elevated blood cholesterol levels, light-colored stools, lower back or side pain.

and nausea and vomiting, jitteriness, painful blisters on the trunk, painful blisters or blisters on the lips, nose, eyes, or genital area, ringing in the ears, a slow or fast heartbeat, abdominal pain or bloating, yellowing of the whites of the eyes or skin.

Itrimod (Etrasimod) drug interactions

1. Antiarrhythmic drugs and drugs that prolong the QT interval

Due to possible additive effects on heart rate, concurrent use of itrasimod with Class Ia and Class III antiarrhythmic drugs and drugs that prolong the QT interval may increase the risk of QT prolongation and torsade de pointes.

Prior to initiating treatment with itrimod, patients should seek the advice of a cardiologist if they are taking Class Ia (e.g., quinidine, procainamide), Class III antiarrhythmic drugs (e.g., amiodarone, sotalol) or other drugs that prolong the QT interval.

2. Beta-blockers or calcium channel blockers

Concomitant use of itramod in patients receiving stable beta-blockers did not result in additive lowering effects on heart rate; however, the risk of additive heart rate decreases after initiating beta-blocker therapy during stable itridimod therapy, or after concurrent use of other drugs that may decrease heart rate (e.g., calcium channel blockers), is unknown.

3. Moderate to strong inhibitors of CYP2C9 and CYP3A4

When using a drug that is a moderate to strong inhibitor of both CYP2C9 and CYP3A4 (i.e., fluconazole), an increase in itramod exposure was observed. Concomitant use with a drug that is a moderate to strong inhibitor of both CYP2C9 and CYP3A4 is not recommended.

Usage of Itramod (Etrasimod) for special groups

1. Pregnancy

According to findings from animal studies, pregnant women taking Etrasimod may cause harm to the fetus. Existing data from pregnancy reports in the itrimod clinical development program are insufficient to determine the risk of drug-related major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Increased disease activity of inflammatory bowel disease during pregnancy poses risks to mother and fetus.

2. Lactation period

There are no data on whether itrimod is present in human milk, its effects on breastfed infants, or its effects on milk production. When itrimod was administered orally to female rats during pregnancy and lactation, itrimod was detected in the plasma of the offspring, suggesting that itrimod is excreted in milk.

The developmental and health benefits of breastfeeding should be considered, taking into account the mother's clinical need for istrimod and any potential adverse effects of itrimod or the underlying maternal condition on the breastfed infant.

3. Women of childbearing potential

Before initiating treatment with istrimod, women of childbearing potential should be informed of the serious potential risks to the fetus and the need to use effective contraception during treatment with istrimod and for one week after the last dose.

4. Pediatric use

The safety and effectiveness of itrimod in pediatric patients have not been determined.

5. Geriatric use

Clinical studies of itramod did not include a sufficient number of subjects aged 65 and over to determine whether their responses were different from those of younger adult subjects. The pharmacokinetics of istrimod in subjects 65 years of age and older are similar to those in younger adult subjects.

6. Liver function impairment

The exposure of itrimod in subjects with mild and moderate hepatic impairment (Child-Pugh Class A and B) is similar to that in subjects with normal liver function. The exposure of itridimod in subjects with severe hepatic impairment (Child-Pugh Class C) is increased compared with subjects with normal liver function.

Itrimod is not recommended for use in patients with severe hepatic impairment, and no dose adjustment is required in patients with mild to moderate hepatic impairment.

7. Poor metabolizers of CYP2C9

For poor metabolizers of CYP2C9, concurrent use of moderate to strong inhibitors of CYP2C8 or CYP3A4 is expected to increase the exposure of itridimod. Concomitant use of istrimod is not recommended in these patients.

Mechanism of action of Etrasimod

Etrasimod is a sphingosine-1-phosphate receptor modulator that binds with high affinity to S1P receptors 1, 4, and 5. Itrimod has minimal activity on S1P3 (25 times less than Cmax at recommended doses) and no activity on S1P2. Itrimod partially and reversibly blocks the ability of lymphocytes to egress from lymphoid organs, reducing the number of lymphocytes in the peripheral blood. The mechanism by which itrimod exerts its therapeutic effect in UC is unknown but may involve reducing lymphocyte migration into the intestine.

Itramod (Etrasimod) Pharmacokinetics

1. Absorption

After oral administration, the median time for itrasimod to reach Cmax is approximately 4 hours (range 2 to 8 hours).

Food Effects: No clinically significant differences in istrimod pharmacokinetics were observed when itrimod was administered following a high-fat meal (800 to 1000 calories).

2. Distribution

The average apparent volume of distribution of Itrimod is 66L, and the plasma protein binding rate of Itrimod is 97.9%.

3. Elimination

The average plasma elimination half-life of itrimod is approximately 30 hours, and the apparent steady-state oral clearance rate after oral administration is approximately 1L/h.

4. Metabolism

Itramod is metabolized through oxidation and dehydrogenation, mainly mediated by CYP2C8, CYP2C9 and CYP3A4, with minor contributions from CYP2C19 and CYP2J2. Itramod also undergoes a conjugation reaction, primarily mediated by UGT, with a minor contribution from sulfotransferases. Unaltered itrimod is the major circulating component in plasma.

5. Excretion

Approximately 82% of the total dose of radiolabeled itrimod was recovered from the feces within 336 hours, and 5% was recovered from the urine. Approximately 11% of the administered radioactive dose is excreted unchanged in the feces, with no unchanged drug excreted in the urine.

Special Population Pharmacokinetics of Itramod (Etrasimod)

No clinically significant differences in the pharmacokinetics of Etrasimod were observed based on age (>65 years), sex, weight, race, ethnicity, disease (healthy subjects vs. subjects with ulcerative colitis), and severe renal impairment.

Compared with subjects with normal liver function, the Itrimod AUC increased by 13%, 29% and 57% in subjects with mild (Child-Pugh Class A), moderate (Child-Pugh Class B) and severe (Child-Pugh Class C) hepatic impairment, respectively. No clinically significant differences in AUC of unbound istrimod were observed.

Storage of Etrasimod

Store at 20°C to 25°C (68°F to 77°F); excursions allowed between 15°C and 30°C (59°F to 86°F).

Warm reminder

1. Cardiac effects

Inform patients that starting treatment with istrimod may cause a temporary decrease in heart rate.

2. Liver damage

Inform patients that itrimod may increase liver enzymes. Advise patients to contact their medical provider if they experience any unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine.

3. Macular edema

Inform patients that itrimod may cause macular edema and that they should have an eye examination when starting treatment with itrimod, have their eyes monitored by an ophthalmologist regularly during treatment, and contact their medical provider if there are any changes in vision while taking itrimod.