那他珠单抗(Natalizumab)的详细说明书：作用与功效,用法用量,副作用,注意事项等

Natalizumab was originally developed by Biogen (in collaboration with Elan) and was approved for marketing by the US FDA under accelerated review in 2004.

Indications for Natalizumab

1. Multiple sclerosis (MS)

It is designated as monotherapy for adults with relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease and active secondary progressive disease. Natalizumab increases the risk of progressive multifocal leukoencephalopathy (PML). When initiating and continuing natalizumab therapy, physicians should consider whether the expected benefits of natalizumab are sufficient to offset this risk.

2. Crohn's disease (CD)

Natalizumab is indicated to induce and maintain clinical responses and remissions in adult patients with moderately to severely active Crohn's disease with evidence of inflammation who have an inadequate response to or intolerance to conventional CD therapies and tumor necrosis factor-alpha (TNF-alpha) inhibitors. Natalizumab should not be used in combination with immunosuppressants (eg, 6-mercaptopurine, azathioprine, cyclosporine, or methotrexate) or TNF-α inhibitors.

Natalizumab usage and dosage

1. Multiple sclerosis (MS)

Only prescribers registered to participate in the MSTOUCH prescription program can prescribe natalizumab for multiple sclerosis. The recommended dose of natalizumab for multiple sclerosis is 300 mg as an intravenous infusion over one hour every four weeks.

2. Crohn's disease (CD)

The recommended dose of natalizumab for Crohn's disease is 300 mg once every four weeks as an intravenous infusion for one hour. Natalizumab should not be used in combination with concomitant immunosuppressants (e.g., 6-mercaptopurine, azathioprine, cyclosporine, or methotrexate) or concomitant TNF-α inhibitors. Aminosalicylates may be continued during natalizumab treatment.

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.

3. Treatment with discontinuation

If patients with Crohn's disease do not experience therapeutic benefit after 12 weeks of induction therapy, natalizumab should be discontinued. For patients with Crohn's disease who are receiving chronic oral corticosteroid therapy when initiating natalizumab, a tapering of the steroid dose should be initiated as soon as a benefit from natalizumab treatment occurs.

If a patient with Crohn's disease cannot discontinue oral corticosteroids within six months of starting natalizumab, natalizumab should be discontinued. In addition to the initial six-month tapering period, prescribers should consider discontinuing natalizumab in patients who require additional steroid use for more than three months in the calendar year to control their Crohn's disease.

4. Dilution instructions

Aseptic techniques must be used when preparing natalizumab solutions for intravenous infusion. Each vial is for single use only. Discard any unused portion.

Natalizumab is a colorless, clear to slightly opalescent solution. Natalizumab vials should be inspected for particulate matter and discoloration prior to dilution and administration. If visible particulates and/or discoloration of the liquid in the vial is observed, the vial should not be used.

To prepare the dilute solution, use a sterile needle and syringe to withdraw 15 mL of natalizumab from the vial. Inject natalizumab into 100 mL of 0.9% sodium chloride injection (USP). No other intravenous diluents should be used to prepare dilute solutions of natalizumab.

Gently invert the natalizumab diluted solution to mix thoroughly without shaking. Visually inspect the solution for particulate matter before dosing. The final dose of the diluted solution should be 2.6 mg/mL.

5. Administration Instructions

Complete infusion of natalizumab 300 mg in 100 mL of 0.9% sodium chloride injection (USP) over approximately one hour (at an infusion rate of approximately 5 mg per minute). Do not give natalizumab as an intravenous push or bolus injection. After the infusion is completed, flush the line with 0.9% sodium chloride injection (USP).

Observe the patient during all infusions. Stop the infusion immediately if any signs or symptoms consistent with a type of hypersensitivity reaction are observed.

After infusion, for the first 12 infusions, observe the patient for one hour after the infusion is completed. For patients who have received 12 infusions without evidence of hypersensitivity, observation after the 13th and subsequent infusions should be based on clinical judgment.

The use of filtering devices during drug administration has not been evaluated. Other drugs should not be injected into the side port of the infusion device or mixed with natalizumab.

6. Dosage forms and specifications

Injection: 300mg/15mL (20mg/mL), a colorless, transparent to slightly opalescent solution, packed in a single-dose vial, which needs to be diluted before infusion.

Contraindications of Natalizumab

1. Natalizumab is contraindicated in patients who have or have had progressive multifocal leukoencephalopathy (PML).

2. Natalizumab is contraindicated in patients with hypersensitivity reactions to natalizumab. Observed reactions range from hives to anaphylaxis.

Natalizumab (Natalizumab) Precautions

1. Progressive multifocal leukoencephalopathy (PML)

Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the brain caused by JC virus (JCV). It usually only occurs in patients with low immune function and usually leads to death or severe disability. It has occurred in patients treated with natalizumab.

Three factors known to increase the risk of PML in natalizumab-treated patients have been identified:

The presence of anti-JCV antibodies. Patients with positive anti-JCV antibodies are at higher risk of developing PML.

Longer treatment duration, especially more than 2 years.

Prior immunosuppressive therapy (e.g., mitoxantrone, azathioprine, methotrexate, cyclophosphamide, mycophenolate mofetil).

These factors should be considered in the context of expected benefit when initiating and continuing natalizumab therapy.

2. Herpetic encephalitis and meningitis

Natalizumab increases the risk of encephalitis and meningitis caused by herpes simplex virus and varicella-zoster virus. The duration of natalizumab treatment before the onset of symptoms ranged from months to years. Patients receiving natalizumab should be monitored for signs and symptoms of meningitis and encephalitis. If herpetic encephalitis or meningitis occurs, natalizumab should be discontinued and appropriate herpetic encephalitis/meningitis treatment should be instituted.

3. Acute retinal necrosis

Acute retinal necrosis (ARN) is a fulminant retinal virus infection caused by the herpes virus family (eg, varicella-zoster virus, herpes simplex virus). A higher risk of ARN has been observed in patients treated with natalizumab. Patients who develop ocular symptoms including decreased vision, redness, or eye pain should be referred for ARN retinal screening.

4. Hepatotoxicity

During post-marketing surveillance, clinically significant liver injury (including acute liver failure requiring transplantation) has been reported in patients treated with natalizumab. Signs of liver injury, including significant elevations in serum liver enzymes and total bilirubin, may occur as early as six days after the first dose; first signs of liver injury have also been reported after multiple doses.

In some patients, liver injury recurred after rechallenge, suggesting that natalizumab caused the injury. The coexistence of elevated transaminases and elevated bilirubin without evidence of obstruction is generally considered an important predictor of severe liver injury, which may lead to death or the need for liver transplantation in some patients.

Natalizumab should be discontinued in patients who develop jaundice or other evidence of significant liver injury (e.g., laboratory evidence).

5. Hypersensitivity reactions/antibody formation

Hypersensitivity reactions, including severe systemic reactions (e.g., anaphylaxis), have occurred in patients receiving natalizumab. Incidence<1%. These reactions usually occur within two hours of starting the infusion. Symptoms associated with these reactions can include hives, dizziness, fever, rash, chills, itching, nausea, flushing, hypotension, difficulty breathing, and chest pain. Typically, these reactions are associated with antibodies directed against natalizumab.

If a hypersensitivity reaction occurs, natalizumab administration should be discontinued and appropriate therapy initiated. Patients who experience a hypersensitivity reaction should not receive natalizumab again. In studies of MS and CD, hypersensitivity reactions were more common in patients who developed natalizumab antibodies than in patients who did not develop natalizumab antibodies. Therefore, the possibility of the presence of natalizumab antibodies should be considered in patients who develop hypersensitivity reactions.

6. Immunosuppression/infection

The immune system effects of natalizumab may increase the risk of infection.

In patients with Crohn's disease who are receiving chronic corticosteroid therapy when initiating natalizumab, steroid withdrawal should be initiated as soon as treatment benefit occurs. If the patient cannot discontinue systemic corticosteroids within six months, discontinue natalizumab.

7. Laboratory test abnormalities

In clinical trials, natalizumab was observed to cause an increase in circulating lymphocytes, monocytes, eosinophils, basophils, and nucleated red blood cells. The observed changes persisted during natalizumab exposure but were reversible, typically returning to baseline levels within 16 weeks of the last dose. No increase in neutrophils was observed. Natalizumab causes a mild decrease in hemoglobin levels (mean decrease 0.6 g/dL), which is usually temporary.

8. Hematological abnormalities

During post-marketing surveillance, there have been reports of thrombocytopenia (including immune thrombocytopenic purpura (ITP)) caused by the use of natalizumab. Symptoms of thrombocytopenia may include easy bruising, abnormal bleeding, and petechiae. Delay in diagnosis and treatment of thrombocytopenia can lead to serious and life-threatening sequelae. If thrombocytopenia is suspected, natalizumab should be discontinued.

Neonatal thrombocytopenia and anemia have been reported in neonates exposed to natalizumab in utero. A complete blood count (CBC) should be obtained in newborns exposed to natalizumab in utero.

9. Immunization

There is no data on the effectiveness of vaccination in patients treated with natalizumab. There are no data on secondary transmission of infection due to the use of live vaccines in natalizumab-treated patients.

Natalizumab Adverse Reactions

In studies of multiple sclerosis (MS) and Crohn's disease (CD), the most common adverse reactions (incidence ≥10%) were headache and fatigue. Other common adverse reactions (incidence ≥10%) in the MS population include arthralgia, urinary tract infection, lower respiratory tract infection, gastroenteritis, vaginitis, depression, limb pain, abdominal discomfort, non-specific diarrhea and rash. Other common adverse reactions (incidence ≥10%) in the CD population include upper respiratory tract infection and nausea.

In MS studies, the most common adverse reactions leading to clinical intervention (i.e., discontinuation of natalizumab) were urticaria (1%) and other hypersensitivity reactions (1%); in CD studies (Study CD1 and CD2), the most common adverse reactions leading to clinical intervention were Crohn's disease plus severe (4.2%) and acute hypersensitivity reactions (1.5%.

Natalizumab drug interactions

Due to the possible increased risk of PML and other infections, patients with Crohn's disease receiving natalizumab should not immunosuppressants (e.g., 6-mercaptopurine, azathioprine, cyclosporine, or methotrexate) or TNF-α inhibitors, and corticosteroid dosage should be tapered < /p>

Natalizumab should not be used to treat patients with multiple sclerosis who are receiving chronic immunosuppressive or immunomodulatory treatment.

Natalizumab (Natalizumab) special population use

1. Pregnancy

There are insufficient data on the risk of major birth defects, miscarriage, or other adverse maternal outcomes in pregnant women taking natalizumab. Adverse fetal outcomes have been reported including neonatal thrombocytopenia and anemia (see Clinical Considerations).

2. Lactation

Natalizumab has been detected in human milk. There are no data on the effects of this exposure on breastfed infants, nor on the effects of this drug on milk.

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

3. Pediatric use

The safety and effectiveness of natalizumab in pediatric patients under 18 years of age with multiple sclerosis or Crohn's disease have not been established. Natalizumab is not suitable for use in pediatric patients.

4. Elderly use

Clinical studies of natalizumab did not include a sufficient number of patients aged 65 and above to determine whether their responses were different from those of younger patients. Other reported clinical experience has not found a difference in response between older and younger patients.

Natalizumab mechanism of action

Natalizumab binds to the α4 subunit of α4β1 and α4β7 integrins expressed on the surface of all leukocytes except neutrophils, and inhibits the α4-mediated adhesion of leukocytes to their corresponding receptors (s). Receptors of the α4 integrin family include vascular cell adhesion molecule-1 (VCAM-1), which is expressed on activated vascular endothelium, and mucosal addressin cell adhesion molecule-1 (MAdCAM-1), which is present on vascular endothelial cells in the gastrointestinal tract.

Disruption of these molecular interactions prevents leukocytes from crossing the endothelium and entering inflamed parenchymal tissue.

In vitro, anti-α4-integrin antibodies also block α4-mediated cellular binding to ligands such as osteopontin and an alternatively spliced ​​domain of fibronectin, junction fragment-1 (CS-1).

In vivo, natalizumab may further inhibit the interaction of α4-expressing leukocytes with their ligand(s) on the extracellular matrix and parenchymal cells, thereby inhibiting further recruitment of activated immune cells and inflammatory activity.

The specific mechanisms by which natalizumab works in multiple sclerosis and Crohn's disease are not fully understood.

Natalizumab pharmacokinetics

1. Multiple sclerosis (MS) patients

In MS patients, after repeated intravenous administration of 300 mg doses of natalizumab, the mean ± standard deviation (SD) maximum observed serum concentration was 110 ± 52 mcg/mL. Average steady-state trough concentrations ranged from 23mcg/mL to 29mcg/mL. The time to steady state was observed to be approximately 24 weeks after dosing every four weeks. The mean ±SD half-life, volume of distribution, and clearance of natalizumab were 11±4 days, 5.7±1.9L, and 16±5mL/hour, respectively.

The effect of covariates such as body weight, age, sex, and the presence of anti-natalizumab antibodies on natalizumab pharmacokinetics was studied in a population pharmacokinetic study (n=2195). The clearance of natalizumab increased with increasing body weight, but the increase was less than proportional, with a 43% increase in body weight resulting in a 32% increase in clearance. The presence of persistent anti-natalizumab antibodies increases natalizumab clearance approximately 3-fold.

2. Patients with Crohn's disease (CD)

In patients with CD, after repeated intravenous administration of natalizumab at a dose of 300 mg, the mean ± SD maximum observed serum concentration was 101 ± 34 mcg/mL. The mean ± SD mean steady-state trough concentration was 10 ± 9 mcg/mL. The estimated time to reach steady state is approximately 16 to 24 weeks after dosing every four weeks. The mean ±SD half-life, volume of distribution, and clearance of natalizumab were 10±7 days, 5.2±2.8L, and 22±22mL/hour, respectively.

The effects of total body weight, age, sex, race, selected hematology and serum chemistry parameters, concomitant medications (infliximab, immunosuppressants, or steroids), and the presence of anti-natalizumab antibodies were studied in a population pharmacokinetic analysis (n=1156). The presence of anti-natalizumab antibodies was observed to increase natalizumab clearance.

The pharmacokinetics of natalizumab have not been studied in patients with renal or hepatic impairment.

Natalizumab storage

Natalizumab single-dose vials must be refrigerated at 2°C to 8°C (36°F to 46°F). Do not use beyond the expiry date printed on the box and vial label. Do not shake or freeze. Store away from light.

Storage diluted natalizumab solution should be refrigerated at 2°C to 8°C (36°F to 46°F).

Warm Tips

1. Read the Medication Guide before starting natalizumab and before each natalizumab infusion.

2. If any new symptoms that last for several days or symptoms that continue to worsen occur, report it to your prescribing doctor immediately.

3. Inform all doctors that they are receiving natalizumab.

4. Plan to see your prescribing physician three months after the first infusion, six months after the first infusion, every six months thereafter, and at least six months after stopping natalizumab.