Lemtrada® (Lemtrada®)

It is necessary to stop taking interferons beta and glatiramer acetate 28 days before the start of treatment with Lemtrada.

The use of Lemtrada is not recommended for patients who have an inactive or stable course of the disease.

Women of childbearing age

Approximately 30 days after each course of therapy, serum drug concentrations are low or not determined. Women of childbearing age should use reliable methods of contraception during the course of treatment with the drug Lemtrada and within 4 months after the last infusion.

In mothers with Graves' disease, maternal antibodies to the thyroid-stimulating hormone receptor can be transmitted to the fetus and cause a transient Graves disease of the newborn.

Patient monitoring

Treatment is recommended in the form of two courses of infusions (see section "Dosage"). In this case, patients should be monitored during the treatment period and within 48 months after the last infusion.

Premedication

In the first 3 days of each course of therapy with Lemtrada, the patient should be prescribed corticosteroids. In clinical trials, all participants received methylprednisolone in a dose of 1000 mg in the first three days of each course of treatment with the drug Lemtrada.

In addition, a day before the infusion, the patient may be prescribed antihistamines and / or antipyretics.

Prevention with an anti-herpetic drug for oral administration should be started on the first day of drug use alemtuzumab and continue for at least 1 month after each course of therapy. In clinical trials, patients received acyclovir in a dose of 200 mg twice a day.

Renal or hepatic impairment

Patients with renal or hepatic insufficiency did not participate in the clinical trials of Lemtrada.

Pediatric population

The safety and efficacy of Lemtrada in children with multiple sclerosis aged 0 to 18 years is not established. There is no experience of the use of alemtuzumab in children aged 0 to 10 years for the treatment of multiple sclerosis.

Elderly patients

In clinical trials, patients older than 55 years did not participate. There is no evidence that the response to treatment of this age group differs from the response of younger patients.

Infusion reactions (IR)

In controlled clinical trials with infusion reactions (IR), any adverse reactions noted during the infusion of the Lemtrada® drug or at least 24 hours after it were considered. Most of them can be caused by the release of cytokines during infusion. In controlled clinical trials, most patients with PC, who received the drug Lemtrada. MI progressed from mild to moderate severity during or within 24 hours after the administration of Lemtrad® at a dose of 12 mg.The most frequent reactions were headache, rash, fever, nausea, urticaria, pruritus, insomnia, chills, "hot flashes", fatigue, dyspnea, dysgeusia, chest discomfort, generalized rash, tachycardia, dyspepsia, dizziness and pain. Serious complications arose in 3% of patients and included cases of fever, urticaria, atrial fibrillation, nausea, chest discomfort and hypotension. Clinical manifestations of anaphylaxis may be similar to clinical manifestations of infusion reactions, but they tend to be more severe and life threatening. Unlike infusion, anaphylactic reactions are rare.

To reduce the severity of infusion reactions, a premedication is recommended. Most patients in controlled clinical trials received antihistamines and / or antipyretic drugs at least before one infusion of Lemtrad®. Conducting premedication does not exclude the development of IR. It is recommended to carefully monitor the patient's condition during the infusion of Lemtrad® and for two hours after the end.If necessary, the occurrence of MI should be treated accordingly. Typically, the duration of the infusion is 4 hours. If the infusion is poorly tolerated by the patient, the rate of administration of the drug can be reduced. If severe infusion reactions occur, the drug should be stopped immediately. During clinical trials, anaphylactic or other severe reactions requiring interruption of treatment were very rare.

The physician should be aware of the cardiovascular disease of the patient, since IR can cause complications from the heart, for example, tachycardia.

During the infusion, funds must be available to treat anaphylactic or other severe reactions.

Autoimmune diseases

On the background of treatment with the drug Lemtrada, autoantibodies can form, which can lead to the development of autoimmune diseases, including thyroid disease, immune thrombocytopenic purpura (ITP) or, rarely, nephropathy (for example, Goodpasture's cider). Care should be taken when treating patients who had previously had other (non-multiple sclerosis) autoimmune diseases.At the same time, the available data suggest that the treatment with alemtuzumab does not burden the current autoimmune diseases.

Thyroid gland diseases

Autoimmune thyroid diseases were detected within 48 months after the first infusion in approximately 36% of patients with PC, who received the drug Lemtrada at a dose of 12 mg in clinical trials. As in the group of patients who received the drug Lemtrada, and in the group of patients who received interferon beta-1a (INFβ-la), the incidence of thyroid disease was higher in patients with a history of such a pathology. Patients with current thyroid disease should receive the Lemtrade® drug only when the intended benefit exceeds the estimated risk. The participants in the studies noted both hyperthyroidism and hypothyroidism. In most cases, these disorders were mild or moderate. Severe illnesses were observed in less than 1% of patients and more than one patient, and included severe cases of Based's disease (also known as Graves' disease), hyperthyroidism and hypothyroidism.Most of the thyroid gland diseases succumbed to standard oral therapy, but some patients required surgical intervention. In clinical trials, patients who developed thyroid disorders were allowed to receive a second course of treatment with Lemtrada^®. There is limited evidence that patients who received a second course did not usually have a worsening of the course of the thyroid disease. Continuation of treatment with Lemtrad® should be planned individually, taking into account the clinical state of the patient.

Thyroid function studies, such as the level of thyroid-stimulating hormone, should be performed before treatment and then monthly for 48 months after the last infusion. At the end of this period, the tests are performed on the basis of clinical data, suggesting a violation of the thyroid gland.

In clinical studies, there was no association between the level of antibodies to thyroid peroxidase (AT-TPO) and the development of adverse reactions from the thyroid gland.At the stage of inclusion in the study In a half of patients with positive titers of AT-TPO and a quarter of patients with negative titers of AT-TPO at the stage of inclusion, thyroid diseases were later diagnosed. The vast majority (about 80%) of patients who developed thyroid disease after treatment had a negative titer of AT-TPO at the stage of enrollment. Therefore, thyroid disease can develop in a patient, regardless of the initial status of the AT-TPO, and it should periodically undergo all examinations, as described above.

Immune thrombocytopenic purpura (ITP)

Severe cases of ITP were observed in about 1% of patients with PC, who took part in controlled clinical trials. One case of ITP was not diagnosed in time, as it occurred before the introduction of mandatory monthly monitoring requirements for clinical blood analysis. The patient died of a hemorrhagic stroke. ITP usually develops between 14 and 36 months after the first infusion of the drug. Symptoms of ITP may include, but are not limited to, easily emerging skin hemorrhages, pinpoint hemorrhages, spontaneous cutaneous mucosal bleeding (eg, epistaxis,hemoptysis), more abundant than usual, or irregular menstrual bleeding. Hemoptysis can also be a manifestation of Goodpasture's syndrome (see below), therefore appropriate differential diagnosis should be performed. The patient should be aware of the possibility of these symptoms, and in case of any doubt, immediately consult a doctor. A complete clinical blood count with the counting of the formed elements should be performed before the start of treatment, and then monthly within 48 months after the last infusion. After the end of this period, the tests are performed on the basis of clinical data, suggesting ITP. If an ITP is suspected, a complete clinical blood test should be performed immediately.

When confirming the diagnosis of ITP, appropriate measures should immediately be taken, including an urgent referral to a specialist.

The potential risk associated with repeated treatment with Lemtrad® after the development of ITP is unknown.

Nephropathies

Nephropathies, including Goodpasture's syndrome (SG), were observed in 0.3% of patients with PC, who took part in controlled clinical trials.As a rule, they were noted within 39 months after the last infusion of the Lemtrada® preparation. Two cases of hypertension have been reported in clinical studies. Both cases were severe, but thanks to clinical and laboratory monitoring, they were identified in a timely manner and their treatment was successful.

Clinical manifestations of nephropathy may include increased levels of serum creatinine, hematuria and / or proteinuria. With SG may be noted alveolar bleeding, manifested hemoptysis. It should be noted that in the course of clinical trials, cases of alveolar bleeding were not detected. Hemoptysis may also be a sign of ITP (see above), so proper differential diagnosis should be carried out. You should carefully consider the possibility of these symptoms, and in case of their development, seek medical help immediately.

SG may lead to the development of renal insufficiency requiring dialysis and / or transplantation with untimely initiated therapy. In the absence of treatment, there may be a threat to life.

It is necessary to determine the level of creatinine and conduct a clinical analysis of urine with microscopy of sediment before the start of therapy with alemtuzumab.These examinations should be repeated monthly during the course of treatment, and also in the future within 48 months after the last infusion of alemtuzumab. The detection of clinically significant deviations from baseline serum creatinine, hematuria, and / or proteinuria may indicate the development of nephropathy. The patient should be immediately referred to the appropriate specialist. Early diagnosis and treatment of nephropathies can reduce the risk of an adverse outcome. After the end of the period of 48 months after the last infusion, the tests are performed on the basis of clinical data suggesting a violation of kidney function.

The potential risk associated with repeated treatment with Lemtrad® after the development of nephropathy is unknown.

Cytopenia

Autoimmune cytopenias, such as neutropenia, hemolytic anemia, and pancytopenia, were rarely seen in clinical studies. For the timely detection of cytopenia, a full clinical blood test should be performed monthly (see the section "ITP" above). If cytopenia is confirmed, appropriate measures should be taken immediately, including referring the patient to a specialist.

Infectious diseases

In controlled clinical trials lasting up to two years with the participation of patients with PC Infectious diseases occurred in 71% of patients who received Lemtrad® 12 mg, whereas in the group of patients who received interferon beta-1a (IFNβ-1a) (44 μg three times a week), they occurred in 53% of patients; most of the infectious diseases were of mild or moderate severity. Infectious diseases that occurred more often in patients treated with Lemtrad® compared to the IFN-beta-1a group included nasopharyngitis, urinary tract infection, upper respiratory tract infection, sinusitis, oral cavity, flu and bronchitis. In controlled clinical trials, severe infectious diseases occurred in 2.7% of patients who received the drug Lemtrada, and 1% of patients who received IFN-beta-1a. Severe infectious diseases in the group of patients treated with Lemtrade® included appendicitis, gastroenteritis, pneumonia, shingles and dental infections. Typically, the duration of the disease was normal, and they were resolved after the application of standard drug treatment.

In clinical trials, severe infections caused by the varicella-zoster virus, including primary and re-infection, were more common in patients treated with LEMTRADA® 12 mg (0.3%) than those receiving INFP-1a (0%). In the group of patients who received the drug Lemtrada 12 mg, there were also cases of infection with the human papillomavirus (HPV), including cervical dysplasia (2%). It is recommended that an annual examination of patients for HPV detection be performed.

In controlled clinical trials, tuberculosis cases were also detected, both in the group of patients who received the Lemtrade® drug, and in the group of patients receiving IFN-beta-1a. Active and latent tuberculosis was noted in 0.3% of patients receiving LEMTRADA®. Most often, these cases were recorded in endemic areas. Prior to treatment in accordance with local requirements, screening for active or latent tuberculosis should be carried out.

In controlled clinical trials involving patients with PC superficial fungal infections, especially oral candidiasis and vaginal, were more common in patients who received LEMTRADA® (12%) than patients who received IFNβ-1a (3%).

If the patient has an active infectious disease, the doctor must delay the initiation of treatment with Lemtrada before achieving complete control over the course of the disease.

There is no evidence of the effect of Lemtrade® on the reactivation of hepatitis B (HBV) or hepatitis C (HBV-C) viruses, since patients with signs of active or chronic infectious diseases were excluded from participation in clinical trials. Before starting treatment with Lemtrad®, screening for carriage of VG-B and / or VG-C viruses should be performed. Caution should be exercised when prescribing Lemtrad® to carriers of VG-B and / or VG-C viruses, since there is a risk of reactivation of the virus and the occurrence of irreversible hepatic failure in these patients.

Malignant neoplasms

As in the case of other immunomodulators, caution should be exercised in the preparation of Lemtrada® in patients with previous or existing malignant neoplasms. At this time, it is not known whether alemtuzumab risk of developing a thyroid cancer, because an autoimmune thyroid disease can itself be a risk factor for malignancy.

Contraception

Women of childbearing age should use reliable contraceptive methods during treatment with Lemtrada * and within four months after the last infusion.

Vaccination

It is desirable that patients fulfill local immunization requirements no later than six weeks before starting treatment with Lemtrada. The ability of an organism to reproduce an immune response to a vaccine after treatment with Lemtrad® has not been studied.

In controlled clinical trials involving patients with PC the safety of immunization with live viral vaccines after the course of treatment with Lemtrad® has not been studied. Patients who have recently been treated with Lemtrada® are not recommended to be immunized with live viral vaccines.

Testing for antibodies to varicella zoster virus / vaccination against infection caused by the varicella zoster virus

As with any other immunomodulating medication, prior to initiating a course of treatment with Lemtrad®, patients who did not have an indication of previous varicella zoster infection or who did not receive vaccination against the infection caused by the varicella zoster virus (VVZ) should be tested for antibodies to the VVZ.Vaccination of patients with a negative test of antibodies to VVZ should be performed before starting treatment with Lemtrada. In order for the vaccination effect to be fully manifested, treatment with Lemtrad® should be given no earlier than six weeks after vaccination.

Recommended laboratory tests for monitoring patients

Laboratory tests should be performed at regular intervals throughout the course of treatment, and also within 48 months after the last infusion of the Lemtrade® preparation, which will allow timely diagnosis of an autoimmune disease:

- Complete clinical analysis of blood counting the form elements (before treatment and then monthly);

- The level of serum creatinine (before treatment and then monthly);

- General urine analysis and sediment microscopy (before treatment and then monthly);

- Examination of the thyroid function, for example, the level of thyroid-stimulating hormone (TSH) (before treatment and then every 3 months).

At the end of a period of 48 months after the last infusion, additional examinations are performed if any clinical signs of nephropathy or thyroid dysfunction occur.

Information on the use of alemtuzumab outside of the company-sponsored studies prior to the registration of Lemtrad®

The following adverse reactions have been identified with the use of alemtuzumab for the treatment of B-cell chronic lymphocytic leukemia (B-CLL), as well as for the treatment of other diseases, usually at higher doses (eg, 30 mg) and at a higher frequency than recommended for treatment PC. As the information on these reactions came spontaneously and the size of the population receiving the treatment is not determined, it is not always possible to reliably estimate their frequency or to reveal a connection with the reception of alemtuzumab.

Autoimmune diseases

Autoimmune diseases described against alemtuzumab therapy include neutropenia, hemolytic anemia (including one lethal case), acquired hemophilia, Goodpasture's syndrome, and thyroid disease. Severe and sometimes lethal autoimmune diseases, including autoimmune hemolytic anemia, autoimmune thrombocytopenia, aplastic anemia, Guillain-Barre syndrome and chronic inflammatory demyelinating polyradiculoneuropathy, have been described in patients who received alemtuzumab and not suffering PC. One patient with a malignant neoplasm receiving alemtuzumab, a positive Coombs reaction was noted. In another patient with oncological disease, infusion resulted in death in connection with the development of the "graft versus host" reaction.

Infusion reactions

Severe and sometimes lethal IR, including bronchospasm, hypoxia, syncope, pulmonary infiltrates, acute respiratory distress syndrome syndrome, respiratory arrest, myocardial infarction, arrhythmias, acute heart failure and cardiac arrest, were observed in patients not suffering from PC and received alemtuzumab in higher doses and with a greater frequency, this is recommended for treatment PC. As a rule, these reactions were more severe than in patients with PC. Also reported were severe anaphylactic reactions and other hypersensitivity reactions, including anaphylactic shock and Quincke edema.

Infections and invasions