Treatment with Rewlimide should be started and carried out under the supervision of an experienced hematologist or chemotherapist.
Pregnancy Protection Program
Strict adherence to all requirements of the Pregnancy Protection Program should apply to both women and men.
For women with unserved fertility potential:
A female patient or woman, a sexual partner of a male patient, is NOT considered fertile in the presence of at least one of the following factors:
- age> 50 years and the duration of natural amenorrhea> 1 year *
- early failure of the ovaries, confirmed by a gynecologist
- bilateral salpingo-oophorectomy or hysterectomy in anamnesis
- genotype XY, Turner's syndrome, anatomical defect of the uterus
* - amenorrhea due to anticancer therapy or during breastfeeding does not exclude the presence of a childbearing potential.
The use of lenalidomide in women with preserved reproductive potential is contraindicated in those cases when the following conditions are not met:
female
- must To know about the likely teratogenic effect of Revlimid on fetus
- must understand the need continuous use of effective methods of contraception for 4 weeks before the start of treatment, during treatment and 4 weeks after the end of treatment
- even in the case of amenorrhea should follow recommendations to use effective contraception
- be able to comply with all the rules of effective contraception
- should know and understand the possible consequences of pregnancy, as well as the need for urgent treatment for advice in case of suspected pregnancy
- should understand the need for immediate initiation of lenalidomide treatment immediately after receiving negative pregnancy test results
- should be aware of the need for a test and perform a pregnancy test every 4 weeks, with the exception of patients who have undergone sterilization by ligation of the fallopian tubes
- must confirm that he understands the risk of possible undesirable consequences and the need for their prevention during the treatment with lenalidomide
Application in men:
Data from the study of the pharmacokinetics of lenalidomide in male volunteers indicate that during treatment lenalidomide can be contained in extremely low concentrations in the patient's semen and is not determined 3 days after discontinuation of the drug in healthy volunteers (see "Pharmacological action, Pharmacokinetics"). As a precaution, given the possible reduction in the rate of excretion of lenalidomide in specific groups of patients (in patients with impaired renal function), for all male patients lenalidomide, the following conditions must be met:
Man
- should understand the possible risk of teratogenic action of the drug Revlimid in sexual contact with a pregnant woman or a woman with a preserved childbearing potential
- should understand the need for condoms (even after a vasectomy) during sexual contact with pregnant women or women with preserved reproductive potential that do not use reliable contraceptive methods during the treatment period and within 1 week after stopping treatment and / or completing treatment
- should understand that if his partner becomes pregnant during his treatment with Revlimid® or shortly after discontinuing Rewlimid®, he should immediately inform his or her attending physician about this, and his partner is advised to seek a consultation and consultation with a teratologist.
A doctor who prescribes treatment with Revlimid for women with preserved reproductive potential should
- make sure that the patient meets all the conditions of the Pregnancy Protection Program, including confirmation that she adequately understands the situation
- To obtain the patient's consent to the obligatory observance by her of all the conditions of the above-mentioned Program.
Contraceptive rules:
Women with preserved childbearing potential should use one of the highly effective methods of contraception for 4 weeks before the start of treatment, during therapy and for 4 weeks after the end of therapy with Revlimid®, even during breaks in treatment. Exception is made by patients who throughout the specified period abstain from heterosexual relations, which is documented monthly.If the patient does not have an effective method of contraception, she should be referred to a gynecologist for the method of effective contraception. The patient should immediately start using the effective method of contraception.
The highly effective methods of contraception include:
- Subcutaneous hormonal implants;
- Intrauterine devices that release levonorgestrel;
- Depot preparations medroxyprogesterone acetate;
- Ligation of fallopian tubes;
- Vasectomy of the partner (confirmed by two negative analyzes of seminal fluid);
- Progesterone-containing pills that inhibit ovulation (for example, desogestrel). The use of combined oral contraceptives is not indicated in patients with MM due to an increased risk of thromboembolic complications with combined therapy with lenalidomide. For effective contraception these patients are recommended to use one of the methods listed above. An increased risk of thromboembolism persists for 4-6 weeks after discontinuation of combined contraceptives.
The effectiveness of hormonal contraceptives can be reduced with the simultaneous administration of dexamethasone.
Patients with neutropenia using as a contraceptive subcutaneous hormonal implants or intrauterine systems that release levonorgestrel, it is necessary to prophylaxisally prescribe antibiotics in connection with an increased risk of infectious complications at the time of installation of these therapeutic systems.
The use of intrauterine systems that release copper is generally not recommended due to a high risk of developing infectious complications at the time of implantation and increased blood loss during menstruation, which may increase the severity of neutropenia or thrombocytopenia in the patient.
Pregnancy test (sensitivity of at least 25 mIU / mL) should be performed in the presence of a physician for all women with preserved reproductive potential, including those who completely and continuously refrain from heterosexual relationships. After patients use an effective method of contraception for 4 or more weeks, the tests are performed on the day of treatment or 3 days before the visit to the treating doctor, and then every 4 weeks, including within 4 weeks after completion of treatment, except for those patients who have been confirmed to be sterilized by ligation of the fallopian tubes.The results of the test should confirm the absence of pregnancy in the patient at the time of initiation of therapy.
Male patient should use condoms during the entire course of treatment, during a break in treatment and within 1 week after cessation of treatment if his sexual partner is a pregnant woman or a woman with a preserved childbearing potential that does not use highly effective methods of contraception (even if the man underwent a vasectomy).
Additional precautions
Patients should not transfer Revlimid® to others. The unused medication should be returned to the medical institution at the end of the treatment.
Patients are not allowed to donate blood or sperm as a donor throughout the treatment with Rewlimid ® and within 1 week after the end.
Teaching materials, restrictions in the appointment and dispensing of the drug
To help patients prevent the effects of lenalidomide on the fetus, the holder of the registration certificate will provide medical personnel with training materials to justify warnings about the teratogenicity of lenalidomide, recommend contraception before starting therapy, and explain the need for pregnancy tests.The physician should inform male and female patients about the risk of developing a teratogenic effect of lenalidomide and strict measures to prevent pregnancy in accordance with the Pregnancy Protection Program. The physician must provide the patient with a training brochure and patient card, as well as other equivalent instructions in accordance with the state patient card system. A controlled distribution system includes the use of patient cards and / or an equivalent instrument to control the appointment and / or dispensing of the drug and to collect detailed data relevant to the indication, in order to closely monitor the use of the indications not approved by the Russian Federation. Ideally, a pregnancy test, treatment appointment and drug delivery should occur on the same day. Delivery of lenalidomide to women with preserved reproductive potential should occur no later than 7 days after the appointment of therapy and receiving a negative result of a pregnancy test performed under the supervision of a doctor. To women of reproductive age lenalidomide can be issued / discharged for a maximum of up to 4 weeks, while for other patients - for up to 12 weeks.
Cardiovascular diseases
Myocardial infarction
There are reports of cases of myocardial infarction in patients taking lenalidomide, in particular in individuals with risk factors for cardiovascular disease and during the first 12 months of combined use with dexamethasone. In case of presence of risk factors, including, first of all, thromboses in the anamnesis, it is necessary to monitor the patients' condition, and also take actions aimed at possible reduction of the influence of risk factors (smoking, hypertension, hyperlipidemia).
Venous and arterial thromboembolism
Against the background of combined therapy with Revlimid® and dexamethasone, there is an increase in the frequency of venous thromboembolism (mainly deep vein thrombosis and pulmonary embolism), as well as arterial thromboembolism (mainly myocardial infarction and stroke) in patients with multiple myeloma. Venous thromboembolism was less common with the use of lenalidomide in combination with melphalan and prednisolone for the first time diagnosed with MM and with monotherapy of the myelodysplastic syndrome (cf."Interaction with other medicinal products" and "Side effect"). Therefore, it is necessary to observe patients who have risk factors for thromboembolism, including thrombosis in the anamnesis. Steps should be taken to eliminate risk factors such as smoking, hypertension, hyperlipidemia. The greatest prognostic value has thromboembolic complications in the anamnesis, concomitant therapy with erythropoietin, hormone replacement therapy. Thus, drugs with erythropoietic activity, as well as other drugs that may increase the risk of developing thrombosis (eg, hormone replacement therapy) should be administered with caution to the patient with MM taking lenalidomide along with dexamethasone. Concentration of hemoglobin above 120 g / l suggests the cessation of therapy with erythropoietin.
Physicians and patients should carefully evaluate the clinical signs that indicate possible thromboembolism. Patients should be warned about the need to seek immediate medical attention in the event of symptoms such as shortness of breath, chest pain, swelling of the upper or lower extremity.
For prevention of venous thromboembolism, especially in patients with additional risk factors, it is recommended to use low molecular weight heparins or warfarin. The decision to prescribe antithrombotic therapy should be taken after a thorough assessment of individual risk factors.
If a patient develops symptoms of thromboembolism, it is necessary to stop lenalidomide treatment and prescribe standard anticoagulant therapy. After the patient's condition stabilizes on anticoagulant therapy, and the symptoms of thromboembolism are eliminated, lenalidomide can be re-started at the same dose, with a favorable benefit / risk ratio. The patient should continue anticoagulant therapy throughout the further treatment with lenalidomide.
Neutropenia and thrombocytopenia
Severe dose-limiting toxic phenomena of lenalidomide are neutropenia and thrombocytopenia. An extensive blood test, including the determination of the number of leukocytes, blood formulas, platelet counts, hemoglobin, hematocrit should be performed before therapy, every week during the first 8 weeks of lenalidomide therapy and,then, monthly to monitor cytopenia. With the development of neutropenia, a dose reduction of the drug may be required (see "Method of administration and dose"). In the case of development of neutropenia, the use of growth factor drugs is advisable. Patients should be informed of the need to inform the doctor in a timely manner about any temperature increases. It should be used with caution lenalidomide with other mielodepressive drugs.
- The first diagnosed MM in patients receiving lenalidomide in combination with low doses of dexamethasone
Neutropenia of grade 4 was less common in patients who received lenalidomide in combination with low doses of dexamethasone than in the control group (8.5% for continuous treatment or treatment for 18 four-week cycles group lenalidomide / dexamethasone, compared with 15% in the group receiving melphalan / prednisone / thalidomide (MAT), see the "Side effect" section). Episodes of febrile neutropenia of grade 4 occurred at the same frequency in the lenalidomide / dexamethasone group and in the comparison group (0.6% in patients treated with lenalidomide / dexamethasone compared with 0.7% in the group receiving MAT cm. to "Side effect").Patients should be advised to report febrile episodes immediately, a dose reduction may be required (see "Dosage and Administration").
Thrombocytopenia of grade 3 or 4 was less observed in the lenalidomide / dexamethasone group than in the comparison group (8.1% versus 11.1%, respectively). Patients and doctors are advised to observe the signs and symptoms of bleeding, including petechiae and nosebleeds, especially in cases when concomitant medications are capable of increasing the tendency to bleeding (see "Side effect, Hemorrhagic complications").
- The first diagnosed MM in patients receiving lenalidomide in combination with melphalan and prednisolone
The use of lenalidomide with melphalan and prednisolone in clinical trials in patients with newly diagnosed MM was accompanied by a higher frequency of grade 4 neutropenia. Episodes of febrile neutropenia of grade 4 were rare. The use of lenalidomide with melphalan and prednisolone in patients with MM was accompanied by a higher incidence of grade 3 and 4 thrombocytopenia.Patients and doctors are advised to observe the signs and symptoms of bleeding, including petechiae and nosebleeds, especially in cases when concomitant medications are capable of increasing the tendency to bleeding (see "Side-Effects.").
- MM in patients who received at least one line of therapy
The risk of developing grade 4 neutropenia in patients with MM with simultaneous prescription Rewlimid and dexamethasone is very high (5.1% in the group treated with Revlimid / Dexamethasone versus 0.6% in the placebo / dexamethasone group). Episodes of febrile neutropenia of 4 severity are infrequent (0.6% in the group treated with Revlimid® / dexamethasone, relatively 0.0% in the placebo / dexamethasone group). Patients should be advised to report febrile episodes immediately, a dose reduction may be required (see "Dosage and Administration"). With the development of neutropenia should consider the appropriateness of the patient's appointment of a growth factor.A high incidence of grade 3 and 4 thrombocytopenia was observed in MM patients with concomitant administration of Revlimid® and dexamethasone (9.9% and 1.4%, respectively, with Revlimid® / dexamethasone compared to 2.3% and 0 , 0% - against the background of placebo / dexamethasone treatment). It is recommended to carefully monitor both the doctor and the patient the symptoms of increased bleeding, including petechiae and nosebleeds, especially in cases when concomitant medications are capable of increasing the tendency to bleeding (see "Venous and arterial thromboembolism" and "Side effects, hemorrhagic complications ").
Infection with or without neutropenia
Patients with MM are susceptible to the development of infections, including pneumonia. A higher infection rate was observed with lenalidomide in combination with dexamethasone, rather than with MPT. Infections> 3 degrees of severity developed in conditions of neutropenia less than one-third of patients. Patients with known risk factors for infection should be closely monitored. All patients are advised to immediately consult a doctor at the first sign of infection(for example, cough, fever, etc.), which allows for early treatment to reduce the severity.
Renal insufficiency
Given the primary allocation of lenalidomide by the kidneys, patients with renal insufficiency should carefully monitor the status of kidney function and the dose of Revlimid® (see "Method of administration and dose").
Thyroid gland diseases
There are reports of cases of hypothyroidism and hyperthyroidism. Before the start of treatment, it is necessary to evaluate concomitant diseases that can affect the function of the thyroid gland. It is recommended to evaluate thyroid function before treatment and its regular monitoring during treatment with Revlimid.
Peripheral Neuropathy
The molecule of lenalidomide is structurally similar to the molecule of thalidomide, which is known for its ability to cause severe peripheral neuropathy. Nevertheless, there was no increased incidence of peripheral neuropathy in the long-term use of lenalidomide in the treatment of newly diagnosed MM.
Tumor lysis syndrome
In connection with the pronounced antineoplastic activity of lenalidomide, the development of tumor lysis syndrome is possible, especially in patients with a large tumor mass.These patients should be carefully monitored with appropriate preventive measures.
Allergic reactions
There have been reports of cases of allergic reactions / reactions of hypersensitivity in patients taking lenalidomide (see "Side effect"). Due to the fact that there are scientific publications on possible cross-reactions between lenalidomide and thalidomide, patients with a history of allergic reactions during thalidomide treatment should be carefully monitored.
Severe skin reactions
There are reports of cases of Stevens-Johnson syndrome (SDS) and toxic epidermal necrolysis (TEN). When exfoliative or bullous skin rashes, or suspected development of SDS or TEN, lenalidomide should be discontinued immediately, and treatment should not be resumed after the disappearance of skin manifestations. The need for a break or cancellation of lenalidomide should be considered in case of appearance of other types of skin reactions depending on their severity. Lenalidomide Do not administer to patients who have a history of severe skin reactions with thalidomide.
The development of primary malignant tumors of other localization (PODL)
In clinical trials, a higher incidence of primary malignant tumors was noted in patients previously treated with lenalidomide and dexamethasone (3.98 per 100 patient-years) compared with the control group (1.38 per 100 patient-years). Non-invasive subleases included basal cell carcinoma and squamous cell carcinoma. Most of the invasive podlas were solid tumors.
In clinical trials in patients with newly diagnosed MM who were not shown to have TSCAs who received lenalidomide in combination with melphalan and prednisolone to progression (1.75 per 100 person-years), there was an increase in the incidence of hematologic GAD (acute myelogenous leukemia, myelodysplastic syndrome) by 4.9 times compared with melphalan in combination with prednisolone (0.36 per 100 person -years).
An increase in the incidence of solid PID was 2.12 times in patients who received lenalidomide (9 cycles) in combination with melphalan and prednisolone (1.57 per 100 person-years) compared with melphalan in combination with prednisolone (0.74 per 100 person-years).
In patients who received lenalidomide in combination with dexamethasone to progression or for 18 months, the incidence of hematologic PID did not increase (0.16 per 100 person-years) compared with the use of MAT (0.79 per 100 person-years).
The increase in the incidence of solid PID is 1.3 times in patients who received lenalidomide in combination with dexamethasone to progression or for 18 months (1.58 per 100 person-years) compared with receiving MAT (1.19 per 100 person-years).
In clinical trials in patients with newly diagnosed MM who had been shown to have a TSCT, an increase in the incidence of hematologic GAD was observed in those patients who received lenalidomide immediately after a high dose of melphalan and autologous TSCC, compared to patients receiving placebo (1.27 to 1.56 compared to 0.46 to 0.53 per 100 person-years, respectively). Cases of B-cell malignancies (including Hodgkin's lymphoma) observed in clinical trials were found in patients who received lenalidomide in the period after TSCC.
The risk of developing hematologic GAD should be considered before prescribing Revlimid® in combination with melphalan, and after using a high dose of melphalan and TSCC. Doctors should carefully examine patients using standard diagnostic methods to detect PID before and during therapy. Treatment should be conducted according to generally accepted recommendations.
Disorders from the side of the liver
Hepatic insufficiency, including cases with fatal outcome, was registered in patients who received lenalidomide in the combined therapy: acute hepatic insufficiency, toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis and mixed cytolytic / cholestatic hepatitis. The mechanisms of severe drug hepatotoxicity remain unknown, although in some cases, a previous viral disease of the liver, an initial increase in the activity of liver enzymes, and possibly antibiotic treatment may be a risk factor.
Functional liver abnormalities were often recorded, but they were usually asymptomatic and reversible after discontinuation of therapy.After recovery to baseline, therapy can be resumed at a lower dose. Lenalidomide is excreted by the kidneys. It is important to adjust the dose of the drug in patients with renal insufficiency in order to avoid reaching concentrations in the blood plasma that may increase the risk of hematologic NLR or hepatotoxicity. It is recommended to monitor liver function, especially if there is a concomitant viral disease of the liver or a history of it, or when lenalidomide is used in combination with drugs that cause liver dysfunction.
Patients with newly diagnosed MM
In patients older than 75 years, with stage III according to the international staging system (ISS), with the sum of points on the scale ECOG ≤2 or CC <60 ml / min, a higher level of intolerance was observed (grade 3 or grade 4 NLP, severe NLR, discontinuation of treatment) with lenalidomide in combination. Before the appointment of lenalidomide in combination with other drugs, you should carefully evaluate the tolerability of this therapy in elderly patients, taking into account the age, stage III ISS, ECOG ≤2 or KK <60 ml / min.section "Method of administration and dose" and "Side effect").
Cataract
With a higher frequency, cataracts were noted in patients who received lenalidomide in combination with dexamethasone, especially with prolonged therapy. Regular monitoring of vision is recommended.
Unused Capsules
Patients should be warned that they never give their medication to other patients, and at the end of the course of therapy, unused capsules are returned to the treating doctor.