Mabthera concentrate solution for infusion 500 mg/50 ml 50 ml
Before using MabThera, you should carefully read the instructions and make sure that the dosage form of the drug (“concentrate for solution for infusion” or “solution for subcutaneous administration”) and dosage correspond to those prescribed to the patient. MabThera should only be administered when the necessary conditions for resuscitation are available under the close supervision of an oncologist, hematologist or rheumatologist. MabThera in the dosage form “concentrate for solution for infusion” is not intended for subcutaneous administration! MabThera is administered only intravenously through a separate catheter! It is impossible to administer the drug intravenously as a bolus or bolus! Rules for preparing and storing the solution. The required amount of the drug is taken under aseptic conditions and diluted to the calculated concentration (1-4 mg/ml) in an infusion bottle (bag) with 0.9% sodium chloride solution for infusion or 5% dextrose solution (solutions must be sterile and pyrogen-free). To mix, carefully turn the bottle (package) over to avoid foaming. Before administration, it is necessary to inspect the solution for the absence of foreign impurities or discoloration. The doctor is responsible for the preparation, conditions and storage time of the prepared solution before its use. Since MabThera does not contain preservatives, the prepared solution must be used immediately. The prepared infusion solution of MabThera is physically and chemically stable for 12 hours at room temperature or for no more than 24 hours at a temperature of 2 to 8°C. Standard dosage regimen. Low-grade or follicular non-Hodgkin's lymphoma. Before each use of MabThera, premedication (analgesic/antipyretic, e.g. paracetamol; antihistamine, e.g. diphenhydramine) must be given. If MabThera is not used in combination with chemotherapy containing glucocorticosteroids, glucocorticosteroids are also included in the premedication. Dose adjustment during therapy. It is not recommended to reduce the dose of MabThera. If MabThera is administered in combination with chemotherapy, dose reduction of chemotherapy drugs is carried out according to standard recommendations. Initial therapy: - monotherapy for adult patients: 375 mg/m2 once a week for 4 weeks; - in combination with chemotherapy according to any regimen: 375 mg/m2 on the first day of the chemotherapy cycle after intravenous administration of a glucocorticosteroid as a component of therapy, for: 8 cycles (cycle: 21 days) with the R-CVP regimen (rituximab, cyclophosphamide, vincristine, prednisolone); 8 cycles (cycle: 28 days) with the R-MCP regimen (rituximab, mitoxantrone, chlorambucil, prednisolone); 8 cycles (cycle: 21 days) with the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone); if complete remission is achieved after 4 cycles, it is possible to limit yourself to 6 cycles; 6 cycles (cycle: 21 days) with the R-CHVP-Interferon regimen (rituximab, cyclophosphamide, doxorubicin, teniposide, prednisolone + interferon). Repeated use in case of relapse (in patients who responded to the first course of therapy): 375 mg/m2 once a week for 4 weeks. Maintenance therapy (after response to induction therapy): in previously untreated patients: 375 mg/m2 once every 2 months, not more than 2 years (12 infusions). If signs of disease progression appear, MabThera therapy should be discontinued; for recurrent or chemoresistant lymphoma: 375 mg/m2 once every 3 months, no more than 2 years. If signs of disease progression appear, MabThera therapy should be discontinued. The recommended initial rate of the first infusion is 50 mg/h, subsequently it can be increased by 50 mg/h every 30 minutes, leading to a maximum rate of 400 mg/h. Subsequent infusions can be started at a rate of 100 mg/hour and increased by 100 mg/hour every 30 minutes to a maximum rate of 400 mg/hour. Diffuse large B-cell non-Hodgkin lymphoma. Before each use of MabThera, premedication (analgesic/antipyretic, e.g. paracetamol; antihistamine, e.g. diphenhydramine) must be given. If MabThera is not used in combination with chemotherapy containing glucocorticosteroids, glucocorticosteroids are also included in the premedication. Dose adjustment during therapy. It is not recommended to reduce the dose of MabThera. If MabThera is administered in combination with chemotherapy, dose reduction of chemotherapy drugs is carried out according to standard recommendations. In combination with chemotherapy according to the CHOP regimen: 375 mg/m2 on the first day of each chemotherapy cycle after intravenous administration of a glucocorticosteroid, 8 cycles. The other components of the CHOP regimen (cyclophosphamide, doxorubicin and vincristine) are administered after MabThera is prescribed. The recommended initial rate of the first infusion is 50 mg/h, subsequently it can be increased by 50 mg/h every 30 minutes, leading to a maximum rate of 400 mg/h. Subsequent infusions can be started at a rate of 100 mg/hour and increased by 100 mg/hour every 30 minutes to a maximum rate of 400 mg/hour. Chronic lymphocytic leukemia. Before each use of MabThera, premedication (analgesic/antipyretic, eg paracetamol; antihistamine, eg diphenhydramine) should be given. If MabThera is not used in combination with chemotherapy containing glucocorticosteroids, glucocorticosteroids are also included in the premedication. To reduce the risk of tumor lysis syndrome, prophylactic provision of adequate hydration and administration of uricostatics 48 hours before the start of therapy is recommended. In patients with chronic lymphocytic leukemia and a lymphocyte count >25 thousand/μL, intravenous prednisone/prednisolone 100 mg is recommended 1 hour before MabThera administration to reduce the frequency and severity of acute infusion reactions and/or cytokine release syndrome. Dose adjustment during therapy. It is not recommended to reduce the dose of MabThera. If MabThera is administered in combination with chemotherapy, dose reduction of chemotherapy drugs is carried out according to standard recommendations. In combination with chemotherapy (in patients who have not previously received standard therapy and with relapsed/chemoresistant lymphocytic leukemia): 375 mg/m2 on the first day of the first cycle, then 500 mg/m2 on the first day of each subsequent cycle, 6 cycles. Chemotherapy is given after MabThera is administered. The recommended initial rate of the first infusion is 50 mg/h, subsequently it can be increased by 50 mg/h every 30 minutes, leading to a maximum rate of 400 mg/h. Subsequent infusions can be started at a rate of 100 mg/hour and increased by 100 mg/hour every 30 minutes to a maximum rate of 400 mg/hour. Rheumatoid arthritis. Premedication (analgesic/antipyretic, eg paracetamol; antihistamine, eg diphenhydramine) must be given before each MabThera infusion. In addition, premedication with glucocorticosteroids should be performed to reduce the frequency and severity of infusion reactions. Patients should receive 100 mg methylprednisolone IV 30 minutes before each MabThera infusion. Initial therapy: 1000 mg IV drip, slowly, once every 2 weeks, course - 2 infusions. Repeated use: the need for repeated courses of therapy is recommended to be assessed 24 weeks after the previous course. Repeated use is carried out if there is residual disease activity or if disease activity increases to more than 2.6 according to DAS28-ESR (index of disease activity for 28 joints and erythrocyte sedimentation rate). Repeated courses can be prescribed no earlier than 16 weeks after the previous course. Recommended dosage regimen for repeated use: 1000 mg once every 2 weeks, course – 2 infusions. The recommended initial rate of the first infusion is 50 mg/h, subsequently it can be increased by 50 mg/h every 30 minutes, leading to a maximum rate of 400 mg/h. Infusion time is 4 hours 15 minutes. Subsequent infusions can be started at a rate of 100 mg/hour and increased by 100 mg/hour every 30 minutes to a maximum rate of 400 mg/hour. Infusion time is 3 hours 15 minutes. An alternative regimen for increasing the rate of subsequent infusions in patients with rheumatoid arthritis. If the patient has not previously developed a serious infusion reaction when administered MabThera, an alternative time for subsequent infusions of MabThera diluted to a concentration of 4 mg/ml (250 ml solution) is 120 minutes: during the first 30 minutes the drug is administered at a rate of 250 mg/h, the next 90 minutes - at a rate of 600 mg/h. If well tolerated, infusions lasting 120 minutes can also be recommended for subsequent infusions and courses. An alternative regimen to increase the rate of subsequent infusions should not be used in patients with clinically significant cardiovascular disease, including arrhythmias, or a history of serious infusion reactions to biological agents, including rituximab. Granulomatosis with polyangiitis (Wegener's granulomatosis) and microscopic polyangiitis. Premedication (analgesic/antipyretic, eg paracetamol; antihistamine, eg diphenhydramine) must be given before each MabThera infusion. Recommended Dosing: Corticosteroid therapy is recommended to begin within 2 weeks before the first MabThera infusion or immediately on the day of the first MabThera infusion: methylprednisolone (IV) at a dose of 1000 mg/day for 1 to 3 days, then oral prednisolone at a dose of 1 mg/kg/day (but not more than 80 mg/day) with a gradual reduction in the dose of the latter until complete withdrawal (the rate of dose reduction is determined by the specific clinical situation). Oral corticosteroid therapy may be continued during and after discontinuation of MabThera; Mabthera – 375 mg/m2 once a week for 4 weeks. The recommended initial rate of the first infusion is 50 mg/h, subsequently it can be increased by 50 mg/h every 30 minutes, leading to a maximum rate of 400 mg/h. Subsequent infusions can be started at a rate of 100 mg/hour and increased by 100 mg/hour every 30 minutes to a maximum rate of 400 mg/hour. During and after completion of MabThera therapy in patients with granulomatosis with polyangiitis (Wegener's granulomatosis) and microscopic polyangiitis, prophylaxis against Pneumocystis jiroveci is recommended.
Mabthera®
The following criteria are used to assess the frequency of adverse reactions: very
often >10%, often >1% - <10%, infrequently >0.1% - <1%.
Experience in using the drug for oncohematological diseases
The safety profile of MabThera® in the dosage form “solution for subcutaneous administration” is comparable to the safety profile of MabThera® in the dosage form “concentrate for solution for infusion”. With subcutaneous administration, local skin reactions, including reactions at the injection site, were very common and included pain, swelling, induration, bleeding, erythema, itching and rash. In most cases, the events were mild or moderate in severity.
There were no cases of anaphylaxis or severe hypersensitivity reactions, cytokine release syndrome or tumor lysis syndrome with MabThera® subcutaneous solution dosage form in clinical studies.
Reactions observed with intravenous administration of MabThera® in the dosage form “concentrate for solution for infusion”
Mabthera
®
in the treatment of low-grade or follicular non-Hodgkin's lymphoma - monotherapy/maintenance therapy
Adverse reactions were reported within 12 months after monotherapy and up to 1 month after maintenance therapy with MabThera®.
Infectious and parasitic diseases:
very often - bacterial and viral infections; often - respiratory tract infections*, pneumonia*, sepsis, herpes zoster*, infections accompanied by fever*, fungal infections, infections of unknown etiology.
Blood and lymphatic system disorders:
very often - leukopenia, neutropenia; often - thrombocytopenia, anemia; uncommon - lymphadenopathy, bleeding disorder, transient partial aplastic anemia, hemolytic anemia.
Disorders of the respiratory system, chest and mediastinal organs:
often - rhinitis, bronchospasm, cough, respiratory diseases, shortness of breath, chest pain; uncommon - hypoxia, impaired pulmonary function, bronchiolitis obliterans, bronchial asthma.
Immune system disorders:
very often - angioedema; often - hypersensitivity reactions.
Metabolic and nutritional disorders:
often - hyperglycemia, weight loss, peripheral edema, facial edema, increased lactate dehydrogenase (LDH) activity, hypocalcemia.
General disorders and disorders at the injection site:
very often - headache, fever, chills, asthenia; often - pain in tumor foci, flu-like syndrome, hot flashes, weakness; Uncommon: pain at the injection site.
Gastrointestinal disorders
: very often - nausea; often - vomiting, diarrhea, dyspepsia, lack of appetite, dysphagia, stomatitis, constipation, abdominal pain, sore throat; infrequently - abdominal enlargement.
Cardiovascular system disorders:
often - decreased blood pressure, increased blood pressure, orthostatic hypotension, tachycardia, arrhythmia, atrial fibrillation*, myocardial infarction*, cardiac pathology*; uncommon - left ventricular heart failure*, ventricular and supraventricular tachycardia*, bradycardia, myocardial ischemia*, angina*.
Nervous system disorders:
often - dizziness, paresthesia, hypoesthesia, sleep disturbance, anxiety, agitation, vasodilation; infrequently - perversion of taste.
Mental disorders:
infrequently - nervousness, depression.
Musculoskeletal and connective tissue disorders:
often - myalgia, arthralgia, muscle hypertonicity, back pain, neck pain, pain.
Disorders of the skin and subcutaneous tissues:
very often - itching, rash; often - urticaria, increased sweating at night, sweating, alopecia*.
Visual disorders:
often - lacrimation disorders, conjunctivitis.
Hearing and labyrinthine disorders:
often - pain and tinnitus.
Laboratory and instrumental data:
very often - a decrease in the concentration of immunoglobulin G (IgG).
- The frequency is indicated only for adverse reactions of >3 severity in accordance with the National Cancer Institute toxicity criteria (NCI-CTC).
Mabthera
®
in combination with chemotherapy ( CHOP , C V P, FC ) for non-Hodgkin's lymphoma and chronic lymphocytic leukemia
The following are severe adverse reactions in addition to those observed with monotherapy/maintenance therapy and/or occurring with a higher frequency.
Infectious and parasitic diseases:
very often - bronchitis; often - acute bronchitis, sinusitis, hepatitis B* (reactivation of the hepatitis B virus and primary infection).
Blood and lymphatic system disorders:
very often - neutropenia**, febrile neutropenia, thrombocytopenia;
often - pancytopenia, granulocytopenia. Disorders of the skin and subcutaneous tissues:
very often - alopecia; often - skin diseases.
General disorders and disorders at the injection site:
often - fatigue, chills.
— the frequency is indicated based on observations during the treatment of relapsed/chemoresistant chronic lymphocytic leukemia according to the R-FC regimen (rituximab, fludarabine, cyclophosphamide).
** Prolonged and/or delayed neutropenia has been observed after completion of R-FC therapy in previously untreated patients or in patients with relapsed/chemoresistant chronic lymphocytic leukemia.
The following are adverse events that occurred during MabThera therapy with the same frequency (or less frequently) compared to the control group: hematotoxicity, neutropenic infections, urinary tract infections, septic shock, pulmonary superinfections, implant infections, staphylococcal septicemia, mucous nasal discharge, pulmonary edema, heart failure, sensory disturbances, venous thrombosis, incl. deep vein thrombosis of the extremities, mucositis, edema of the lower extremities, decreased left ventricular ejection fraction, increased body temperature, deterioration of general health, fall, multiple organ failure, bacteremia, decompensation of diabetes mellitus.
The safety profile of MabThera in combination with MCP, CHVP-IFN chemotherapy regimens does not differ from that in combination with CVP, CHOP or FC in appropriate populations.
Reactions associated with drug administration
Monotherapy with MabThera
®
(for 4 weeks)
More than 50% of patients experienced events resembling infusion reactions, most often during the first infusions. Infusion reactions include chills, trembling, weakness, shortness of breath, nausea, rash, hot flashes, low blood pressure, fever, itching, urticaria, irritation of the tongue or swelling of the larynx (angioedema), rhinitis, vomiting, pain in tumor areas, headache pain, bronchospasm. The development of signs of tumor lysis syndrome has been reported.
Mabthera
®
in combination with chemotherapy according to the following regimens: R - CVP (rituximab, diclophosphamide, vincristine, prednisolone) for non-Hodgkin's lymphoma; R - CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) for diffuse large B-cell non-Hodgkin lymphoma.
Grade 3 and 4 infusion reactions during infusion or within 24 hours after infusion of MabThera® were observed during the first cycle of chemotherapy in 12% sick. The incidence of infusion reactions decreased with each subsequent cycle and by the 8th cycle of chemotherapy, the incidence of infusion reactions was less than 1%. Infusion reactions, in addition to those mentioned above (with MabThera monotherapy), included: dyspepsia, rash, increased blood pressure, tachycardia, signs of tumor lysis syndrome, in some cases - myocardial infarction, atrial fibrillation, pulmonary edema and acute reversible thrombocytopenia.
Infections
Monotherapy with MabThera
®
(for 4 weeks)
MabThera® causes B-cell depletion in 70-80% of patients and a decrease in serum immunoglobulin concentrations in a small number of patients. Bacterial, viral, fungal infections and infections of unspecified etiology (all, regardless of cause) develop in 30.3% of patients. Severe infections (grades 3 and 4), including sepsis, were noted in 3.9% of patients.
Maintenance therapy (non-Hodgkin's lymphoma) up to 2 years
An increase in the overall incidence of infections, including grade 3-4 infections, was observed during MabThera therapy. There was no increase in the incidence of infectious complications with maintenance therapy lasting 2 years. Fatal progressive multifocal leukoencephalopathy (PML) has been reported in patients with non-Hodgkin's lymphoma after disease progression and re-treatment.
Mabthera
® in
combination with chemotherapy according to the following regimens: R - CVP for non-Hodgkin's lymphoma; R - CHOP for diffuse large B-cell non-Hodgkin's lymphoma
There was no increase in the incidence of infections or invasions when treated with MabThera® according to the R-CVP regimen. Upper respiratory tract infections were most common (12.3% in the R-CVP group). Serious infections occurred in 4.3% of patients receiving R-CVP chemotherapy; No life-threatening infections were reported. The proportion of patients with grade 2-4 infections and/or febrile neutropenia in the R-CHOP group was 55.4%. The total incidence of grade 2-4 infections in the R-CHOP group was 45.5%. The incidence of grade 2-4 fungal infections in the R-CHOP group was higher than in the CHOP group due to a higher incidence of local candidiasis and amounted to 4.5%. The incidence of grade 2-4 herpes infection was higher in the R-CHOP group compared to the CHOP group and amounted to 4.5%.
From the blood system
Monotherapy with MabThera
®
(for 4 weeks)
Severe thrombocytopenia (grade 3 and 4) was observed in 1.7% of patients, severe neutropenia - in 4.2% of patients, severe anemia (grade 3 and 4) - in 1.1% of patients.
Maintenance therapy (non-Hodgkin's lymphoma) up to 2 years
Leukopenia (grades 3 and 4) was observed in 5% of patients, neutropenia (grades 3 and 4) - in 10% of patients receiving MabThera®. The incidence of thrombocytopenia (grade 3-4) during MabThera therapy was low and amounted to <1%.
Approximately 50% of patients for whom B-cell recovery data were available took 12 months or more to recover B-cell counts to normal levels after completion of induction therapy with MabThera.
Mabthera
®
in combination with chemotherapy according to the following regimens: R - CVP for non-Hodgkin's lymphoma: R - CHOP for diffuse large B-cell non-Hodgkin's lymphoma
Severe neutropenia and leukopenia (grades 3 and 4):
in patients receiving
MabThera® in combination with chemotherapy, grade 3 and 4 leukopenia was observed more often compared to patients receiving chemotherapy alone. The incidence of severe leukopenia was 88% in patients receiving R-CHOP. The incidence of severe neutropenia was 24% in the R-CVP group, 97% in the R-CHOP group. The higher incidence of neutropenia in patients receiving MabThera 5 and chemotherapy was not associated with an increased incidence of infections and infestations compared with patients receiving chemotherapy alone.
Severe anemia and thrombocytopenia (grades 3 and 4):
There was no significant difference in the incidence of anemia and thrombocytopenia of grades 3 and 4 in the groups.
From the cardiovascular system
Monotherapy with MabThera
®
(for 4 weeks)
Side effects from the cardiovascular system were noted in 18.8%. The most common symptoms are low and high blood pressure. In isolated cases, cardiac arrhythmias of grade 3 and 4 were observed (including ventricular and supraventricular tachycardia) and angina pectoris.
Maintenance therapy (non-Hodgkin's lymphoma) up to 2 years
The incidence of grade 3 and 4 cardiovascular events was similar in patients receiving MabThera® and those not receiving it. Serious cardiovascular events occurred in less than 1% of patients not receiving MabThera® and in 3% of patients receiving the drug (atrial fibrillation in 1%, myocardial infarction in 1%, left ventricular failure in <1%, myocardial ischemia in < 1%).
Mabtersg in combination with chemotherapy according to the following regimens: R - CVP
for non-Hodgkin's lymphoma: R - CHOP for diffuse large B-cell non-Hodgkin's lymphoma
Frequency of heart rhythm disturbances of grade 3 and 4, mainly supraventricular arrhythmias (tachycardia, flutter and atrial fibrillation), in the R-CHOP group was higher than in the CHOP group and amounted to 6.9%. All arrhythmias developed either in connection with the infusion of MabThera® or were associated with predisposing conditions such as fever, infection, acute myocardial infarction or concomitant diseases of the respiratory and cardiovascular systems. The R-CHOP and CHOP groups did not differ in the incidence of other grade 3 and 4 cardiac adverse events, including heart failure, myocardial disease, and manifestation of coronary artery disease.
Nervous system
MabThera ®
in combination with chemotherapy according to the following regimens: R - CVP for non-Hodgkin's lymphoma; R - CHOP for diffuse large B-cell non-Hodgkin's lymphoma
Patients (2%) in the R-CHOP group with cardiovascular risk factors developed thromboembolic cerebrovascular accidents during the first cycle of therapy, in contrast to patients in the CHOP group who had cerebrovascular accidents. blood circulations developed during the observation period without treatment. There was no difference between groups in the incidence of other thromboembolism.
IgG
concentration Maintenance therapy (non-Hodgkin's lymphoma) up to 2 years
After induction therapy, IgG concentrations were below the lower limit of normal (<7 g/L) in the MabThera-treated and untreated groups. In the group not receiving MabThera®, the median IgG concentration increased consistently and exceeded the lower limit of normal, while the median IgG concentration did not change in the group receiving MabThera®. In 60% of patients treated with MabThera ®
over a period of 2 years, IgG concentrations remained below the lower limit.
In the group without treatment with MabThera ®
after 2 years, the IgG concentration remained below the lower limit in 36% of patients.
Special categories of patients
Monotherapy with MabThera ®
(for 4 weeks)
Elderly
(>65 years): The frequency and severity of all adverse reactions and grade 3 and 4 adverse reactions does not differ from that in younger patients.
Combination therapy
High tumor burden
(diameter of single lesions more than 10 cm): increased frequency of adverse reactions of grade 3 and 4.
Repeat therapy
: the frequency and severity of adverse reactions do not differ from those during initial therapy.
Post-registration use of MabThera® in the dosage form “concentrate for solution for infusion” for non-Hodgkin’s lymphoma and chronic lymphocytic leukemia
From the cardiovascular system:
severe cardiovascular events associated with infusion reactions, such as heart failure and myocardial infarction, mainly in patients with a history of cardiovascular disease and/or receiving cytotoxic chemotherapy; very rarely - vasculitis,
predominantly cutaneous (leukocytoclastic).
From the respiratory system:
respiratory failure and pulmonary infiltrates caused by infusion reactions; In addition to pulmonary adverse events due to infusion reactions, interstitial lung disease, in some cases fatal, has been observed.
From the circulatory and lymphatic system:
reversible acute thrombocytopenia associated with infusion reactions.
From the skin and its appendages
: rarely - severe bullous reactions, including toxic epidermal necrolysis and Stevens-Johnson syndrome, in some cases fatal.
From the nervous system
: rarely - neuropathy of the cranial nerves in combination with peripheral neuropathy or without it (marked decrease in visual acuity, hearing, damage to other sensory organs, paresis of the facial nerve) during various periods of therapy up to several months after completion of treatment with MabThera®. Posterior reversible encephalopathy syndrome (PRES)/cHHapoMa posterior reversible leukoencephalopathy syndrome (PRLS) have been reported in patients treated with MabThera. Symptoms included blurred vision, headache, seizures and mental disturbances, with or without increased blood pressure. The diagnosis of PRES/PRLS can be confirmed using brain imaging techniques. In the cases described, patients had risk factors for developing PRES/PRLS, such as underlying disease, hypertension, immunosuppressive therapy and/or chemotherapy.
From the body as a whole, reactions at the injection site
: rarely - serum sickness.
Infections:
reactivation of the hepatitis B virus (in most cases with a combination of MabThera® and cytotoxic chemotherapy); as well as other severe viral infections (primary infection, viral reactivation or exacerbation), some of which were fatal, caused by cytomegalovirus, Varicella Zoster, Herpes simplex, JC polyomavirus (PML), hepatitis C virus.
When MabThera® was prescribed for indications not covered by the instructions for medical use, sarcoma progression was observed in patients with previously diagnosed Kaposi's sarcoma (most patients were HIV-positive).
From the gastrointestinal tract:
perforation of the stomach and/or intestines (possibly fatal) when MabThera® is combined with chemotherapy for non-Hodgkin's lymphoma.
From the blood and lymphatic system:
rarely - neutropenia that occurred 4 weeks after the last administration of rituximab; a transient increase in IgM concentration in patients with Waldenström's macroglobulinemia, followed by a return to its original value after 4 months.
