Lenalidomide Capsules Instructions

Date of approval.
Date of revision.
Lenalidomide capsules instructions
Warning.
Embryo-fetal toxicity, hematologic toxicity, and venous and arterial thrombosis
Embryo-fetal toxicity
Do not use this product during pregnancy. Lenalidomide is an analogue of thalidomide, which has been shown to cause limb malformations in developmental studies in monkeys. Thalidomide is known to be teratogenic in humans and can cause serious life-threatening human birth defects. Lenalidomide may cause birth defects or embryo-fetal death in the fetus if used during pregnancy. Women who may become pregnant should have 2 pregnancy tests prior to initiating treatment with this product and both tests must be negative, and should use two methods of contraception or remain free of sexual relations with the opposite sex both during and for 4 weeks after treatment (see [PRECAUTIONS] and [MEDICATION FOR PREGNANT AND BREAST-FEEDING WOMEN]).
Hematologic Toxicity (Neutropenia and Thrombocytopenia)
This product causes significant neutropenia and thrombocytopenia. Patients may require dose suspension and/or downward dose adjustment. Patients may also need to receive blood products and/or growth factors (see [DOSAGE AND ADMINISTRATION] and [PRECAUTIONS]).
Deep Vein Thrombosis and Pulmonary Embolism
In patients with multiple myeloma treated with this product and dexamethasone, it has been shown to significantly increase the risk of deep vein thrombosis (DVT), and pulmonary embolism (PE), myocardial infarction, and stroke. Signs and symptoms of thromboembolism should be monitored, and patients should be given appropriate instructions and advice. Advise patients to seek immediate medical attention if they develop symptoms (e.g., shortness of breath, chest pain, swelling in the arms or thighs). Thromboprophylaxis is recommended and the dosing regimen should be evaluated based on the patient’s potential risk factors. (See [Adverse Reactions] and [Precautions])
 
 
 Drug Name]
Generic Name: Lenalidomide Capsules
English name: Lenalidomide Capsules
Hanyu Pinyin: Lainadu’an Jiaonang
Ingredients
The main ingredient of this product is: Lenalidomide.
Chemical name: 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione
Chemical structure formula.
Molecular formula: C13H13N3O3
Molecular weight: 259.26
Properties
This product is a hard capsule, the contents are white or off-white powder.
Indications】
This product is used in combination with dexamethasone to treat adult patients with previously untreated multiple myeloma who are unsuitable for transplantation.
This product is used in combination with dexamethasone to treat adult patients with multiple myeloma who have received at least one previous therapy.
Specification
25mg
Dosage]
Therapeutic dosing must be initiated and provided under the supervision of a physician experienced in the treatment of multiple myeloma.
This product should not be initiated if the patient has an absolute neutrophil count (ANC) <1.0 × 109/L, and/or a platelet count <50 × 109/L.
Recommended Dose
The recommended starting dose of dexamethasone is 25 mg orally daily on days 1 to 21 of each repeated 28-day cycle until disease progression. The recommended dose of dexamethasone is 40 mg orally on days 1, 8, 15, and 22 of each 28-day treatment cycle. The prescriber should select the starting dose of dexamethasone and subsequent dose adjustments based on the patient’s age (see Table 1).
Table 1: Starting dose of dexamethasone by age
Age ≤ 75 years Age > 75 years Dexamethasone: 40 mg/day orally every 28-day cycle on days 1, 8, 15, and 22 Dexamethasone: 20 mg/day orally every 28-day cycle on days 1, 8, 15, and 22
 Dosing method
This product should be taken at approximately the same time each day. The capsule should not be opened, broken or chewed, but swallowed whole, preferably with water, with food or on an empty stomach. If a dose is missed by less than 12 hours, the patient may make up the dose. If a missed dose is greater than 12 hours, the patient should not take the next dose at the normal dosing time the next day. Do not take a 2-day dose at the same time because of a missed dose.
Recommended dose adjustments during treatment and at restart of treatment
Untreated and unsuitable for transplantation multiple myeloma
Lenalidomide is used in combination with dexamethasone to treat patients with multiple myeloma who are not candidates for transplantation until disease progression.
Dose adjustments are recommended in the event of grade 3 or 4 thrombocytopenia or neutropenia, or other grade 3 or 4 toxicities associated with lenalidomide, with the following dose adjustment regimen.
Dose downward adjustment steps
Dose level Lenalidomide a Dexamethasone a Starting dose 25 mg 40 mg Dose level – 120 mg 20 mg Dose level – 215 mg 12 mg Dose level – 310 mg 8 mg Dose level – 45 mg 4 mg Dose level – 55 mg Every other day NAa Dose downward adjustment can be made separately for both drugs
Thrombocytopenia
When the platelet count falls to < 25 x 109/L for the remainder of the recommended course of therapy, treatment with this drug needs to be suspended. b Return to ≥ 50 x 109/L When treatment resumes in the next cycle, reduce the dose level of lenalidomide by one dose level for treatment with this drug. b If dose-limiting toxicity (DLT) occurs after day 15 of a treatment cycle, suspend dosing for at least the remaining days of that 28-day cycle.
Neutropenia
Suspend therapy when neutrophils fall to < 0.5 x 109/L for the first time in the recommended course of therapy. Resume once-daily treatment with this product at the starting dose when recovery to ≥1×109/L and neutropenia is the only toxicity observed. Recovery to ≥0.5×109/L but dose-dependent hematologic toxicity observed in addition to neutropenia Restart once-daily treatment at dose level-1. Subsequent reductions to <0.5×109/L each time suspended this treatment. Return to ≥0.5 x 109/L and restart once-daily treatment at the lower dose level. In the event of hematologic toxicity, the lenalidomide dose may be reinstated to the next higher dose level if continued lenalidomide/dexamethasone therapy results in improved bone marrow function (at least two consecutive cycles without hematologic toxicity and at the start of a new cycle with the current dose level, ANC ≥ 1.5 × 109/μL and platelet count ≥ 100 × 109/μL) (no more than starting dose).
Multiple myeloma who have received at least one previous therapy
The recommended dose adjustments in the event of grade 3 or 4 neutropenia or thrombocytopenia, or other grade 3 or 4 toxicities judged to be associated with lenalidomide, are summarized below.
Dose downward adjustment steps
Dose level c Starting dose of lenalidomide for days 1 to 21 of each 28-day cycle Day 1 to 21, 25 mg/day Dose down level-1 Day 1 to 21, 20 mg/day Dose down level-2 Day 1 to 21, 15 mg/day Dose down level-3 Day 1 to 21, 10 mg/day Dose down level-4 Day 1 to 21, 5 mg/day c Should be based on the starting dose level of lenalidomide The dose reduction step should be implemented gradually based on the starting dose level of lenalidomide. For example, if the starting dose level is already 15 mg, a dose step down to the next dose level should be followed if a lower dose is needed (i.e., a starting dose level of 15 mg [Dose Step Down Level-2] should be followed to 10 mg [Dose Step Down Level-3]).
The dose adjustment regimen for lenalidomide was previously used in a clinical trial in Chinese patients (MM-021), and the dose of lenalidomide was adjusted accordingly when the patient developed some grade 3 or 4 hematologic toxicity as described below. If the dose is adjusted downward for hematologic toxicity, the treating physician may adjust the dose back to a higher dose level (up to the starting dose) based on his or her judgment of recovery of bone marrow function.
Platelet count
Recommended Dose Adjustment for Thrombocytopenia
When the platelet count falls to < 25 × 109/L for the first time in the recommended course of therapy, treatment is suspended for the remainder of the cycle. When treatment resumes in the next cycle, reduce the dose of lenalidomide by one dose level. Thereafter, suspend treatment for the remainder of the treatment cycle whenever the dose drops to < 25 × 109/L.
 Restart once-daily treatment at a lower dose level (dose reduction level -1, -2 or -3). The dose administered every other day should not be less than 5 mg.
 Absolute Neutrophil Count (ANC)
Recommended Dose Adjustment in Neutropenia
When the recommended neutrophil regimen drops to < 0.5 × 109/L, or (temperature ≥ 38.5°C and ANC < 1 × 109/L) the remainder of the treatment cycle requires suspension of this product and weekly check of the complete blood count. If the event occurs within the first 15 days of a treatment cycle and has improved, once-daily treatment may be restarted after 7 days of discontinuation of the drug. If the event occurs after day 15 of a treatment cycle, dosing is suspended for at least the remaining days of that 28-day cycle.
On the first day of the next treatment cycle, if neutrophils are the only dose-limiting toxicity and GCSF therapy is continued, the dose of lenalidomide may be maintained. Otherwise, at the start of the next cycle of therapy, lenalidomide should be reduced by one dose level. Thereafter, lenalidomide should be suspended for the remainder of the treatment cycle whenever it falls to <0.5 × 109/L. Once-daily treatment may be restarted at a lower dose level (dose reduction level -1, -2, or -3). If neutropenia develops, the physician should consider treating the patient with growth factors (G-CSF).
 Start a new cycle of lenalidomide in combination with low-dose dexamethasone (after cycle 1).
Lenalidomide-related dose-limiting toxicity must have resolved or improved
ANC must be ≥ 1,000/mL and platelet count must be ≥ 50,000/mL
Other grade 3/4 toxicities in patients with multiple myeloma
If a grade 3/4 toxic reaction associated with this product occurs, treatment is suspended for the remainder of the cycle until 7 days after lenalidomide is discontinued and the toxic reaction resolves (occurs ≤ 15 days into a treatment cycle) and once-daily treatment is restarted for that cycle; if the toxic reaction occurs > 15 days into a cycle, then lenalidomide is suspended for the remaining days of the current 28-day treatment cycle . Dosing will be reduced by one dose level when the physician determines that dosing can be resumed in the next cycle.
Dosing in Patients with Hepatic Insufficiency
This product has not been formally studied in patients with hepatic insufficiency and no specific dosing recommendations are available for this population. Lenalidomide is not thought to be metabolized by the liver; unmetabolized lenalidomide is primarily cleared by the renal route.
Dosing in Patients with Renal Insufficiency
This product is primarily excreted by the kidneys; patients with more severe renal insufficiency may not tolerate treatment and therefore dose selection should be made with caution and renal function should be monitored.
 No dose adjustment is required in patients with creatinine clearance (CLcr) ≥ 60 mL/min. For patients with creatinine clearance <60 mL/min at the start of therapy, the following dose adjustments are recommended for lenalidomide.
Table 2: Starting dose of lenalidomide according to renal function status
Renal function d Lenalidomide dose Creatinine clearance ≥ 60 mL/min Lenalidomide: every 28-day cycle, days 1 to 21.
25 mg/day orally. Creatinine clearance ≥ 30 mL/min but < 60 mL/min Lenalidomide: 10 mg/day orally every 28-day cycle, days 1 to 21e. Creatinine clearance < 30 mL/min without dialysis Lenalidomide: 15 mg/day orally every 28-day cycle, every other day (i.e., days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21) for 3 weeks. day, for 3 weeks of treatment. Creatinine clearance< 30 mL/min, requiring dialysis
Lenalidomide: every 28-day cycle, days 1 to 21.
5 mg/day orally. On the day of dialysis treatment, it should be given orally at the end of dialysis. d
Calculate creatinine clearance according to the Cockcroft-Gault formula or measure creatinine clearance.
e If the patient can tolerate a 10 mg dose of lenalidomide without drug toxicity, the treating physician may decide to increase the 10 mg dose to 15 mg after cycle 2. See Dose Down Procedure above and Table 3 Dose Down Procedure for Patients with Renal Insufficiency.
Dose Adjustment for Patients with Severe Renal Insufficiency (Creatinine Clearance < 30 mL/min and not requiring dialysis)
The recommended starting dose for patients with severe renal insufficiency (creatinine clearance< 30 mL/min) is lenalidomide 15 mg every other day from day 1 to day 21 of a 28-day cycle. if Grade 3/4 toxicities occur as described above, dose of lenalidomide is adjusted downward according to the following steps.
Table 3:Lenalidomide dose downward adjustment steps for patients with severe renal insufficiency (alternate-day dosing regimen) (creatinine clearance < 30 mL/min and no dialysis required)
Dose level Lenalidomide dose starting dose on days 1 to 21 of each 28-day cycle 15 mg on alternate days 1 to 21 Dose step-down level-1 10 mg on alternate days 1 to 21 Dose step-down level-2 5 mg on alternate days 1 to 21
 Patients with moderate or severe renal insufficiency immediately prior to treatment (day 1 of the first cycle) whose creatinine clearance improves during treatment may be appropriately dosed, based on the physician’s judgment, if continued treatment with lenalidomide in combination with dexamethasone results in improvement in myelopoietic function (no dose-limiting toxicity for at least 2 consecutive cycles and at the current dose level at the start of a new cycle) ANC ≥ 1,500/μL and platelet count ≥ 100,000/μL), the dose may be adjusted upward to an appropriate level (see Table 2).
Discontinuation of Dosing
Patients who have experienced grade 4 rash with prior thalidomide use should avoid this product. If grade 2 to 3 rash occurs, suspension or discontinuation of the drug should be considered. If angioedema, grade 4 rash, exfoliative or maculopapular rash, or suspected Stevens-Johnson syndrome (SJS), toxic necrolytic epidermolysis bullosa (TEN), and drug reactions with eosinophilia and systemic symptoms (DRESS) occur, the drug must be discontinued and should not be restarted after these reactions resolve.
[Adverse Reactions].
Summary of Safety Data in Previously Untreated Patients With Multiple Myeloma Who Are Not Suitable for Transplantation (MM-020)
In a large randomized, multicenter, 3-arm, open phase III study (MM-020) including 1623 patients, patients in two groups received at least one dose of lenalidomide plus low-dose dexamethasone (Rd) for different durations (one group continued dosing until disease progression [Rd continuous group; N=532], and the other group was given 18 cycles (one every 28 days) [72 weeks, N=532]. The median duration of treatment in the Rd continuous group was 80.2 weeks (range 0.7 to 246.7 weeks) or 18.4 months (0.16 to 56.7 months).
Overall, the most common adverse reactions reported in both the Rd continuous and Rd 18 groups were similar and included diarrhea, anemia, constipation, peripheral edema, neutropenia, fatigue, back pain, nausea, malaise, and insomnia. The most frequently reported grade 3 or 4 adverse reactions included neutropenia, anemia, thrombocytopenia, pneumonia, malaise, back pain, hypokalemia, rash, cataracts, lymphopenia, dyspnea, deep vein thrombosis, hyperglycemia, and leukopenia. The incidence of infection was highest in the Rd persistent group (75%) compared to the MPT group (56%). the incidence of grade 3, grade 4 and serious adverse reactions was higher in the Rd persistent group than in the MPT or Rd 18 groups.
In the Rd persistent group, infection (28.8%) was the most common adverse reaction leading to lenalidomide dose suspension; overall, the median time to first lenalidomide dose suspension was 7 weeks. in the Rd persistent group, hematologic events (10.7%) were the most common adverse reaction leading to lenalidomide dose downward adjustment; overall, the median time to first lenalidomide dose downward adjustment was 16 weeks. In the Rd persistence group, infection (3.4%) was the most common adverse event leading to lenalidomide discontinuation.
With the exception of cataract, the frequency of adverse events in both Rd groups was generally highest in the first 6 months of the treatment period and then decreased over time or remained stable throughout the treatment course. In contrast, the frequency of cataracts increased over time, ranging from 0.7% in the Rd sustained group during the first 6 months to as high as 9.6% by the second year of treatment.
The adverse reactions reported in the Rd continuous group, Rd 18 group, and MPT group are summarized in Table 4.
Table 4: All adverse reactions with an incidence of ≥5.0% and ≥1.0% grade 3/grade 4 adverse reactions* in the Rd continuous group or Rd 18 group
Body system/adverse reactions All adverse reactionsa Grade 3/grade 4 adverse reactionsb Rd sustained (N = 532)Rd 18 (N = 540)MPT (N = 541)Rd sustained (N = 532)Rd 18 (N = 540)MPT (N = 541)Systemic disease and administration site condition fatigue %173 (32.5)177 (32.8)154 ( 28.5)39 (7.3)46 (8.5)31 (5.7)malaise150 (28.2)123 (22.8)124 (22.9)41 (7.7)33 (6.1)32 (5.9)feverc114 (21.4)102 (18.9)76 (14.0)13 (2.4)7 (1.3)7 (1.3)non-cardiogenic chest pain f29 (5.5)31 (5.7)18 (3.3)< 1%< 1%< 1%Gastrointestinal disordersDiarrhea242 (45.5)208 (38.5)89 (16.5)21 (3.9)18 (3.3)8 (1.5)Abdominal pain%, f109 (20.5)78 (14.4)60 (11.1)7 (1.3)9 (1.7)< 1% dyspepsiaf57 (10.7)28 (5.2)36 (6.7)< 1%< 1%0 (0.0)Skeletal muscle and connective tissue disordersBack painc170 (32)145 (26.9)116 (21.4)37 (7)34 (6.3)28 (5.2)Muscle spasmsf109 (20.5)102 (18.9)61 (11.3)< 1%< 1%< 1%< 1% joint painf101 (19.0)71 (13.1)66 (12.2)9 (1.7)8 (1.5)8 (1.5)bone painf87 (16.4)77 (14.3)62 (11.5)16 (3.0)15 (2.8)14 (2.6)limb painf79 (14.8)66 (12.2)61 (11.3)8 (1.5)8 (1.5)7 (1.3)Musculoskeletal painf67 (12.6)59 (10.9)36 (6.7)< 1%< 1%< 1%< 1%Chest pain of musculoskeletal originf60 (11.3)51 (9.4)39 (7.2)6 (1.1)& lt; 1%< 1% muscle weaknessf43 (8.1)35 (6.5)29 (5.4)< 1%8 (1.5)< 1% neck painf40 (7.5)19 (3.5)10 (1.8)< 1%< 1%< 1%< 1% infection and infectious bronchitisc90 (16.9)59 (10.9)43 (7.9)9 (1.7)6 (1.1)3 (0.6)Nasopharyngitisf80 (15)54 (10)33 (6.1)0 (0.0)0 (0.0)0 (0.0)0 (0.0)Urinary tract infectionsf76 (14.3)63 (11.7)41 (7.6)8 (1.5)8 (1.5)< 1% Upper respiratory tract infectionsc,%, f69 (13.0)53 (9.8) 31 (5.7)< 1%8 (1.5)< 1% pneumoniac,@93 (17.5)87 (16.1)56 (10.4)60 (11.3)57 (10.5)41 (7.6)Respiratory infections%35 (6.6)25 (4.6)21 ( 3.9)7 ( 1.3)4 ( 0.7)1 ( 0.2)Influenzaf33 ( 6.2)23 (4.3)15 (2.8)< 1%< 1%0 (0.0)gastroenteritisf32 (6.0)17 (3.1)13 (2.4)0 (0.0)< 1%< 1%lower respiratory tract infections29 (5.5)14 (2.6)16 (3.0)10 (1.9)3 (0.6)3 (0.6)rhinitisf29 ( 5.5)24 ( 4.4)14 ( 2.6)0 (0.0)0 (0.0)0 (0.0)0 (0.0)cellulitisc< 5%< 5%< 5%< 5%8 (1.5)3 ( 0.6)2 ( 0.4)sepsisc,@33 (6.2)26 (4.8)18 (3.3)26 (4.9)20 (3.7)13 (2.4)neurological Disease headachef75 (14.1)52 (9.6)56 (10.4)< 1%< 1%< 1%< 1% taste disorderf39 (7.3)45 (8.3)22 (4.1)< 1%0 (0.0)< 1% blood and lymphatic system disordersd anemia233 (43.8)193 (35.7)229 (42.3) 97 (18.2)85 (15.7)102 (18.9)Neutropenia186 (35.0)178 (33)328 (60.6)148 (27.8)143 (26.5)243 (44.9)Thrombocytopenia104 (19.5)100 (18.5)135 (25.0)44 (8.3)43 (8.0) 60 (11.1)Neutropenia with fever7 (1.3)17 (3.1)15 (2.8)6 (1.1)16 (3.0)14 (2.6)Holocytopenia5 (0.9)6 (1.1)7 (1.3)1 (0.2)3 (0.6)5 (0.9)Respiratory, thoracic and mediastinal disease coughf121 (22.7)94 ( 17.4)68 (12.6)< 1%< 1%< 1% Respiratory distressc,e117 (22.0)89 (16.5)113 (20.9)30 (5.6)22 (4.1)18 (3.3)Rhinorrheaf32 (6.0)31 (5.7)17 (3.1)< 1%< 1%0 (0.0)Mouth pharyngeal painf30 (5.6)22 (4.1)14 (2.6)0 (0.0)0 (0.0)0 (0.0)0 (0.0)Exertional dyspneae27 (5.1)29 (5.4)< 5%6 (1.1)2 (0.4)0 (0.0)Metabolic and nutritional disordersLoss of appetite123 (23.1)115 (21.3)72 (13.3)14 ( 2.6)7 (1.3)5 (0.9)Hypokalemia%91 (17.1)62 (11.5)38 ( 7)35 (6.6)20 (3.7)11 (2.0)Hyperglycemia62 (11.7)52 (9.6)19 (3.5)28 (5.3)23 (4.3)9 (1.7)Hypocalcemia57 (10.7)56 (10.4) 31 (5.7)23 (4.3)19 (3.5)8 (1.5)dehydration%25 ( 4.7)29 ( 5.4)17 ( 3.1)8 (1.5)13 (2.4)9 (1.7)goute< 5%< 5%< 5%8 (1.5)0 (0.0)0 (0.0)diabetes%, e< 5%< 5%&lt ; 5%8 (1.5)4 (0.7)2 (0.4)Hypophosphatemiae< 5%< 5%< 5%< 5%7 (1.3)3 (0.6)1 (0.2)Hyponatremia% ,e< 5%< 5%< 5%< 5%7 (1.3)13 (2.4)6 (1.1)Skin and subcutaneous tissue disordersRash139 (26.1)151 ( 28.0)105 (19.4)39 (7.3)38 (7.0)33 (6.1)Pruritusf47 (8.8)49 (9.1)24 (4.4)< 1%< 1%< 1%< 1% Psychiatric disorders Insomnia147 (27.6)127 (23.5)53 (9.8)4 (0.8)6 (1.1)0 (0.0)Depression58 (10.9)46 (8.5)30 (5.5)10 (1.9)4 (0.7)1 (0.2)Vascular disease deep vein thrombosisc,%55 (10.3)39 (7.2)22 (4.1)30 (5.6)20 (3.7)15 (2.8)Hypotensionc,%51 (9.6)35 (6.5)36 (6.7)11 (2.1)8 (1.5)6 (1.1)Injury, poisoning and surgical complications Fallsf43 (8.1)25 (4.6)25 (4.6)< 1%6 (1.1)6 (1.1)Contusionsf33 (6.2)24 (4.4)15 (2.8)< 1%< 1%0 (0.0)Ocular disease Cataracts73 (13.7)31 (5.7)5 ( 0.9)31 (5.8)14 (2.6)3 (0.6)Subcapsular cataracte< 5%< 5%< 5%< 5%7 (1.3)0 (0.0)0 (0.0)Examination Weight loss72 (13.5)78 (14.4)48 (8.9)11 (2.1)4 (0.7)4 (0.7)Cardiac disease Atrial fibrillationc37 (7.0)25 (4.6)25 (4.6)13 (2.4)9 (1.7)6 (1.1)Myocardial infarction (including acute)c ,e< 5%< 5%< 5%< 5%10 (1.9)3 (0.6)5 (0.9)Renal and urologic diseasesRenal failure (including acute)c,@,f49 (9.2)54 (10.0)37 (6.8)28 (5.3 )33 (6.1)29 (5.4)Benign, malignant, and tumors of unknown nature (including cystic and polypoid) squamous cell carcinomac, e< 5%< 5%< 5%< 5%8 (1.5)4 (0.7)0 (0.0)Basal cell carcinomac, e,f< 5%< 5%< 5%< 1%< 1%0 (0.0)Note. Subjects with multiple occurrences of a particular adverse reaction were counted only once under the appropriate body system/adverse reaction.
a Adverse reactions that occurred in at least 5.0% of subjects in the Rd continuous group or Rd 18 group and that occurred at least 2.0% more frequently in either the Rd continuous or Rd 18 group than in the MPT group for all treatments.
b Adverse reactions occurring in at least 1.0% of subjects in the Rd continuous group or Rd 18 group and at least 1.0% higher in either the Rd continuous or Rd 18 group than in the MPT group for all Grade 3/ Grade 4 treatments.
c Serious adverse reactions occurring in at least 1.0% of subjects in the Rd persistent or Rd 18 groups and with an incidence rate at least 1.0% higher in either the Rd persistent or Rd 18 groups than in the MPT group.
d Based on medical judgment, the preferred terminology for known adverse reactions in the Rd persistent/Rd 18 group is assigned to the Hematologic and Lymphatic Disorders Body System and is reported as a serious adverse reaction.
e Footnote “a” is not applicable
f Footnote “b” does not apply
@-at least one adverse reaction with a fatal outcome
% – At least one case of life-threatening adverse reactions, (if the event ended in death, the case is classified as a death).
*Generalized adverse reactions.
Abdominal pain: abdominal pain, epigastric pain, lower abdominal pain, gastrointestinal pain
Pneumonia: pneumonia, lobar pneumonia, pneumococcal pneumonia, bronchopneumonia, Ehrlichia pneumonia, Legionella pneumonia, staphylococcal pneumonia, Klebsiella pneumonia, atypical pneumonia, bacterial pneumonia, Escherichia pneumonia, streptococcal pneumonia, viral pneumonia
Sepsis: sepsis, infectious shock, urinary sepsis, ehrlichia sepsis, neutropenic sepsis, pneumococcal sepsis, staphylococcal sepsis, bacterial sepsis, meningococcal sepsis, enterococcal sepsis, Klebsiella sepsis, pseudomonas septicaemia
Rash: rash, pruritic rash, erythematous rash, maculopapular rash, generalized rash, papular rash, epidermolysis bullosa rash, follicular rash, maculopapular rash, drug rash with eosinophilia and systemic symptoms, erythema multiforme, pustular rash
Deep vein thrombosis: deep vein thrombosis, extremity vein thrombosis, venous thrombosis
Summary of safety data in patients with relapsed/refractory multiple myeloma (MM-009 and MM-010)
In the 2 pivotal, placebo-controlled phase III clinical studies (MM-009 and MM-010), the dose of lenalidomide was 25 mg orally once daily on days 1 to 21 of each 28-day cycle, and the dose of dexamethasone was 40 mg orally once daily on days 1 to 4, 9 to 12, and 17 to 20 of each of the first 4 28-day cycles. 40 mg; for each 28-day cycle thereafter, oral dexamethasone 40 mg was administered once daily on days 1 to 4 of each cycle only.
The data evaluated were from 703 patients who received at least one dose of lenalidomide/dexamethasone (353 patients) or placebo/dexamethasone (350 patients) in both studies. The median duration of study treatment exposure was significantly longer in the lenalidomide/dexamethasone group (44.0 weeks) than in the placebo/dexamethasone group (23.1 weeks), with this difference due to a lower incidence of study treatment discontinuation due to disease progression in the lenalidomide/dexamethasone group (39.7%) than in the placebo/dexamethasone group (70.4%).
At least one adverse reaction occurred in 325 (92%) patients in the lenalidomide/dexamethasone group compared with 288 (82%) in the placebo/dexamethasone group.
The most serious adverse reactions included.
Venous thrombosis (deep vein thrombosis, pulmonary embolism) (see [Precautions]).
Grade 4 neutropenia (see [Precautions]).
The most common adverse reactions were: fatigue (43.9%), neutropenia (42.2%), constipation (40.5%), diarrhea (38.5%), muscle cramps (33.4%), anemia (31.4%), thrombocytopenia (21.5%), and rash (21.2%).
In the lenalidomide/dexamethasone treatment group, at least one dose suspension occurred in 269 (76%) patients, some of whom had had a dose downward adjustment. This compares with 199 patients (57%) in the placebo/dexamethasone treatment group. Of those patients who had a dose suspension (including a dose down), 50% of patients in the lenalidomide/dexamethasone group had at least one additional dose suspension, some of which had a dose down. This compares with 21% of patients in the placebo/dexamethasone group who had such episodes. Most adverse events, as well as Grade 3/4 adverse events, occurred more frequently in the lenalidomide/dexamethasone group than in the placebo/dexamethasone group.
Tables 5, 6, and 7 summarize the adverse reactions reported in the lenalidomide/dexamethasone and placebo/dexamethasone groups.
Table 5: Adverse reactions with an incidence of ≥5% and a difference in incidence of ≥2% between the lenalidomide/dexamethasone and placebo/dexamethasone groups
Body system/adverse reactions Lenalidomide/dexamethasone
(n=353)
n (%)
Placebo/dexamethasone
(n=350)
n (%)
Blood and lymphatic system disorders  
Neutropenia %
149 (42.2)
22 (6.3)
Anemia@
111 (31.4)
83 (23.7)
Thrombocytopenia@
76 (21.5)
37 (10.6)
Leukopenia 28 (7.9)
4 (1.1)
Lymphocytopenia 19 (5.4)
5 (1.4)
Systemic disease and administration site reactions  
Fatigue 155 (43.9)
146 (41.7)
Fever
97 (27.5)
82 (23.4)
Peripheral edema 93 (26.3)
74 (21.1)
Chest pain 29 (8.2)
20 (5.7)
Drowsiness 24 ( 6.8)
8 (2.3)
Gastrointestinal disorders  
Constipation143（ 40.5)
74 (21.1)
Diarrhea@
136 (38.5)
96 (27.4)
Nausea@ 92 (26.1)
75 (21.4)
Vomiting@
43 (12.2)
33 (9.4)
Abdominal pain@
35 (9.9)
22 (6.3)
Dry mouth 25 (7.1)
13 (3.7)
Musculoskeletal and connective tissue disorders  
Muscle spasms 118 (33.4)
74 (21.1)
Back pain 91 (25.8)
65 (18.6)
Bone pain 48 (13.6)
39 (11.1)
Pain in the extremities
42 (11.9)
32 (9.1)
Neurological disorders  
Dizziness 82 (23.2)
59 (16.9)
Tremor 75 (21.2)
26 (7.4)
Taste disorders 54 (15.3)
34 (9.7)
Hyperalgesia 36 (10.2)
25 (7.1)
Neuropathy
23 (6.5)
13 (3.7)
Respiratory, thoracic and mediastinal disorders  
Respiratory distress 83 (23.5)
60 (17.1)
Nasopharyngitis 62 (17.6)
31 (8.9)
Pharyngitis 48 (13.6)
33 (9.4)
Bronchitis 40 (11.3)
30 (8.6)
Infections and infections  
Upper respiratory tract infections 87 (24.6)
55 (15.7)
Pneumonia@
48 (13.6)
29 (8.3)
Urinary tract infection
30 (8.5)
19 (5.4)
Sinusitis
26 (7.4)
16 (4.6)
Skin and subcutaneous tissue diseases
  
Rash C
75 (21.2)
33 (9.4)
Hyperhidrosis 35 (9.9)
25 (7.1)
Dry skin 33 (9.3)
14 (4.0)
Itching 27 (7.6)
18 (5.1)
Metabolic and nutritional disorders Anorexia 55 (15.6) 34 ( 9.7)
Hypokalemia 48 (13.6) 21 (6.0)
Hypocalcemia 31 (8.8)
10 (2.9)
Loss of appetite 24 (6.8)
14 (4.0)
Dehydration 23 (6.5) 15 (4.3)
Hypomagnesemia 24 (6.8)
10 (2.9)
Examination
  
Weight loss 69 (19.5)
52 (14.9)
Ophthalmologic disease  
Blurred vision 61 (17.3)
40 (11.4)
Vascular diseases  
Deep vein thrombosis %33 (9.3)
15 (4.3)
Hypertension 28 (7.9)
20 (5.7)
Hypotension 25 (7.1)
15 (4.3)
 Table 6: Grade 3/4 adverse reactions with an incidence of ≥2% and a difference in incidence of ≥1% between the lenalidomide/dexamethasone and placebo/dexamethasone groups
Body system/adverse reactions Lenalidomide/dexamethasone
(n=353)
n (%)
Placebo/dexamethasone
(n=350)
n (%)
Blood and lymphatic system disorders  
Neutropenia %
118 (33.4)
12 (3.4)
Thrombocytopenia@
43 (12.2)
22 (6.3)
Anemia@
35 (9.9)
20 (5.7)
Leukopenia 14 (4.0)
1 (0.3)
Lymphocytopenia 10 (2.8)
4 (1.1)
Febrile neutropenia %
8 (2.3)
0 (0.0)
Systemic disease and administration site reactions  
Fatigue 23 (6.5)
17 (4.9)
Vascular disease  
Deep vein thrombosis %
29 (8.2)
12 (3.4)
Infections and infections  
Pneumonia@
30 (8.5)
19 (5.4)
Urinary tract infections 5 (1.4)
1 (0.3)
Metabolic and nutritional diseases  
Hypokalemia 17 (4.8)
5 (1.4)
Hypocalcemia 13 (3.7)
6 (1.7)
Hypophosphatemia 9 (2.5)
0 (0.0)
Respiratory, thoracic and mediastinal disorders  
Pulmonary embolism@14 (4.0)
3 (0.9)
Respiratory distress@
4 (1.1)
0 (0.0)
Musculoskeletal and connective tissue disorders  
Myasthenia gravis 20 (5.7)
10 (2.9)
Gastrointestinal disorders  
Diarrhea@
11 (3.1)
4 (1.1)
Constipation 7 (2.0)
1 (0.3)
Nausea@
6 (1.7)
2 (0.6)
Heart disease  
Atrial fibrillation@ 13 (3.7)
4 (1.1)
Tachycardia@6 (1.7)
1 (0.3)
Congestive heart failure@
5 (1.4)
1 (0.3)
Neurological disorders  
Syncope 10 (2.8)
3 (0.9)
Dizziness 7 (2.0)
3 (0.9)
Ophthalmologic diseases  
Cataract 6 (1.7)
1 (0.3)
Unilateral cataract 5 (1.4)
0 (0.0)
Mental illness
  
Depression 10 (2.8)
6 (1.7)
 Table 7: Serious adverse reactions with an incidence of ≥1% and a difference in incidence of ≥1% between the lenalidomide/dexamethasone and placebo/dexamethasone groups
Body system
Adverse reactions Lenalidomide/dexamethasone
(n=353)
n (%)
Placebo/dexamethasone
(n=350)
n (%)
Hematologic and lymphatic system disorders  
Febrile neutropenia %6 (1.7)
0 (0.0)
Vascular diseases  
Deep vein thrombosis%26 (7.4)
11 (3.1)
Infections and infections  
Pneumonia@
33 (9.3)
21 (6.0)
Respiratory, thoracic and mediastinal diseases  
Pulmonary embolism@ 13 (3.7)
3 (0.9)
Heart disease
  
Atrial fibrillation@
11 (3.1)
2 (0.6)
Congestive heart failure@ 5(1.4)
0 (0.0)
Neurological disorders  
Cerebrovascular accident@
7 (2.0)
3 (0.9)
Gastrointestinal disorders  
Diarrhea@
6 (1.7)
2 (0.6)
Musculoskeletal and connective tissue disorders  
Bone pain 4 (1.1)
0 (0.0)
Tables 5, 6 and 7 above.
@ At least one case of adverse drug reaction leading to a fatal outcome.
%
At least one adverse drug reaction considered to be life-threatening (classified as a fatal case if the outcome of the event was death)
The median duration of drug administration for patients was 44 weeks in the lenalidomide/dexamethasone treatment group compared with 23 weeks in the placebo/dexamethasone group, and this should be taken into account when comparing the incidence of adverse events between the lenalidomide/dexamethasone treatment group and the placebo/dexamethasone treatment group.
Summary of safety data in Chinese patients with relapsed/refractory multiple myeloma (MM-021)
A multicenter, single-arm, open phase II clinical study (MM-021) was conducted in Chinese patients with multiple myeloma at a dose of lenalidomide 25 mg orally daily on days 1 to 21 of every 28-day cycle, combined with low-dose dexamethasone: administered on days 1, 8, 15, and 22 of every 28-day cycle.
The data in Tables 8, 9 and 10 are derived from the clinical study report of MM-021.
In this trial, 199 patients received at least one dose of study drug. 69 (34.7%) patients had interruptions in lenalidomide dosing due to adverse events, and 29 (14.6%) of these 69 patients underwent a dose downward adjustment after interruption of dosing.
The most common grade 3/4 adverse events were
anemia
Decreased neutrophil count
The most common adverse events were anemia (121/199 subjects, 60.8%), decreased neutrophil count (82/199 subjects, 41.2%), neutropenia (71/199 subjects, 35.7%), and decreased white blood cell count (66/199 subjects, 33.2%).
Table 8: Adverse events with an incidence of ≥5%
Body systema/adverse reactionsb Safety population
(N=199) Number of subjects (%) Presence of at least 1 treatment-induced adverse event (AE) 191 (96.0) Hematologic and lymphatic system disorders 148 (74.4) Anemia 121 (60.8) Neutropenia 71 (35.7) Thrombocytopenia 43 (21.6) Leukopenia 35 (17.6) Laboratory tests 122 (61.3) Neutrophil granulocyte count decreased82 (41.2)White blood cell count decreased66 (33.2)Platelet count decreased43 (21.6)Weight loss30 (15.1)Weight gain11 (5.5)Infections and infections83 (41.7)Upper respiratory tract infections39 (19.6)Pneumonia37 (18.6)Systemic diseases and medication site conditions71 (35.7)Fatigue39 (19.6)Fever24 (12.1)Peripheral edema15 (7.5)Metabolic and nutritional disorders67 (33.7)Hypokalemia25 (12.6)Hyperglycemia13 (6.5)Hypoalbuminemia13 (6.5)Hyperuricemia10 (5.0)Gastrointestinal disorders58 (29.1)Constipation24 (12.1)Diarrhea17 (8.5)Skeletal muscle and connective tissue disease51 (25.6)bone pain13 (6.5)muscle spasm11 (5.5)back pain10 (5.0)neurological disease50 (25.1)hyperalgesia14 (7.0)respiratory, thoracic and mediastinal disease26 (13.1)cough15 (7.5)vascular disease16 (8.0)hypertension12 (6.0)AE=adverse events.
aArranged in descending order of frequency of adverse events by safety population.
bArranged in descending order of frequency of adverse events by system organ classification.
The most common grade 3/4 adverse events were anemia (52/199, 26.1%) and neutropenia (50/199, 25.1%), followed by thrombocytopenia (29/199, 14.6%), pneumonia (26/199, 13.1%), leukopenia (19/199, 9.5%), and neutrophil count reduction (17/199 8.5%).
Table 9: Grade 3 or 4 adverse events with an incidence of ≥2%
Physical Systema/Adverse Reactionb Safety Population
(N=199) Number of subjects (%) NCI CTCAE grade 3 grade 4 grade 3/grade 4 occurrence of at least 1 grade 3/grade 4 treatment-induced adverse event (TEAE) 96 (48.2) 43 (21.6) 139 (69.8) hematologic and lymphatic system disorders 60 (30.2) 24 (12.1) 84 (42.2) anemia 41 (20.6) 11 ( (5.5) 52 (26.1) Neutropenia 42 (21.1) 8 (4.0) 50 (25.1) Thrombocytopenia 15 (7.5) 14 (7.0) 29 (14.6) Leukopenia 16 (8.0) 3 (1.5) 19 (9.5) Metabolic and nutritional disorders 30 (15.1) 11 (5.5) 41 (20.6) Hypokalemia 13 (6.5) 1 (0.5) 14 (7.0) Hyperuricemia 1 (0.5) 7 (3.5) 8 (4.0) Hyperglycemia 5 (2.5) 0 (0.0) 5 (2.5) Hypocalcemia C3 (1.5) 2 (1.0) 5 (2.5) Hypercalcemia C1 (0.5) 3 (1.5) 4 (2.0) Hypoalbuminemia 4 (2.0) 0 (0.0) 4 ( 2.0) Infections and infections38 (19.1) 1 (0.5) 39 (19.6) Pneumonia25 (12.6) 1 (0.5) 26 (13.1) Upper respiratory tract infection8 (4.0) 0 (0.0) 8 (4.0) Laboratory tests27 (13.6) 10 (5.0) 37 (18.6) Decreased neutrophil count12 (6.0) 5 (2.5) 17 (8.5) Decreased white blood cell count 12 (6.0) 2 (1.0) 14 (7.0) Decreased platelet count 11 (5.5) 3 (1.5) 14 (7.0) Decreased lymphocyte count 6 (3.0) 0 (0.0) 6 (3.0) Systemic disease and medication site conditions 11 (5.5) 0 (0.0) 11 (5.5) Fatigue 8 (4.0) 0 ( 0.0) 8 (4.0) Skeletal muscle and connective tissue disorders7 (3.5) 1 (0.5) 8 (4.0) Bone pain C3 (1.5) 1 (0.5) 4 (2.0) Renal and urologic disorders 3 (1.5) 4 (2.0) 7 (3.5) Acute renal failure 0 (0.0) 4 (2.0) 4 (2.0) CTCAE = Common Terminology Criteria for Adverse Events. NCI = National Cancer Institute.
aAll enrolled subjects taking at least 1 dose of study drug (lenalidomide or dexamethasone).
bListed in descending order of frequency of grade 3/4 AEs in the safety population.
cArranged in descending order of frequency of grade 3/4 AEs by system organ classification.
Table 10 summarizes the frequency of serious adverse events occurring during treatment by body system/adverse reaction.
Table 10: Summary of serious adverse events
 Body Systema/Adverse Reactionb Safety Population
(N=199) Number of subjects (%) Occurrence of at least 1 treatment-induced serious adverse event (SAE) 58 (29.1) Infections and infections 27 (13.6) Pneumonia 23 (11.6) Bronchopneumonia 1 (0.5) Herpes simplex 1 (0.5) Herpes zoster 1 (0.5) Lobar pneumonia 1 (0.5) Pulmonary infection 1 (0.5) Septic shock 1 (0.5 ) Urinary tract infection 1 (0.5) Heart disease 10 (5.0) Heart failure 4 (2.0) Arrhythmia 2 (1.0) Heart and lung failure 2 (1.0) Acute myocardial infarction 1 (0.5) Congestive heart failure 1 (0.5) Coronary artery disease 1 (0.5) Blood and lymphatic system disorders 9 (4.5) Thrombocytopenia 7 (3.5) Anemia 4 (2.0) Neutropenia 2 (1.0) Disseminated intravascular coagulation 1 (0.5) Systemic disease and site of administration 9 (4.5) Death 6 (3.0) Fever 2 (1.0) Multi-organ failure 1 (0.5) Non-cardiogenic chest pain 1 (0.5) Neurological disease 6 (3.0) Intracranial hemorrhage 2 (1.0) Cauda equina syndrome 1 (0.5) Convulsions 1 (0.5) Ischemic cerebral infarction 1 ( 0.5) Spinal cord compression 1 (0.5) Renal and urologic disorders 6 (3.0) Acute renal failure 3 (1.5) Renal failure 2 (1.0) Chronic renal failure 1 (0.5) Gastrointestinal disorders 4 (2.0) Gastrointestinal bleeding 1 (0.5) Intestinal obstruction 1 (0.5) Intussusception 1 (0.5) Lower gastrointestinal bleeding 1 (0.5) Metabolic and nutritional disorders 4 ( 2.0) Hypercalcemia 1 (0.5) Hypocalcemia 1 (0.5) Hypokalemia 1 (0.5) Hyponatremia 1 (0.5) Tumor lysis syndrome 1 (0.5) Benign, malignant and unspecified neoplasms (including cysts and polyps) 4 (2.0) Multiple myeloma 4 (2.0) Skeletal muscle and connective tissue disorders 3 (1.5) Back pain 1 (0.5) Bone pain 1 (0.5) Lumbar disc herniation 1 (0.5) Respiratory, thoracic and mediastinal disease 2 (1.0) Respiratory failure 2 (1.0) Vascular disease 2 (1.0) Deep vein thrombosis 1 (0.5) Hypertension 1 (0.5) Hepatobiliary disease 1 (0.5) Liver injury 1 (0.5) Trauma, poisoning and operational complications 1 (0.5) Vertebral compression fracture 1 (0.5) SAE = serious adverse event.
aAll enrolled subjects taking at least 1 dose of study drug (lenalidomide or dexamethasone).
bIn descending order of frequency of serious adverse events by system organ classification in the safety population.
Venous thromboembolism*
Deep vein thrombosis and pulmonary embolism
(See [Precautions])
Increased incidence of venous thromboembolic events (VTE [DVT and PE]) and arterial thromboembolic events (ATE, myocardial infarction and stroke) in patients treated with this product.
In two studies (MM-009 and MM-010) in patients who had received at least one therapy, a higher proportion of deep vein thrombosis (DVT) was reported as a serious adverse drug reaction (7.4%) or a severe adverse drug reaction (8.2%) in the lenalidomide/dexamethasone group than in the placebo/dexamethasone group (3.1% and 3.4%, respectively). The proportion of drug discontinuations due to deep vein thrombosis was similar between the two groups.
In the MM-020 study, the proportion of DVT adverse reactions (all grades) was 10.3%, 7.2%, and 4.1% in the Rd continuous, Rd 18, and MPT groups, respectively, and the proportion of serious DVT adverse reactions was 3.6%, 2.0%, and 1.7% in the Rd continuous, Rd 18, and MPT groups, respectively, and 5.6%, 3.7%, and 2.8% in the Grade 3/Grade 4 DVT adverse reactions, respectively. the proportion of DVT adverse reactions (all grades) in the Rd continuous and Rd 18 The proportion of discontinuations and dose reductions due to DVT adverse reactions was similar in the Rd persistent and Rd 18 groups (both <1%). 2.3% and 1.5% of the Rd persistent and Rd 18 groups, respectively, discontinued lenalidomide treatment due to DVT adverse reactions.
In the MM-009 and MM-010 studies, pulmonary embolism was reported as a serious adverse drug reaction (3.7%) or grade 3/4 adverse reaction (4.0%) in the lenalidomide/dexamethasone group for subjects who had received at least one therapy, and the proportion of this adverse reaction was higher than in the placebo/dexamethasone group (0.9%) (serious adverse reaction or grade 3/4 adverse reaction). The proportion of discontinuations due to pulmonary embolism was similar between the two groups.
In the MM-020 study, the rates of PE adverse reactions (all grades, 3.9%, 3.3%, and 4.3%, respectively), PE serious adverse reactions (3.8%, 2.8%, and 3.7%, respectively), and PE grade 3/4 adverse reactions (3.8%, 3.0%, and 3.7%, respectively) were similar in the Rd continuous, Rd 18, and MPT groups.
A higher proportion of myocardial infarctions were reported as serious adverse drug reactions (1.7%) or severe adverse drug reactions (1.7%) in the lenalidomide/dexamethasone group than in the placebo/dexamethasone group (0.6% and 0.6%, respectively). The proportion of discontinuations due to myocardial infarction (including acute) was 0.8% in the lenalidomide/dexamethasone group compared with 0 in the placebo/dexamethasone group. in the MM-020 study, the proportions of myocardial infarction (including acute) adverse reactions (all grades) in the Rd continuous, Rd 18, and MPT groups were 2.4%, 0.6%, and 1.1%, respectively, and the proportions of myocardial infarction (including acute) serious adverse reactions were 2.3%, 0.6%, and 1.1%, respectively, and the proportions of myocardial infarction (including acute) severe adverse reactions were 1.9%, 0.6%, and 0.9%, respectively.
The proportion of strokes (CVAs) reported as serious adverse drug reactions or serious adverse reactions in the lenalidomide/dexamethasone group was 2.3% and 2.0%, respectively, compared with 0.9% and 0.9% in the placebo/dexamethasone group, respectively. The proportion of discontinuations due to stroke (CVA) in the lenalidomide/dexamethasone group was 1.4% compared with 0.3% in the placebo/dexamethasone group. In the MM-020 study, the proportions of CVA adverse reactions (all grades) in the Rd continuous, Rd 18 and MPT groups were 0.8%, 0.6% and 0.6%, respectively, and the proportions of serious CVA adverse reactions were 0.8%, 0.6% and 0.6%, respectively, and the proportions of serious CVA adverse reactions were 0.6%, 0.6% and 0.2%, respectively.
[*Note: According to the clinical study of MM-021 conducted in Chinese patients with myeloma, one case of deep vein thrombosis (DVT) was observed in 199 patients. All subjects were treated with thromboprophylaxis based on the protocol. The decision on whether prophylaxis should be administered should be made with caution after an assessment of potential risk factors in individual patients].
Other Adverse Reactions
Adverse drug reactions not listed above but occurring at ≥1% and at least twice as frequently as in the placebo group were also reported in studies MM-009 and MM-010, including
Hematologic and lymphatic system disorders: complete blood cytopenia, autoimmune hemolytic anemia
Cardiac disorders: bradycardia, myocardial infarction, angina pectoris
Endocrine disorders: hirsutism
Ophthalmic diseases: blindness, high intraocular pressure
Gastrointestinal disorders: gastrointestinal bleeding, tongue pain
Systemic diseases and administration site reactions: discomfort
Screening: abnormal liver function tests, elevated glutamate transaminase
Neurological disorders: cerebral ischemia
Psychiatric disorders: mood swings, hallucinations, lack of sexual desire
Reproductive and breast disorders: erectile dysfunction
Respiratory, thoracic and mediastinal disorders: cough, hoarseness
Skin and subcutaneous tissue disorders: rash, hyperpigmentation of the skin
Post-marketing experience
The following adverse drug reactions have been reported after the global launch of lenalidomide. Because these reports are spontaneous reports from an unknown population size, it is more difficult to reliably assess their incidence or to establish a causal relationship with drug exposure. (See [Caution])
Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, toxic necrolytic epidermolysis bullosa, drug reactions with eosinophilia and systemic symptoms (DRESS)
Immune system disorders: angioedema, acute graft-versus-host disease (after allogeneic HSCT), solid organ transplant rejection
Benign, malignant and tumors of unknown nature (including cystic and polypoid): tumor lysis syndrome, burning tumor reaction
Respiratory, thoracic and mediastinal diseases: pneumonia
Hepatobiliary disease: hepatic failure (including fatal events), toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, mixed cytolytic/cholestatic hepatitis, and transient abnormal liver laboratory findings
Infections and infections: viral reactivation (e.g., hepatitis B virus and herpes zoster)
Endocrine disorders: hypothyroidism, hyperthyroidism
[Contraindicated].
Pregnant women.
Women who may become pregnant who have not met all contraceptive requirements. (See [Precautions] and [Use in Pregnant and Lactating Women])
Hypersensitivity to the active ingredients of this product or any of the excipients.
[Precautions].
Pregnancy Warning
Lenalidomide is a chemical analogue of thalidomide and is structurally similar to thalidomide. Thalidomide is an active substance known to have teratogenic effects in humans and can cause serious life-threatening birth defects. The malformations induced by lenalidomide in monkeys are similar to the effects of thalidomide. Teratogenic effects may occur if lenalidomide is administered during pregnancy.
To minimize the risks associated with the administration of this product, especially fetal exposure, it must be prescribed under the guidance of a Risk Management Plan (RMP) of a Pregnancy Prevention Program (PPP).
 This Risk Management Plan (RMP) has the following mandatory requirements.
Training information for prescribers and patients
Controlled drug distribution system
A follow-up assessment of the effectiveness of the RMP by the Company
The RMP classifies patients taking the product into different risk groups.
Women with the potential to become pregnant (WCBP)
Women without the possibility of pregnancy
Males
To minimize the risk of pregnancy occurring while on treatment with this product, there are different requirements for each risk type.
All patients are required to comply with our Risk Management Plan (RMP) to prevent the occurrence of pregnancy unless there is reliable evidence that the patient is not likely to become pregnant.
Criteria for determining women with no likelihood of pregnancy
The following women are considered to have no possibility of pregnancy and do not require pregnancy testing or counseling for contraception
Women who have undergone a hysterectomy or bilateral oophorectomy.
A woman has been spontaneously menopausal (but pregnancy cannot be ruled out in cases of amenorrhea after cancer treatment) for at least 24 months (i.e., she has not had a period at any time during the previous 24 consecutive months).
If the treating physician is unsure whether a female patient meets the criteria for determining a woman with no possibility of pregnancy, it is recommended that a gynecologist be consulted.
Consultations
This product is contraindicated in women with a risk of pregnancy unless all of the following conditions are met.
The patient must be aware of the expected teratogenic risk to the fetus.
The patient is aware of the need for uninterrupted use of effective contraception for 4 weeks prior to initiation of treatment and throughout the duration of treatment, during interruptions in administration, and for at least 4 weeks after completion of treatment.
All recommendations for effective contraception must be followed even if a woman who is at risk of pregnancy develops amenorrhea.
Patients should have the ability to follow effective contraception.
The patient has been informed and is aware of the possible consequences of pregnancy and needs to consult her physician immediately if a risk of pregnancy is identified.
Patients should be aware of the need to start treatment immediately after obtaining lenalidomide as a result of a negative pregnancy test result.
Patients should be aware of the need for pregnancy testing every 4 weeks and should undergo testing on a regular basis, except for those who have had a confirmed tubal ligation.
The patient declares that he/she is aware of the possible risks associated with the use of lenalidomide and the precautions that must be taken.
For male patients taking this product, pharmacokinetic data show that lenalidomide is present in semen at very low levels. As a precaution, all male patients taking lenalidomide must meet the following conditions.
Be aware of the potential teratogenic risk to the fetus if they have sex with a pregnant woman or a woman who is potentially pregnant.
Be aware of the need to use a condom if having sex with a pregnant woman or a woman at risk of pregnancy, even if a vasectomy has been performed.
Know the possible risk of fetal malformation if sperm or semen is donated.
For women at risk of pregnancy, the prescribing physician must ensure that
The patient follows the requirements of our risk management program for the prevention of pregnancy, including confirmation that the patient has a full understanding of these requirements
The patient declares her agreement to all of the aforementioned conditions.
 Contraception
Female patients at risk of pregnancy must use two reliable methods of contraception, including a highly effective method of contraception and an additional effective method of contraception, for 4 weeks prior to initiation of treatment, for the entire duration of treatment, and for 4 weeks after completion of treatment, even if there is a break in dosing, unless the patient commits to absolute and continuous abstinence and this is confirmed on a monthly basis. If effective contraception is not being used, the patient must consult with a trained health care professional about contraception in order to begin effective contraception.
The following are examples of appropriate contraceptive methods.
Highly effective contraceptive methods
Intrauterine device (IUD)
Hormonal (hormone implants, levonorgestrel intrauterine delayed release system (IUS), long-acting medroxyprogesterone acetate, ovulation inhibiting luteinizing hormone – tablets only, e.g. dexprogesterone)
Tubal ligation
Spousal vasectomy
Effective contraceptive methods
Male condom
Female diaphragm
Cervical cap
Contraception using hormonal methods should be started 4 weeks prior to treatment with this product.
Combining oral combination contraceptives is not recommended because of the increased risk of venous thromboembolism in patients with multiple myeloma treated with lenalidomide and dexamethasone (see [Drug Interactions]). If a patient is currently using a combination of oral combination contraceptives, they should switch to any of the effective contraceptive methods listed above. The risk of venous thromboembolism persists for 4 to 6 weeks after discontinuation of oral combination contraceptives. The efficacy of steroidal contraceptives may be reduced if used in combination with dexamethasone (see [Drug Interactions]).
Implants and levonorgestrel intrauterine release system at the time of implantation may increase the risk of infection and irregular vaginal bleeding. Prophylactic antibiotics should be considered especially in patients with neutropenia.
Copper-containing IUDs are generally not recommended because of the potential risk of infection and menstrual blood loss at the time of implantation, which may exacerbate the condition of patients with neutropenia and thrombocytopenia.
Pregnancy testing
In accordance with local medical practice, a pregnancy test must be performed under medical supervision for women at risk of pregnancy, requiring a sensitivity of at least 25 mIU/mL. This requirement still applies to women at risk of pregnancy who practice absolute and continuous abstinence. Pregnancy testing, prescribing and dispensing of medications should preferably all be done on the same day. The product should be dispensed to a female patient at risk of pregnancy no later than 7 days after it is prescribed.
Before starting treatment
Two medically supervised pregnancy tests should be performed; the first test should be performed 10 to 14 days prior to starting treatment after the patient has been using effective contraception for at least 4 weeks; the second test should be performed within 24 hours prior to starting treatment. These tests are performed to ensure that the patient is not pregnant at the time of initiation of treatment with this product.
Follow-up and at the end of treatment
Medically supervised pregnancy tests should be repeated every 4 weeks (including 4 weeks after the end of treatment), unless it has been confirmed that the patient has undergone tubal ligation. These pregnancy tests should be completed within 24 hours prior to the patient’s visit to the hospital to receive the prescription.
Males
In healthy subjects, lenalidomide levels in semen were extremely low during dosing; the product was not detectable in semen 3 days after discontinuation. As a precautionary measure, and in consideration of the prolonged drug elimination time in special populations (e.g., those with impaired renal function), all male patients taking lenalidomide whose partners are pregnant or at risk of pregnancy but are not using highly effective contraception should use condoms for the entire duration of treatment, during withdrawal, and for up to 4 weeks after discontinuation of treatment, even if the male patient has a vasectomy. Male patients should not donate semen while taking this product.
Educational materials
To help patients avoid fetal exposure to lenalidomide, the marketing licensee will provide educational materials to healthcare professionals designed to emphasize the warning that lenalidomide is expected to be teratogenic, provide contraceptive advice prior to treatment initiation, and provide guidelines for the need for pregnancy testing. Prescribers should provide all patient information about the expected teratogenic risks of lenalidomide and strict contraception (see “Contraception”) to female patients who may become pregnant as well as to male patients.
Other Special Warnings and Medication Precautions
Myocardial Infarction
Myocardial infarction has been reported in patients receiving lenalidomide, particularly in those with known risk factors and in patients within the first 12 months of combined dexamethasone use. Patients with known risk factors, including previous thrombosis, should be monitored closely and measures should be taken to minimize all controllable risk factors (e.g., smoking, hypertension, and hyperlipidemia).
Venous and arterial thromboembolism
Lenalidomide combined with dexamethasone for the treatment of patients with multiple myeloma increases the risk of venous thrombosis (especially the risk of deep vein thrombosis and pulmonary embolism). In contrast, lenalidomide combined with melphalan and prednisone treatment has a lower risk of venous thrombosis.
Patients with multiple myeloma treated with lenalidomide monotherapy are at risk for venous thrombosis (especially risk of deep vein thrombosis and pulmonary embolism), but the risk is lower than in patients with multiple myeloma treated with lenalidomide in combination (see [Drug Interactions] and [Adverse Reactions]).
Lenalidomide combined with dexamethasone for patients with multiple myeloma increases the risk of arterial thrombosis (especially myocardial infarction and cerebrovascular events), while the risk of arterial thrombosis is lower when lenalidomide is combined with melphalan and prednisone. Lenalidomide monotherapy is associated with a lower risk of arterial thrombosis than lenalidomide combined with other drugs for multiple myeloma.
Therefore, patients with known risk factors for thromboembolism (including those with prior thrombosis) should be monitored closely. Measures should be taken to minimize all intervenable risk factors (e.g., smoking, hypertension, and hyperlipidemia). Patients with a combination of erythropoietin or a history of thrombosis may be at higher risk of developing thrombosis. Therefore, patients with multiple myeloma receiving lenalidomide and dexamethasone should be cautious about using erythropoietin or other drugs that may increase the risk of thrombosis (e.g., hormone replacement therapy). Erythropoietin should be discontinued at hemoglobin concentrations above 12 g/dl.
Advise patients and physicians to observe signs and symptoms of blood clots. Patients should be advised to seek medical attention if they develop symptoms (e.g. shortness of breath, chest pain, swelling of the arms or thighs). Prophylactic anticoagulant medications are recommended, especially for patients with other thrombotic risk factors. Please evaluate the individual patient’s potential risk factors carefully before deciding whether to take anticoagulation prophylaxis.
If a patient experiences any thrombotic event, treatment must be discontinued and standard anticoagulation therapy must be initiated. Once the patient has been stabilized with anticoagulation and the complications of the thrombotic event have been controlled, lenalidomide therapy may be restarted at the original dose (based on benefit-risk assessment). Patients should continue anticoagulation therapy during lenalidomide therapy.
Neutropenia and thrombocytopenia
The major dose-limiting toxicities of lenalidomide include neutropenia and thrombocytopenia. A complete blood count, including white blood cells and their sorted count, platelet count, hemoglobin, and hematocrit, should be checked weekly at baseline and for the first 8 weeks of lenalidomide therapy, and monitored monthly thereafter (see [DOSAGE]).
If neutropenia occurs, the physician should consider treating the patient with growth factors. Patients are advised to report any fever immediately.
Patients and physicians are advised to closely monitor for signs and symptoms of bleeding, including petechiae and nosebleeds, especially with concomitant use of medications that may increase the risk of bleeding. (See [Adverse Reactions]).
Caution should be exercised when combining this product with other myelosuppressive drugs.
Patients with previously untreated multiple myeloma who are not candidates for transplantation: Lenalidomide in combination with low-dose dexamethasone for patients who are not candidates for transplantation
A lower incidence of grade 4 neutropenia was observed in the lenalidomide combined with low-dose dexamethasone group (8.5% in the Rd and Rd 18 groups versus 15% in the melphalan/prednisone/thalidomide group). the incidence of grade 4 neutropenia with fever was consistent with the control group (0.6% in the Rd and Rd 18 groups versus 0.7% in the melphalan/prednisone/thalidomide group).
The incidence of grade 3 or 4 thrombocytopenic events was lower in the Rd and Rd 18 groups than in the control group (8.1% vs 11.1%, respectively).
Patients with multiple myeloma who had received at least one therapy
Lenalidomide in combination with dexamethasone for multiple myeloma resulted in an increased incidence of grade 4 neutropenia (5.1% in the lenalidomide/dexamethasone treatment group versus 0.6% in the placebo/dexamethasone group). grade 4 neutropenia with fever was occasionally seen (0.6% in the lenalidomide/dexamethasone treatment group versus 0.0% in the placebo/dexamethasone group).
Lenalidomide combined with dexamethasone in the treatment of multiple myeloma resulted in an increased incidence of grade 3 and 4 thrombocytopenia (9.9% and 1.4% in the lenalidomide/dexamethasone treatment group versus 2.3% and 0.0% in the placebo/dexamethasone group; see [Adverse Reactions]).
Thyroid dysfunction
Cases of hypothyroidism and hyperthyroidism have been reported in patients taking lenalidomide. Effective control of comorbidities affecting thyroid function is recommended prior to treatment with this product. Ongoing monitoring of thyroid function at baseline and during treatment is recommended.
Peripheral neuropathy
Lenalidomide has a similar structure to thalidomide, which is known to induce severe peripheral neuropathy. No exacerbation of peripheral neuropathy has been observed in patients with previously untreated multiple myeloma who were unsuitable for transplantation and treated with long-term lenalidomide.
Tumor Burning Response and Tumor Lysis Syndrome
Due to the antitumor activity of lenalidomide, the complication of tumor lysis syndrome (TLS) may occur; TLS and tumor-flaring reaction (TFR) are more common in patients with chronic lymphocytic leukemia (CLL) and less common in lymphoma patients treated with lenalidomide. Fatal TLS events have been reported during lenalidomide treatment. Patients with a high tumor load prior to treatment are at risk for TLS and TFR. Caution should be exercised when treating these patients with lenalidomide, and these patients should be monitored closely, with particular attention to the first cycle or dose escalation process, and appropriate precautions should be taken. TLS has been reported rarely in patients with multiple myeloma treated with lenalidomide and has not been reported in patients with MDS treated with lenalidomide.
Serious skin reactions (including allergic reactions)
Angioedema and severe skin reactions, including Stevens-Johnson syndrome (SJS), toxic necrolytic epidermolysis bullosa (TEN), and drug reactions with eosinophilia and systemic symptoms (DRESS) have been reported.DRESS may present with skin reactions (e.g., rash or exfoliative epidermolysis bullosa), eosinophilia fever, and/or systemic complications of lymphadenopathy, such as hepatitis, nephritis, pneumonia, myocarditis, and/or pericarditis. These events can have fatal consequences. Avoid this product in patients who have had a grade 4 rash with prior thalidomide use. If grade 2 to 3 rash occurs, suspension or discontinuation of the drug should be considered. If angioedema, grade 4 rash, exfoliative or maculopapular rash, or suspected Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS occur, the drug must be discontinued and should not be restarted after these reactions resolve.
Lactose intolerance
Lactose is contained in lenalidomide capsules. It should not be used in patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
Unused capsules
Patients should be cautioned not to give this product to others and to return unused capsules to the pharmacist at the end of treatment.
Second primary tumor
In clinical trials in previously treated patients with multiple myeloma, there was an increased incidence of second primary tumors (SPM) in the lenalidomide/dexamethasone group (3.98/100 patient-years) compared to the control group (1.38/100 patient-years). Non-invasive second primary tumors included basal cell or squamous cell skin cancer. Most invasive second primary tumors are malignant solid tumors.
In clinical trials of primary multiple myeloma not suitable for transplantation, the incidence of hematologic SPM {acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) cases} was 4.9 times higher in the lenalidomide combined with melphalan and prednisone treatment to disease progression group (1.75 per 100 patient-years) than in the melphalan combined with prednisone treatment group (0.36 per 100 patient-years).
The incidence of SPM in solid tumors was 2.12 times higher in the lenalidomide (9 cycles) combined with melphalan and prednisone treatment group (1.57/100 patient-years) than in the melphalan combined with prednisone treatment group (0.74/100 patient-years).
The incidence of hematologic SPM was not higher in patients treated with lenalidomide combined with dexamethasone until disease progression or treated to 18 months (0.16/100 patient-years) than in the thalidomide combined with melphalan and prednisone treatment group (0.79/100 patient-years).
The incidence of SPM in solid tumors was 1.3 times higher in patients treated with lenalidomide combined with dexamethasone until disease progression or up to 18 months of treatment (1.58/100 patient-years) than in the thalidomide combined with melphalan and prednisone treatment group (1.19/100 patient-years).
The increased risk of second primary tumor associated with lenalidomide was also associated with treatment of primary multiple myeloma after stem cell transplantation. Although this risk is not fully defined, this issue should be noted when considering the use of this product in this condition.
The incidence of hematologic malignancies, primarily AML, MDS, and B-cell malignancies (including Hodgkin’s lymphoma) was 1.31/100 patient-years in the lenalidomide group and 0.58/100 patient-years in the placebo group [1.02/100 patient-years in patients treated with lenalidomide after autologous stem cell transplantation (ASCT) and 0.60/100 patient-years in patients not treated with lenalidomide after ASCT 0.60 per 100 patient-years in patients not treated with lenalidomide after ASCT]. The incidence of SPM in solid tumors was 1.36 per 100 patient-years in the lenalidomide group and 1.05 per 100 patient-years in the placebo group (1.26 per 100 patient-years in patients treated with lenalidomide after ASCT and 0.60 per 100 patient-years in patients not treated with lenalidomide after ASCT).
 The risk of hematologic SPM must be considered before lenalidomide combined with melphalan or before starting lenalidomide immediately after high-dose melphalan and ASCT. Physicians should carefully assess patients for the development of SPM before and during treatment using standard cancer screening methods, and if indicated, treatment is required.
Hepatotoxicity
Hepatic failure, including deaths, has been reported in patients treated with lenalidomide in combination with other drugs: acute hepatic failure, toxic hepatitis, cytolytic hepatitis, biliary depletion hepatitis, and mixed cytolytic/biliary depletion hepatitis have been reported. The mechanism of drug-induced severe hepatotoxicity is not known, but in some cases, preexisting viral liver disease elevates baseline liver enzymes and treatment with antibiotics may also be a risk factor.
Commonly abnormal liver function test values are reported that are generally asymptomatic and reversible following suspension of drug administration. Once the parameters return to baseline values, treatment at a lower dose may be considered.
Lenalidomide is excreted through the kidneys. Dose adjustment in patients with renal insufficiency is particularly important to avoid higher hematologic adverse effects or hepatotoxicity that may result from elevated blood levels. Liver function monitoring is recommended, especially if there has been a previous or concurrent viral liver infection, or if lenalidomide is combined with drugs known to cause abnormal liver function.
Infection with or without neutropenia
Patients with multiple myeloma are more likely to develop infections, including pneumonia. In patients with previously untreated multiple myeloma who are not candidates for transplantation, the incidence of infection is higher with lenalidomide in combination with dexamethasone compared with MPT, and in patients with primary multiple myeloma who have been previously treated with ASCT, the incidence of infection is also higher with lenalidomide maintenance therapy compared with placebo. Grade 3 infections with neutropenia occurred in less than one-third of patients. All patients are advised to seek immediate medical attention at the first sign of infection (e.g., cough, fever, etc.) and to treat early to reduce the severity.
Cases of viral reactivation, including severe cases of herpes zoster or hepatitis B virus (HBV) reactivation, have been reported in patients treated with lenalidomide.
Death has occurred in some cases of viral reactivation.
Some cases of herpes zoster that turn into disseminated herpes zoster, herpes zoster meningitis, or ocular herpes zoster require suspension or permanent discontinuation of lenalidomide therapy and adequate antiviral therapy.
Hepatitis B virus reactivation has been reported rarely in patients with prior hepatitis B virus (HBV) infection who were treated with lenalidomide. Some of these cases have progressed to acute liver failure, leading to discontinuation of lenalidomide with adequate
antiviral therapy. Hepatitis B virus status should be clarified prior to initiation of lenalidomide therapy. For patients with positive test results for HBV infection, consultation with a specialist experienced in the treatment of hepatitis B is recommended. Lenalidomide should be used with caution in patients with a history of HBV infection, including those who are anti-HBc antibody positive but HBsAg negative. Signs and symptoms of active HBV infection in this group of patients should be closely monitored throughout the course of treatment.
Adult patients with primary diagnosis of multiple myeloma.
When combined with lenalidomide, the incidence of intolerance (grade 3 or 4 adverse events, serious adverse events, discontinuation) is higher in patients over 75 years of age, ISS stage III, ECOG PS ≤ C or CLcr < 60 mL/min. The tolerability of patients receiving lenalidomide combination therapy should be carefully assessed based on age, ISS stage III, ECOG PS ≤ C or CLcr < 60 mL/min (see [Dosage] and [Adverse Reactions]).
Cataracts
The incidence of cataracts is higher in patients treated with lenalidomide in combination with dexamethasone, especially with long-term use. Regular monitoring of patients’ vision is recommended.
Increased mortality in chronic lymphocytic leukemia
In a prospective randomized (1:1) clinical trial of lenalidomide for the first-line treatment of patients with chronic lymphocytic leukemia (CLL), lenalidomide monotherapy was associated with an increased risk of death compared with nitrogen mustard phenylbutyrate monotherapy. In an interim analysis, 34 of 210 patients in the lenalidomide-treated group died, compared with 18 of 211 patients in the benzodiazepine-treated group, and the risk ratio for overall survival was 1.92 [ 95% confidence interval: 1.08 to 3.41], consistent with a 92% increased risk of death. This study was terminated in July 2013 for safety reasons.
Serious cardiovascular adverse reactions occurred more frequently in the lenalidomide-treated group and included atrial fibrillation, myocardial infarction, and heart failure. Lenalidomide is not approved nor recommended for the treatment of CLL outside of controlled clinical trials.
Other Precautions
Patients should not donate blood during treatment with this product and for 1 week after discontinuation of the drug.
Effects on the ability to drive or operate machinery
This product has a mild to moderate effect on the ability to drive or operate machinery. Fatigue, dizziness, drowsiness, vertigo, and blurred vision have been reported in users of this product. Therefore, caution is recommended when driving and operating machinery.
Cardiac electrophysiology.
A comprehensive QTc study evaluated the effects of lenalidomide on the QT interval in 60 healthy male subjects. Lenalidomide did not prolong the QTc interval when administered at two times the maximum recommended dose. The maximum upper limit of the bilateral 90% CI for the mean difference between the lenalidomide and placebo groups was less than 10 ms.
Pregnant and lactating women]
Pregnancy (see [Contraindications] [Precautions])
The structure of lenalidomide is similar to that of thalidomide. Thalidomide is an active substance known to have teratogenic effects in humans, causing serious life-threatening birth defects.
The malformations induced by lenalidomide in monkeys are similar to the teratogenic results of thalidomide (see [Pharmacology and Toxicology]). Therefore, it is expected that lenalidomide may have teratogenic effects and the product is contraindicated during pregnancy (see [Contraindications]).
Women at risk of pregnancy should use two effective contraceptive measures simultaneously. If pregnancy occurs in a female patient while using lenalidomide, treatment must be discontinued immediately and she should be asked to seek evaluation and advice from a physician with expertise or experience in teratology. If a male patient’s partner becomes pregnant while using lenalidomide, the pregnant female is advised to seek evaluation and advice from a physician with expertise or experience in teratology.
Lenalidomide was present at extremely low levels in human semen during administration to healthy subjects; and it was not detected in semen 3 days after discontinuation of the drug (see [Pharmacokinetics]). As a precautionary measure and in consideration of prolonged drug elimination in special populations (e.g., those with impaired renal function), all male patients using lenalidomide whose spouses are pregnant or at risk of pregnancy but are not using highly effective contraception should use condoms for the entire duration of treatment, during dose suspension, and for 4 weeks after discontinuation of treatment, even if the male patient has had a vasectomy.
Lactating women
It is uncertain whether lenalidomide is secreted through human breast milk, therefore it is recommended that breastfeeding women discontinue breastfeeding during treatment with this product.
Pediatric Dosage]
There is no experience with the use of this product in pediatric and adolescent patients. Therefore, this product should not be used in patients aged 0 to 17 years. Geriatric use]
Previously untreated multiple myeloma and unsuitable for transplantation
Overall, 94% (1521/1613) of the 1613 patients treated with the drug in the MM-020 study were 65 years of age or older, and 35% (561/1613) were 75 years of age or older. The proportion of patients aged 75 years or older was similar across study groups (Rd persistent: 33%; Rd 18: 34%; MPT: 33%). For most AE categories (e.g., all AEs.
Grade 3/4 AE, severe AE), the incidence was higher in older subjects (>75 years) than in younger subjects (≤75 years) in all treatment groups. The incidence of grade 3/4 AEs was consistently higher in older subjects than in younger subjects in all groups for systemic disease and site of administration conditions body systems (difference of at least 5%). The incidence of grade 3 or 4 TEAE for infectious and infectious, cardiac (including heart failure and congestive heart failure), skin and subcutaneous tissue disease, and renal and urinary system disease (including renal failure) SOC was consistently slightly higher in older subjects than in younger subjects in all groups (difference less than 5%). The above trend was not clear with respect to the incidence of grade 3/4 AE in other body systems (e.g., blood and lymphatic system disorders, infections and infections, cardiac disorders, vascular disease). The incidence of severe AEs was overall higher in older subjects than in younger subjects in all groups.
Multiple myeloma who had received at least one therapy
Of the 703 patients with multiple myeloma treated with lenalidomide in the MM-009 and MM-010 studies, 45% were ≥65 years of age and 12% were ≥75 years of age. There was no significant difference in the proportion of patients ≥65 years of age between the lenalidomide/dexamethasone and placebo/dexamethasone groups. Of the 353 patients who received lenalidomide/dexamethasone, 46% were ≥65 years of age. Among the patients who received lenalidomide/dexamethasone in both studies, patients older than 65 years were found to be more likely to have deep vein thrombosis, pulmonary embolism, atrial fibrillation, and renal failure than patients ≤65 years, but no difference in efficacy was seen between the two. Because elderly patients are more likely to have decreased renal function, caution should be exercised in dose selection and monitoring of renal function.
Drug Interactions]
Erythropoietic agents or other drugs (e.g., hormone replacement therapy) may increase the risk of thrombosis in patients with multiple myeloma being treated with lenalidomide in combination with dexamethasone and should be used with caution (see [Precautions] and [Adverse Reactions]).
Oral contraceptives
Interactions between lenalidomide and oral contraceptives have not been studied. Lenalidomide is not an enzyme inducer. In an in vitro study in human hepatocytes, different concentrations of lenalidomide were found to have no induction effect on CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4/5. Therefore, induction of reduced potency (including that of hormonal contraceptives) is not expected to occur with lenalidomide alone. However, dexamethasone is known to have a weak to moderate induction of CYP3A4 and may also have effects on other enzymes and transporters. Therefore, it cannot be excluded that combined dexamethasone treatment may cause a decrease in the efficacy of oral contraceptives. Effective measures must be taken to avoid pregnancy (see [Precautions]).
Warfarin
The combination of multiple doses of lenalidomide (10 mg) has no effect on the single-dose pharmacokinetics of R- or S-warfarin. Co-administration of a single dose of warfarin 25 mg had no effect on the pharmacokinetics of lenalidomide. However, it is unclear whether interactions exist in specific clinical use (when combined with dexamethasone). Dexamethasone has a weak to moderate enzyme-inducing effect, and the effect of this induction on warfarin is not known. Close monitoring of warfarin concentrations during treatment is recommended.
Close monitoring of prothrombin time (PT) and international normalized ratio (INR) in patients with multiple myeloma on warfarin concomitant therapy is recommended.
Digoxin
In combination with lenalidomide 10 mg/day, plasma exposure to digoxin (0.5 mg, single dose) was elevated by 14% (90% CI 0.52% to 28.2%). It is not known whether this effect may vary with changes in treatment regimen (e.g., higher lenalidomide doses or coadministration of dexamethasone). Therefore, monitoring of digoxin concentrations during treatment with this product is recommended.
Statins
Lenalidomide in combination with a statin increases the risk of rhabdomyolysis, which may be a simple superposition of the risks of the two drugs. Intensive clinical and laboratory monitoring is particularly needed during the first weeks of treatment.
Dexamethasone
When lenalidomide is given multiple times (25 mg/day), there is no clinically meaningful effect on the pharmacokinetics of lenalidomide with single or multiple co-administrations of dexamethasone (40 mg/day).
Interaction with P-gp inhibitors
In vitro lenalidomide is a substrate for P-glycoprotein (P-gp), but not an inhibitor of it. The combination of multiple doses of quinidine (600 mg twice daily), a potent P-gp inhibitor, or tamsulosin (25 mg), an intermediate P-gp inhibitor/substrate, did not have a clinically meaningful effect on the pharmacokinetics of lenalidomide (25 mg). The combination of lenalidomide does not alter the pharmacokinetics of temsirolimus.
[Drug Overdose].
There is no experience in the management of lenalidomide overdose in patients with multiple myeloma. The primary adverse events reported were pruritus, urticaria, rash, and elevated hepatic transaminases. The dose-limiting toxicities in clinical studies were neutropenia and thrombocytopenia.
Pharmacology and Toxicology
Pharmacological effects
Mechanism of action: Lenalidomide is an analogue of thalidomide. The mechanism of action has not been fully elucidated, but the known pharmacological effects include anti-tumor, anti-angiogenic, erythropoietic and immunomodulatory properties. Lenalidomide inhibits the proliferation of certain hematopoietic tumor cells (including multiple myeloma plasma cells and tumor cells with chromosome 5 deletion), enhances T cell and natural killer cell-mediated immune function, increases the number of natural killer T cells, inhibits angiogenesis by blocking endothelial cell migration and adhesion and microvessel formation, increases fetal hemoglobin production via CD34+ hematopoietic stem cells, and inhibits the production of hemoglobin by CD34+ hematopoietic stem cells. hemoglobin production, and inhibits the production of pro-inflammatory cytokines (such as TNF-α and IL-6) produced by monocytes.
Lenalidomide is directly attached to the cereblon protein, a component of the Cullin ring E3 ubiquitin ligase complex [the Cullin ring E3 ubiquitin ligase complex contains deoxyribonucleic acid (DNA) damage binding protein (DDB1), cullin 4 (CUL4), and cullins 1 regulator (Roc1)]. In the presence of lenalidomide, cereblon binds to its substrate proteins, the lymphoid transcription factors Aiolos and Ikaros, resulting in their ubiquitination and then degradation, leading to cytotoxic and immunomodulatory effects.
Toxicological study
General toxicology: rats given lenalidomide 75, 150 and 300 mg/kg/day orally for 26 weeks showed reversible, drug-related renal pelvic mineralization in all three dose groups, more pronounced in female rats, with no adverse effect dose (NOAEL) below 75 mg/kg/day (approximately 25 times more than the daily human dose on an AUC basis). In monkeys given lenalidomide 4 and 6 mg/kg/day orally for 20 weeks, animal mortality and significant toxic effects (significant reduction in body weight, decreased erythrocyte white blood cell and platelet counts, multi-organ hemorrhage, gastrointestinal inflammation, lymphatic and bone marrow atrophy) were seen. Monkeys given lenalidomide 1 or 2 mg/kg/day orally for 1 year showed reversible changes such as altered bone marrow cell composition, a slight decrease in granulocyte/erythrocyte ratio and thymic atrophy, and 1 mg/kg/day (comparable to daily human dosage based on body surface area) caused a decrease in white blood cell counts.
Genotoxicity: The results of Ames test for lenalidomide, human lymphocyte chromosome aberration test, mouse lymphoma cell test, Syrian hamster embryonic cell morphological transformation test, and rat micronucleus test were all negative.
Reproductive toxicity: In the fertility and early embryonic development tests, no adverse effects were observed in rats and rat fertility when lenalidomide was given at 500 mg/kg (approximately 200 times the recommended human dose of 25 mg based on body surface area).
In embryo-fetal developmental toxicity tests, teratogenic effects, including thalidomide-like limb defects, were seen in pregnant monkeys given lenalidomide orally during organogenesis, with the lowest dose exposure (AUC) being 0.17 times the human maximum recommended dose (MRHD) of 25 mg; embryonic lethal effects were seen in pregnant rabbits given lenalidomide at 20 times the human maximum recommended dose; pregnant rats No adverse reproductive effects were observed in pregnant rats given lenalidomide at 200 times the maximum recommended human dose.
In a perinatal study, lenalidomide at 500 mg/kg (200 times the recommended human dose of 25 mg on a body surface area basis) in pregnant rats from organogenesis to lactation resulted in a slight delay in sexual maturation in male offspring and a slight decrease in body weight gain in female offspring.
As with thalidomide, the rat model did not adequately show the potential effects of lenalidomide on human embryo-fetal offspring development.
In pregnant rabbits given lenalidomide orally from day 7 to day 20 of gestation, fetal litter blood concentrations were approximately 20-40% of the maternal maximum blood concentration. A single oral administration of radiolabeled lenalidomide to pregnant rats and assays of fetal plasma and tissue drug concentrations showed that fetal tissue radioactivity concentrations were generally lower than maternal tissue radioactivity concentrations. These results suggest that lenalidomide is transmissible to the placenta.
Carcinogenicity: No studies have been conducted on the carcinogenicity of lenalidomide.
Pharmacokinetics
Absorption
After oral administration of lenalidomide to healthy subjects under fasting conditions, the product is rapidly absorbed, with plasma concentrations reaching a maximum within 0.5 to 1.5 hours after administration. Both the maximum plasma concentration (Cmax) and the area under the plasma concentration time curve (AUC) increased proportionally with increasing dose in patients as well as in healthy subjects. Multiple dose administration did not result in significant drug accumulation. The relative plasma exposure of the S- and R-enantiomers of lenalidomide was approximately 56% and 44%, respectively.
The degree of absorption was reduced in healthy subjects receiving both high-fat and high-calorie foods, resulting in an approximately 20% decrease in AUC and a 50% decrease in Cmax. However, in the pivotal registration trial to establish the efficacy and safety of lenalidomide in the treatment of multiple myeloma, feeding status was not considered at the time of dosing. Therefore, lenalidomide may be administered with food or on an empty stomach.
Distribution
In vitro, [14C]-Lenalidomide has a low binding rate to plasma proteins, averaging 23% and 29% in multiple myeloma and healthy subjects, respectively. Lenalidomide was detectable in semen after 25 mg/dose in healthy subjects (at levels less than 0.01% of the dose administered) and was not detected in semen after 3 days of discontinuation (see [Precautions]).
Metabolism
In vitro human metabolism studies have shown that lenalidomide is not metabolized by cytochrome P450 enzymes, suggesting that concomitant administration of lenalidomide and drugs that inhibit cytochrome P450 enzymes are unlikely to cause metabolic drug interactions in humans. In vitro studies have shown no inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A or UGT1A1 by lenalidomide. Therefore, lenalidomide is unlikely to cause clinically significant drug-drug interactions when combined with substrates of these enzymes.
In vitro studies have shown that lenalidomide is not a substrate for: human breast cancer resistance protein (BCRP); multidrug resistance protein (MRT) transporters MRP1, MRP2, or MRP3; organic anion transporters (OAT) OAT1 and OAT3; organic anion transporting polypeptide 1B1 (OATP1B1); organic cation transporters (OCT) OCT1 and OCT2; multidrug and toxin extrusion protein (MATE) MATE1 and novel organic cation transporters (OCTN) OCTN1 and OCTN2.
In vitro studies have shown that lenalidomide does not inhibit bile salt export pump (BSEP), BCRP, MRP2, OAT1, OAT3, OATP1B1, OATP1B3 or OCT2. Lenalidomide also did not inhibit the formation of bilirubin glucosinolate in human liver microsomes of UGT1A1 genotype UGT1A1*1/*1, UGT1A1*1/*28, and UGT1A1*28/*28.
Plasma half-life is approximately 3 hours in healthy volunteers in the dose range of 5 to 25 mg/day; 3 to 5 hours in patients with multiple myeloma, myelodysplastic syndromes, or sarcoid lymphoma.
Excretion
Lenalidomide is excreted primarily through the urinary tract. In subjects with normal renal function, renal excretion accounts for 90% of total clearance, and 4% of lenalidomide is excreted in the feces.
Lenalidomide is rarely metabolized and 82% of the dose is excreted in the urine as the drug in its original form. Hydroxy lenalidomide and N-acetyl lenalidomide accounted for 4.59% and 1.83% of the excretion, respectively. The renal clearance of lenalidomide exceeds the glomerular filtration rate, so there is at least some active secretion of the drug.
Special Populations
Pediatric Patients
No pharmacokinetic data are available for the use of lenalidomide in patients under 18 years of age.
Geriatric Patients
No specific clinical studies have been performed to evaluate the pharmacokinetics of lenalidomide in the elderly population. Population pharmacokinetic analyses included patients ranging in age from 39 to 85 years and showed no effect of age on the clearance (plasma exposure) of lenalidomide. Because older patients are more likely to have decreased renal function, caution should be exercised in dose selection and monitoring of renal function.
Patients with Renal Insufficiency
A pharmacokinetic study of lenalidomide was conducted in US patients with renal insufficiency of non-malignant origin. In this study, five patients with mild renal insufficiency (CLcr 56-74 mL/min), six patients with moderate renal insufficiency (CLcr 33-46 mL/min), six patients with severe renal insufficiency (CLcr 17-29 mL/min) and six patients with end-stage renal disease requiring dialysis received a single oral dose of 25 mg lenalidomide. The control group was 7 healthy subjects of similar age with normal renal function (CLcr 83-145 mL/min) who also received 25 mg of lenalidomide as a single oral dose. The results of this study showed that the pharmacokinetic profile of lenalidomide in patients with mildly impaired renal function was similar to that of healthy subjects. Patients with moderate to severe renal insufficiency had a 3-fold longer half-life, while their total clearance was reduced by 66% to 75% compared to healthy subjects. Patients requiring hemodialysis had an approximately 4.5-fold longer half-life and their total clearance was 80% lower than that of healthy subjects. Patients with renal insufficiency cleared approximately 30% of the drug from their bodies after 4 hours of dialysis. The recommended adjusted dose for patients with renal insufficiency is described in detail in [DOSAGE AND ADMINISTRATION].
Patients with Hepatic Insufficiency
Population pharmacokinetic analysis including a population of patients with mild hepatic impairment (N = 16, total bilirubin > 1.0 ≤ 1.5 x ULN or AST > ULN) showed that mild hepatic impairment did not affect the distribution of lenalidomide in the body. No data are available for patients with moderate to severe hepatic injury.
Other Factors Affecting Pharmacokinetics
Population pharmacokinetic analysis showed that body weight (33-135 kg), gender, race, and different types of malignant hematologic neoplasms did not affect the clearance of lenalidomide in adult patients.
Pharmacokinetics in Chinese patients with multiple myeloma
A pharmacokinetic study was conducted in 11 Chinese patients with refractory/recurrent multiple myeloma who received a daily dose of 25 mg of lenalidomide. Plasma concentrations of lenalidomide peaked after approximately 1 hour of administration, with a mean terminal half-life of approximately 3 hours. The mean plasma exposure levels (Cmax and AUC) observed in Chinese patients were similar to historical data obtained from Caucasian patients.
[Storage].
Seal and store at room temperature (10~30℃).
Package】
Polyvinyl chloride/polyvinylidene chloride solid pharmaceutical compound hard tablets, pharmaceutical aluminum foil; aluminum-plastic packaging, plus composite film bag; 7 capsules/plate, 3 plates/bag/box.
[Expiration date
24 months
【Execution standard
【Approval number
【Drug marketing license holder and manufacturer】 【Approval number
Company Name: Yangtze River Pharmaceutical Group Co.
Address: No. 1, Yangzijiang South Road, Taizhou City, Jiangsu Province
Postal Code: 225321
Telephone number: 400-988-1999
Fax number: (0523) 86976161
Web
Address: www.yangzijiang.com