Date of approval.
Date of revision.
Pemetrexed Disodium for Injection Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Pemetrexed Disodium for Injection
English name: Pemetrexed Disodium for Injection
Hanyu Pinyin: Zhusheyong Peimeiqusai Erna
【Component】Pemetrexed Disodium for Injection
Chemical name: L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-alkyl)ethyl]benzoyl]-,disodium salt, 2.5 hydrate
Chemical structure formula.
Molecular Formula: C20H19N5Na2O6-2.5H2O Molecular Weight: 516.43
Excipients include: mannitol, hydrochloric acid, sodium hydroxide
【Properties】It is a white to light yellow or slightly yellow-green freeze-dried solid.
Indications
Non-small cell lung cancer
It is used in combination with cisplatin for the first-line chemotherapy of patients with locally advanced or metastatic non-squamous cell type non-small cell lung cancer.
It is indicated alone for the maintenance treatment of patients with locally advanced or metastatic non-squamous cell type non-small cell lung cancer who have not progressed after 4 cycles of platinum-based first-line chemotherapy.
This product alone is indicated for the treatment of patients with locally advanced or metastatic non-squamous cell type non-small cell lung cancer that has progressed after prior first-line chemotherapy.
It is not recommended for use in patients with predominantly squamous cell carcinoma histology.
Malignant pleural mesothelioma
This product is used in combination with cisplatin for the treatment of inoperable malignant pleural mesothelioma.
【Specification】.
In C20H21N5O6, (1) 100mg (2) 500mg
Dosage and Administration
This product must be used under the supervision of a qualified physician with experience in the application of antineoplastic chemotherapy. This product can only be used for intravenous infusion.
The preparation of the solution must be in accordance with the instructions of “Preparation of Intravenous Infusion Solution”.
Combination of this product with cisplatin.
Non-squamous cell non-small cell lung cancer and malignant pleural mesothelioma
The recommended dose of this product is 500 mg/m2 body surface area (BSA) over 10 minutes of intravenous infusion. It is administered in cycles of 21 days on day 1 of each cycle. The recommended dose of cisplatin is 75 mg/m2 BSA, which should be infused intravenously over 2 hours, and should be given approximately 30 minutes after the end of pemetrexed administration on day 1 of a 21-day cycle. A suitable hydration regimen should be in place before and/or after receiving cisplatin therapy (see cisplatin instructions for specific dosing recommendations).
This product is administered alone to.
Non-squamous cell type non-small cell lung cancer
For patients with non-small cell lung cancer who have received prior chemotherapy, the recommended dose of this product is 500 mg/m2 BSA administered over 10 minutes by intravenous infusion. Dose is given every 21 days on day 1 of each cycle.
Premedication
Vitamin supplementation
To reduce toxicity, patients treated with pemetrexed must be instructed to take a low-dose oral folic acid preparation or a multivitamin containing folic acid daily. Oral folic acid must be given once daily for at least 5 of the 7 days prior to the first pemetrexed dose and should be continued throughout the course of treatment and for 21 days after the last pemetrexed dose. Patients must also receive one intramuscular injection of vitamin B12 during the week prior to the first dose of pemetrexed and every 3 cycles thereafter. At subsequent vitamin B12 injections, they can be scheduled on the same day as pemetrexed. In clinical trials, the doses of folic acid tested ranged from 350 to 1000 μg and the dose of vitamin B12 was 1000 μg. The most commonly used oral dose of folic acid in clinical trials was 400 μg (see [Precautions]).
Corticosteroid supplementation
The occurrence of rash is more common in patients who do not receive preadministered corticosteroids. Preadministration of dexamethasone (or equivalent) may reduce the incidence and severity of skin reactions. In clinical trials, pemetrexed administration of dexamethasone 4 mg twice daily by mouth was administered the day before, the day of, and the day after pemetrexed administration (see [Precautions]).
Recommendations for Laboratory Monitoring and Dose Adjustment
Monitoring
A complete blood count, including platelet count, should be performed in all patients receiving pemetrexed. Patients should be monitored for nadir and recovery, and in clinical trials, checked before each dose and on days 8 and 15 of each cycle. Periodic biochemical tests should also be performed prior to each dose to assess renal and liver function. The only time to assess renal function is when the absolute neutrophil count (ANC) is ≥1500 cells/mm3, platelet count is ≥100,000 cells/mm3, creatinine clearance is ≥45 mL/min, total bilirubin is ≤1.5 times the upper limit of normal, and alkaline phosphatase (AP), aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT) ≤ 3 times the upper limit of normal before the patient can start the next cycle of treatment. If the tumor involves the liver, alkaline phosphatase, AST and ALT ≤ 5 times the upper limit of normal values are acceptable (see [Precautions]).
Dose Adjustment
At the start of the next treatment cycle, dose adjustment is required based on the lowest blood cell count and the most severe non-hematologic toxicity of the previous treatment cycle. Treatment may be delayed in order to obtain adequate recovery time. After recovery, the patient should be retreated according to the guidelines in Table 1-3, which apply to dose adjustment when pemetrexed is administered as monotherapy or in combination with cisplatin.
Table 1: Dose adjustment for pemetrexed (monotherapy or combination) and cisplatin due to hematologic toxicity
Absolute neutrophil minimum <500/mm3 and platelet minimum ³50,000/mm3 75% of original dose (pemetrexed and cisplatin) Platelet minimum <50,000/mm3 regardless of absolute neutrophil minimum 75% of original dose (pemetrexed and cisplatin) Platelet minimum <50,000/mm3 with bleedinga regardless of Absolute neutrophil minimum of 50% of original dose (pemetrexed and cisplatin)a NCI's CTC criteria (CTC v2.0; NCI, 1998)³ Definition of CTC grade 2 bleeding. ctc = Common Toxicity Response Criteria.
If a patient experiences ³Grade 3 non-hematologic toxicity (excluding neurotoxicity), treatment with this product should be suspended until it returns to pretreatment levels or slightly below pretreatment levels. Treatment should be resumed in accordance with the guidelines in Table 2.
Table 2: Dose adjustment for pemetrexed (alone or in combination) and cisplatin due to non-hematologic toxicitya,b
Pemetrexed dose (mg/m2) Cisplatin dose (mg/m2) 75% of original dose for any grade 3 or 4 toxicity other than mucositis 75% of original dose for diarrhea requiring hospitalization (regardless of grade) or 75% of original dose for grade 3 or 4 diarrhea 75% of original dose for grade 3 or 4 mucositis 50% of original dose for grade 3 or 4 100% of original dosea CTC criteria for NCI
bExcluding neurotoxicity (see Table 3)
Neurotoxicity occurs, see Table 3 for dose adjustment of this product and cisplatin. if grade 3 or 4 neurotoxicity occurs, treatment should be discontinued.
Table 3: Dose adjustment for pemetrexed (alone or in combination) and cisplatin due to neurotoxicity
CTCa Graded pemetrexed dose (mg/m2) cisplatin dose (mg/m2) 0-1 100% of original dose 100% of original dose2 100% of original dose 50% of original dosea NCI’s CTC criteria (CTC v2.0; NCI, 1998)
Discontinuation Recommendations
Pemetrexed therapy should be discontinued if the patient experiences a recurrence of any hematologic or nonhematologic grade 3 or 4 toxicity after 2 dose reductions, or immediately if grade 3 or 4 neurotoxicity has occurred.
Patients with renal impairment
In clinical trials, patients with creatinine clearance ≥45 mL/min did not require dose adjustment beyond the dose adjustment recommendations given to all patients. Because of the insufficient number of treated patients with creatinine clearance below 45 mL/min, dose adjustment recommendations could not be provided for this group of patients (see [Pharmacokinetics]). Therefore, creatinine clearance calculated from the standard Cockcroft and Gault formula (see below) or calculated from glomerular filtration rate (GFR) measured by the Tc99m-DPTA serum clearance method should not be administered if the patient has a creatinine clearance <45 mL/min.
Men: [140 – age] × actual body weight (kg) = mL/min72 × serum creatinine (mg/dL) Women: estimated creatinine clearance in men × 0.85 Caution should be exercised when administering pemetrexed in combination with a nonsteroidal anti-inflammatory drug (NSAID) in patients with a creatinine clearance <80 mL/min (see [Drug Interactions]).
Patients with hepatic impairment.
No relationship was found between AST (SGOT), ALT (SGPT), or total bilirubin and pemetrexed pharmacokinetics. No specific studies were performed in patients with hepatic impairment, such as bilirubin > 1.5 times the upper limit of normal and/or transaminases > 3.0 times the upper limit of normal (in the absence of liver metastases) or > 5.0 times the upper limit of normal (in the presence of liver metastases).
Dosing and Administration Precautions
As with other potentially toxic anticancer drugs, pemetrexed solution should be handled and dispensed with caution. Gloves are recommended. If pemetrexed solution comes in contact with the skin, wash the skin immediately and thoroughly with soap and water. If mucous membranes come in contact with pemetrexed, rinse thoroughly with water.
Pemetrexed is not a herpetogenic agent. There is no specific antidote for pemetrexed extravasation. To date, there have been few reports of severe extravasation of pemetrexed. Treatment of pemetrexed extravasation can be done in accordance with local practice for non-herpetic extravasation.
Preparation of intravenous infusion solutions
1. redissolve and further dilute pemetrexed intravenous infusion solution should be performed aseptically.
2. Calculate the dose of this product and the number of vials used. Each bottle contains a certain amount of excess pemetrexed to ensure that the extraction amount reaches the labeled amount.
3. Dissolve each vial with 20mL (0.5g size) of 0.9% sodium chloride injection (no preservative) to a concentration of 25mg/mL of pemetrexed solution. Slowly rotate until the powder is completely dissolved. The resulting solution is clarified and a colorless to yellow or yellow-green color is normal. The pH of the redissolved solution is 6.6-7.8. and the solution needs to be further diluted.
The solution must be observed for particulate matter and color change before intravenous infusion; if insoluble particles are found, it should not be infused.
The redissolved pemetrexed solution must be further diluted to 100 mL with preservative-free 9 mg/mL (0.9%) sodium chloride injection and infused intravenously over 10 minutes.
Under refrigerated conditions, the chemical and physical properties of the redissolved pemetrexed solution and the infused solution can remain stable for 24 hours after redissolution. The pemetrexed redissolution solution and infusion solution prepared as described above do not contain antimicrobial preservatives. For one-time use only, the unused solution should be discarded.
Pemetrexed prepared as described above is suitable for use with polyvinyl chloride (PVC) delivery devices and intravenous infusion bags.
Prior to intravenous infusion, only 0.9% sodium chloride injection (without preservative) is recommended for redissolution and further dilution prior to intravenous infusion. Pemetrexed is physically incompatible with calcium-containing diluents, including Lactated Ringer’s Injection (USP) and Ringer’s Injection (USP), and therefore, these solutions should not be used. The combination of pemetrexed with other drugs and diluents has not been studied; therefore, the use of pemetrexed in combination with other drugs and diluents is not recommended.
[Adverse Reactions].
Because of the wide variation in conditions among clinical trials, the rate of adverse reactions cannot be used directly to compare with the rate of adverse reactions in other clinical trials and is unlikely to reflect the rate of adverse reactions observed in clinical practice.
In clinical trials, the most common adverse reactions (incidence ≥ 20%) when treated with pemetrexed monotherapy were malaise, nausea and loss of appetite. When pemetrexed was combined with cisplatin, increased common adverse reactions (incidence ≥ 20%) included vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation.
Experience from foreign clinical studies.
Non-small cell lung cancer (NSCLC) – in combination with cisplatin
Table 4 reports the incidence and severity of adverse reactions reported in >5% of the 839 initial NSCLC patients randomized to pemetrexed plus cisplatin in the trial and in the 830 NSCLC patients randomized to gemcitabine plus cisplatin. All patients received the trial treatment as initial therapy for locally advanced or metastatic non-small cell lung cancer, and both groups received adequate amounts of folic acid and vitamin B12 supplementation.
Table 4: Adverse reactions in patients with non-small cell lung cancer treated with pemetrexed plus cisplatin who received adequate supplementationa
Adverse reactionsb Pemetrexed/cisplatin (N=839) Gemcitabine/cisplatin (N=830) All grade toxicity (%) Grade 3-4 toxicity (%) All grade toxicity (%) Grade 3-4 toxicity
(%) All adverse reactions 90 37 91 53 Laboratory Hematology Anemia 33 6 46 10 Neutropenia 29 15 38 27 Leukopenia 18 5 21 8 Thrombocytopenia 10 4 27 13 Renal Creatinine elevation 10 1 7 1 Clinical Systemic symptoms Malaise 43 7 45 5 Gastrointestinal nausea 56 7 53 4 Vomiting 40 6 36 6 Anorexia 27 2 24 1 Constipation 21 1 20 0 Stomatitis/pharyngitis14 1 12 0 Diarrhea12 1 13 2 Dyspepsia/heartburn5 0 6 0 Neurologic Neuropathy-sensory9 0 12 1 Taste disturbance8 0c9 0c Dermatology/skin Alopecia12 0c21 1c Rash/desquamation7 0 8 1 a In this table, all events with an incidence ≥5% that the reporter believes may be related to pemetrexed are included.
b All toxicity levels were referenced to NCI CTC 2.0 criteria.
c This adverse event terminology can only be reported as Grade 1 or 2 according to the NCI CTC 2.0 criteria.
No clinically meaningful differences were found between subgroups of different histological types.
In addition to a lower incidence of hematologic toxicity in the pemetrexed plus cisplatin group compared with the gemcitabine plus cisplatin group, the use of blood transfusions (red blood cells and platelets) and hematopoietic growth factors was also less in this group than in the gemcitabine plus cisplatin group.
The following adverse reactions were also observed in patients with non-small cell lung cancer randomized to pemetrexed plus cisplatin.
Incidence 1% to 5%
Systemic – febrile neutropenia, infection, fever
General disorders – dehydration
Metabolic and nutritional – AST elevation, ALT elevation
Renal – decreased creatinine clearance, renal failure
Special sensations – conjunctivitis
Incidence <1%
Cardiovascular – arrhythmias
General disorders – Chest pain
Metabolic and nutritional – elevated glutamyl transpeptidase (GGT)
Neurological – Motor neuropathy
Non-small cell lung cancer (NSCLC) – maintenance therapy
Table 5 reports the incidence and severity of adverse reactions reported in >5% of the 438 patients with NSCLC who received pemetrexed and 218 patients with NSCLC who received placebo. All patients received the trial drug immediately after receiving 4 cycles of a platinum-containing regimen. Patients in both groups received folic acid and vitamin B12 supplementation.
Table 5: Adverse reactions occurring in patients with non-small cell lung cancer receiving pemetrexed and comparison with placeboa
Adverse reactionsb Pemetrexed (N=438) Placebo (N=218) All grades of toxicity (%) Grade 3-4 toxicity
(%) All levels of toxicity (%) Grade 3-4 toxicity
(%) All adverse reactions 66 16 37 4 Laboratory Hematology Anemia 15 3 6 1 Neutropenia 6 3 0 0 Leukopenia 6 2 1 1 1 Liver ALT elevation 10 0 4 0 AST elevation 8 0 4 0 Clinical Systemic symptoms Malaise 25 5 11 1 Gastrointestinal Nausea 19 1 6 1 Anorexia 19 2 5 0 Vomiting 9 0 1 0 Mucositis/stomatitis 7 1 2 0 Diarrhea 5 1 3 0 Infection 5 2 2 0 Nerve Neuropathy-sensory9 1 4 0 Skin Rash/desquamation10 0 3 0 a In this table, all events with an incidence ≥5% that the reporter believes may be related to pemetrexed are included.
b All toxicity classes were referenced to NCI CTC 2.0 criteria.
No clinically meaningful differences in the incidence of grade 3/4 adverse reactions were found between subgroups by age, sex, race, or histology, with only Caucasian patients having a greater incidence of grade 3/4 malaise than non-Caucasian patients (6.5% vs 0.6%).
Patients receiving at least one dose of pemetrexed (N=438) were evaluated for safety based on exposure. The incidence of adverse reactions was assessed in patients who received ≤6 cycles of pemetrexed and compared with patients who received pemetrexed>for 6 cycles. The incidence of adverse reactions (all grades) increased with longer exposure; however, no clinically meaningful differences were found for grade 3/4 adverse reactions.
Consistent with the higher incidence of anemia (all grades) in the pemetrexed group, the use of blood transfusions (mainly erythrocytes) and erythropoietin-stimulating factors (ESAs; erythropoietin and darbepoetin) was greater in the pemetrexed group than in the placebo group (9.5% vs 3.2% for blood transfusions and 5.9% vs 1.8% for ESAs, respectively).
The following adverse reactions were also observed in patients with non-small cell lung cancer randomized to receive pemetrexed.
Incidence 1% to 5%
Dermatologic/cutaneous – alopecia, pruritus/itch
Gastrointestinal – constipation
General disorders – edema, fever (without neutropenia)
Hematology – thrombocytopenia
Renal – decreased creatinine clearance, elevated creatinine, decreased glomerular filtration rate
Special sensations – ocular surface disease (including conjunctivitis), increased tearing
Incidence <1%
Cardiovascular – Supraventricular arrhythmias
Dermatology/skin – Erythema multiforme
General disorders – febrile neutropenia, allergic reactions/hypersensitivity reactions
Neurological – Motor neuropathy
Renal – renal failure
Non-small cell lung cancer (NSCLC) – second-line therapy
Table 6 reports the incidence and severity of adverse reactions reported in >5% of the 265 patients randomized to pemetrexed monotherapy and folic acid and vitamin B12 supplementation and 276 patients randomized to docetaxel. All of these patients were diagnosed with locally advanced or metastatic non-small cell lung cancer and had received prior chemotherapy.
Table 6: Incidence of adverse reactions in patients with non-small cell lung cancer receiving pemetrexed and adequate supplemental therapy and in patients with non-small cell lung cancer receiving docetaxela
Adverse reactionsb Pemetrexed (N=265) Docetaxel (N=276) All grades of toxicity (%) Grade 3-4 toxicity
(%) All levels of toxicity (%) Grade 3-4 toxicity
(%) Laboratory Hematology Anemia 19 4 22 4 Leukopenia 12 4 34 27 Neutropenia 11 5 45 40 Thrombocytopenia 8 2 1 0 Liver ALT elevation 8 2 1 0 AST elevation 7 1 1 0 Clinical Gastrointestinal Nausea 31 3 17 2 Anorexia 22 2 24 3 Vomiting 16 2 12 1 Stomatitis/pharyngitis 15 1 17 1 Diarrhea 13 0 24 3 Constipation 6 0 4 0 Systemic symptoms Malaise34 5 36 5 Fever 8 0 8 0 Dermatology/skin Rash/desquamation14 0 6 0 Pruritus7 0 2 0 Alopecia6 1c38 2ca In this table, all events with an incidence ≥5% that the reporter believes may be related to pemetrexed are included.
b All toxicity levels were referenced to NCI CTC 2.0 criteria.
cThe adverse event terminology can only be reported as Grade 1 or 2 according to the NCI CTC 2.0 criteria.
No clinically meaningful differences were found between subgroups of different histological types.
The incidence <5% in pemetrexed-treated patients but >5% in docetaxel-treated patients, clinically meaningful adverse reactions included CTC grade 3/4 febrile neutropenia (1.9% for pemetrexed and 12.7% for docetaxel).
The following adverse reactions were also observed in patients with non-small cell lung cancer randomized to pemetrexed treatment.
Incidence 1% to 5%
Systemic – abdominal pain, allergic reactions/hypersensitivity reactions, febrile neutropenia, infections
Dermatologic/cutaneous – erythema multiforme
Neurologic – motor neuropathy, sensory neuropathy
Renal – elevated creatinine
Incidence <1%
Cardiovascular – supraventricular tachycardia
Malignant pleural mesothelioma (MPM) – in combination with cisplatin
Table 7 reports the incidence and severity of adverse reactions reported in >5% of 168 patients with malignant pleural mesothelioma randomized to cisplatin plus pemetrexed and in 163 patients with malignant pleural mesothelioma randomized to cisplatin monotherapy. Both groups were chemotherapy-free and received adequate folic acid and vitamin B12 supplementation.
Table 7: Adverse reactions in patients with malignant pleural mesothelioma who received pemetrexed plus cisplatin and adequate supplementationa
Adverse reactionsb Pemetrexed/cisplatin (N=168) Cisplatin (N=163) All grades of toxicity (%) Grade 3-4 toxicity
(%) All levels of toxicity (%) Grade 3-4 toxicity
(%) Laboratory Hematology Neutropenia56 23 13 3 Leukopenia53 15 17 1 Anemia26 4 10 0 Thrombocytopenia23 5 9 0 Renal Creatinine elevation11 1 10 1 Creatinine clearance reduction16 1 18 2 Clinical Ocular abnormalities Conjunctivitis5 0 1 0 Gastrointestinal Nausea82 12 77 6 Vomiting57 11 50 4 Stomatitis/pharyngitis23 3 6 0 Anorexia20 1 14 1 Diarrhea 17 4 8 0 Constipation 12 1 7 1 Dyspepsia 5 1 1 0 Systemic symptoms Malaise 48 10 42 9 Metabolic and nutritional disorders Dehydration 7 4 1 1 Neurological Neuropathy-sensory 10 0 10 1 Taste disturbance 8 0c6 0c Dermatology/skin Rash 16 1 5 0 Alopecia 11 0c6 0ca In this table, the incidence of ≥5% that the reporter believes may be related to pemetrexed is included of all events.
b All toxicity levels are referenced to NCI CTC 2.0 criteria, with “decreased creatinine clearance” derived from the CTC term “renal/genitourinary-other”.
cThis adverse event terminology can only be reported as Grade 1 or 2 according to the NCI CTC 2.0 criteria.
The following adverse reactions were also observed in patients with malignant pleural mesothelioma randomized to receive pemetrexed plus cisplatin.
Incidence 1% to 5%
Systemic – febrile neutropenia, infection, fever
Dermatologic/cutaneous – urticaria
General disorders – Chest pain
Metabolic and nutritional – Elevated AST, elevated ALT, elevated GGT
Renal – Renal failure
Incidence <1%
Cardiovascular – Cardiac arrhythmias
Neurological – motor neuropathy
Effect of vitamin supplementation
Table 8 reports the incidence of CTC grade 3/4 toxicity (percentage of patients) in the pemetrexed plus cisplatin treatment arm in patients who received daily folic acid and vitamin B12 supplementation from trial entry versus those who did not receive vitamin supplementation.
Table 8: Incidence of grade 3/4 adverse events in the pemetrexed plus cisplatin group in patients who received adequate supplementation versus those who did not receive supplementation (%)
Adverse eventsa (%) Patients receiving adequate supplementation
(N=168) Patients not receiving supplemental therapy
(N=32) Neutropenia/granulocytopenia 23 38 Thrombocytopenia 5 9 Vomiting 11 31 Neutropenic fever 1 9 Infection with grade 3/4 neutropenia 0 6 Diarrhea 4 9 a Each toxicity level was based on laboratory and non-laboratory NCI CTC criteria 2.0.
The incidence of the following adverse events was greater in the adequate supplementation group than in the group of patients not receiving supplementation: hypertension (11%, 3%), chest pain (8%, 6%), and thrombosis/embolism (6%, 3%).
Subgroup population
No gender- or race-related factors were found to influence the safety of pemetrexed, and only a greater incidence of rash was found in men (24%) than in women (16%).
Additional Clinical Trial Adverse Reaction Information
Sepsis occurred in approximately 1% of patients in clinical trials, including some fatal cases.
Esophagitis occurred in less than 1% of patients.
Information on post-marketing adverse reactions abroad
The following adverse reactions were identified following the post-marketing use of pemetrexed. Because these adverse reactions were reported voluntarily in a population with an uncertain sample size, it is not possible to reliably estimate the incidence or to reliably determine a causal relationship with drug exposure.
The following adverse reactions can occur with pemetrexed monotherapy or combination therapy.
Hematologic and lymphatic system – Immune-mediated hemolytic anemia
Gastrointestinal – Colitis
General disorders and dosing site abnormalities – Edema
Trauma, toxicity and surgical complications – Radiation recall injuries have been reported in patients who have received prior radiation therapy
Respiratory – Interstitial pneumonia
Skin – Macrophagic disorders have been reported, including Stevens-Johnson Syndrome and toxic epidermal necrolysis, including some fatal cases.
Information on adverse reactions in Chinese patients.
Table 9 reports the incidence of ≥ 2% of patients with possible trial drug-related CTC grade 3 or 4 toxicities in 106 patients in the pemetrexed arm and 102 patients in the docetaxel arm enrolled in the second-line treatment of patients with advanced non-small cell lung cancer (JMID) study in China.
Table 9: Summary of CTC grade 3 or 4 toxicities in patients with an incidence ≥ 2% that may be related to the trial drug in the JMID study
Adverse events Pemetrexed (N=106) n (%) Docetaxel
(N=102) n (%) P-value [a] All adverse events 22 (20.8) 41 (40.2) 0.003 Laboratory Anemia7 (6.6%) 3 (2.9%) 0.333 Leukopenia4 (3.8%) 21 (20.6%) <0.001 Neutropenia/granulocytopenia5 (4.7%) 29 (28.4%) < 0.001 Thrombocytopenia7 (6.6%) 0 (0.0%) 0.014 Non-laboratory Diarrhea0 (0.0%) 5 (4.9%) 0.027 Malaise (weakness, drowsiness, malaise)3 (2.8%) 5 (4.9%) 0.492 Neutropenic fever2 (1.9%) 4 (3.9%) 0.439 Abbreviations: N = total population number; n = number of adverse number of events.
[a] p values were obtained by comparing grade 3 or 4 toxicity in the two treatment groups using Fisher’s exact test.
A total of 252 patients with non-squamous cell non-small cell lung cancer not previously treated with chemotherapy in the first-line treatment study (JMIL) conducted in China were treated with at least one dose of the trial drug. 125 cases in the AC group and 127 cases in the GC group. Overall, AC was better tolerated. Patients in both treatment groups received a similar number of treatment cycles (median of 6 cycles in both groups), while the AC group required fewer dose adjustments. significantly fewer patients in the AC group had at least one grade 3 or 4 TEAE than in the GC group (63 [50.4%] vs. 84 [66.1%]; p=0.015). Moreover, the proportion of patients with ≥1 possible drug-related grade 3 or 4 adverse event was significantly lower in the AC group (43.2%) than in the GC group (55.9%) (p=0.045). In particular, the incidence of anemia (50 [40.0%] vs. 76 [59.8%]; p=0.002), thrombocytopenia (50 [40.0%] vs. 76 [59.8%]; p=0.002) and rash (4 [3.2%] vs. 15 [11.8%]; p=0.015) was significantly lower in patients in the AC group than in patients in the GC group.
Table 10 lists the frequency and severity of adverse events with an incidence greater than 5%, potentially related to the trial drug and graded by CTCAE, in Chinese patients in the global registry clinical study of maintenance therapy for non-small cell lung cancer (JMEN).
Table 10: Frequency of drug-related adverse events occurring in >5% of all Chinese patients in the JMEN study
Frequencya Eventb Pemetrexed placebo (N = 62) (N = 37) All grades 3 and 4 All grades 3 and 4 (%) (%) (%) (%) Very common Fatigue 32.3 1.6 16.2 2.7 Anorexia 30.6 1.6 13.5 0.0 Elevated ALT (SGPT) 22.6 1.6 16.2 0.0 Rash/desquamation 17.7 0.0 5.4 0.0 AST (SGOT) elevated 16.1 0.0 16.2 0.0 Nausea 16.1 0.0 2.7 0.0 Leukopenia 14.5 0.0 2.7 0.0 Neutropenia/granulocytopenia 11.3 1.6 0.0 0.0 Neuropathy-sensory 11.3 0.0 0.0 0.0 0.0 Common hyperpigmentation 9.7 0.0 0.0 0.0 Fever (none) neutropenia) 8.1 0.0 0.0 0.0 0.0 Edema-head and neck 6.5 0.0 0.0 0.0 0.0 Overflowing tears 6.5 0.0 0.0 0.0 0.0 Abbreviations: ALT=glutamate aminotransferase; AGC=granulocyte absolute count; ANC=neutrophil absolute count; AST=aspartate aminotransferase; CTCAE=adverse event (toxic reaction) common (terminology and grading) criteria (version 3.0, NCI 2003); G=grading; N=number of randomized patients; SGOT=serum glutamic oxalacetic transaminase; SGPT=serum glutamic alanine transaminase; WBC=white blood cells.
a Definition of frequency of occurrence: very common = ≥10%; common = ≥5% but <10%. For events considered by the reporter to be potentially associated with pemetrexed, this table uses a threshold value of 5% as the criterion for event inclusion.
b The toxicity classification was referenced to the CTCAE criteria (version 3.0, NCI 2003).
[Contraindicated].
Pemetrexed is contraindicated in patients with a history of severe hypersensitivity to pemetrexed or any other component of this formulation.
Concomitant vaccination against yellow fever is contraindicated (see [Drug Interactions]).
[Precautions].
Premedication
Folic acid and vitamin B12 supplementation is required
To reduce treatment-related hematologic and gastrointestinal toxicity, patients treated with pemetrexed must be instructed to supplement with folic acid and vitamin B12 as a precautionary measure (see [Dosage]). In clinical trials, the overall toxicity of grade 3/4 hematologic and non-hematologic toxicities such as neutropenia, febrile neutropenia, and infections with grade 3/4 neutropenia were lower and occurred at a reduced rate when folic acid and vitamin B12 were given preemptively.
Corticosteroid supplementation
Higher incidence of rash in patients not receiving corticosteroid prolotherapy in clinical trials. Preadministration of dexamethasone (or equivalent) reduces the incidence and severity of skin reactions (see [DOSAGE]).
Bone marrow suppression
Pemetrexed can suppress the bone marrow as evidenced by neutropenia, thrombocytopenia, and anemia (or pancytopenia) (see [ADVERSE REACTIONS]); myelosuppression is usually a dose-limiting toxicity. Dose adjustment for subsequent cycles should be determined based on the lowest ANC, platelet count, and most severe non-hematologic toxicity in the previous cycle (see [DOSAGE]).
Decreased Renal Function
Pemetrexed is excreted primarily in its native form via the kidneys. Decreased renal function will result in decreased pemetrexed clearance and increased exposure (AUC) (see [DOSAGE] and [PHARMACOLOGY]). In patients with creatinine clearance ≥45 mL/min, no dose adjustment is required. Because of the limited number of patients with creatinine clearance <45 mL/min in the trial, no dosing recommendations can be derived. Therefore, patients with a creatinine clearance <45 mL/min should not receive pemetrexed (see [DOSAGE]).
One patient with severe renal impairment (creatinine clearance of 19 mL/min) who did not receive folic acid and vitamin B12 died from drug-related toxicity after receiving pemetrexed alone.
Serious renal events, including acute renal failure, have been reported with pemetrexed alone or in combination with other chemotherapeutic agents. Many patients who experience these events have underlying risk factors for developing renal events, including dehydration or preexisting hypertension or diabetes mellitus.
The combination of cisplatin with pemetrexed has not been studied in patients with moderate renal impairment.
Combination with NSAIDs in Patients with Mild to Moderate Renal Insufficiency
Caution should be exercised when combining ibuprofen with pemetrexed in patients with mild-to-moderate renal insufficiency (creatinine clearance 45-79 mL/min). Other NSAIDs should also be used with caution (see [Drug Interactions]).
Patients with hepatic impairment
Elevated AST, ALT, or total bilirubin do not affect the pharmacokinetics of pemetrexed (see [Pharmacokinetics]).
See Table 2 for guidelines on dose adjustment for hepatic impairment occurring during pemetrexed treatment (see [DOSAGE]).
Required Laboratory Monitoring
Patients should begin the next cycle of therapy only if the absolute neutrophil count (ANC) is ≥1,500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and the creatinine clearance is ≥45 mL/min (see [DOSAGE AND ADMINISTRATION]).
Pregnancy Category D
Depending on the mechanism of action of pemetrexed, fetal harm may result when pregnant women receive pemetrexed. Intraperitoneal administration of pemetrexed to mice during organogenesis at doses greater than 1/833 of the recommended human dose can result in embryotoxicity, fetal toxicity, and teratogenicity. Patients should be informed of the potential risk to the fetus if pemetrexed is used during pregnancy or if pregnancy occurs during the use of the drug. Women of childbearing potential should be advised to avoid pregnancy. Female patients should be advised of the need to use effective contraception during pemetrexed treatment (see [Medication for Pregnant and Lactating Women]).
Pemetrexed is genotoxic. Sexually mature males are advised not to have children during treatment and for 6 months thereafter. Use of contraception or abstinence is recommended. Because pemetrexed treatment may lead to irreversible infertility, men are advised to consult about sperm preservation before starting treatment.
Gender
In clinical trials of first-line treatment for non-small cell lung cancer, 70% of patients were male and 30% were female. The HR for overall survival time was 0.97 (95% CI: 0.85, 1.10) for men and 0.86 (95% CI: 0.70, 1.06) for women in the intention-to-treat population.
In clinical trials of maintenance therapy for non-small cell lung cancer, 73% of the patients were men and 27% were women. Among male patients in the intention-to-treat population, the HR for overall survival time was 0.78 (95% CI: 0.63, 0.96) and 0.83 (95% CI: 0.56, 1.21) for women.
In clinical trials of second-line treatment for non-small cell lung cancer, 72% of patients were men and 28% were women. Among male patients in the intention-to-treat population, the HR for overall survival time was 0.95 (95% CI: 0.76, 1.19) and 1.28 (95% CI: 0.86, 1.91) for women.
In the mesothelioma clinical trial, 82% of patients were men and 18% were women. The HR for overall survival time was 0.85 (95% CI: 0.66, 1.09) for men and 0.48 (95% CI: 0.27, 0.85) for women in the intention-to-treat population.
Race
In clinical trials of first-line therapy for non-small cell lung cancer, 78% of patients were Caucasian, 13% were East/Southeast Asian, and 9% were of other ethnic origin. In the intention-to-treat population, the HR for overall survival time was 0.92 (95% CI: 0.82, 1.04) for Caucasians, 0.86 (95% CI: 0.61, 1.21) for East/Southeast Asians, and 1.24 (95% CI: 0.84, 1.84) for other ethnic sources.
In clinical trials of maintenance therapy for non-small cell lung cancer, 65% of patients were Caucasian, 23% were East Asian, and 12% were of other ethnic origin. The HR for overall survival time was 0.77 (95% CI: 0.62, 0.97) for Caucasians in the intention-to-treat population, 1.05 (95% CI: 0.70, 1.59) for East Asians, and 0.46 (95% CI: 0.26, 0.79) for other ethnic sources.
In clinical trials of second-line treatment for non-small cell lung cancer, 71% of patients were Caucasian and 29% were of other ethnic origin. The HR for overall survival time was 0.91 (95% CI: 0.73, 1.15) among Caucasians in the intention-to-treat population and 1.27 (95% CI: 0.87, 1.87) among other ethnic sources.
In the mesothelioma clinical trial, 92% of patients were Caucasian and 8% were of other ethnic origin. The HR for overall survival time was 0.77 (95% CI: 0.61, 0.97) among Caucasians in the intention-to-treat population and 0.86 (95% CI: 0.39, 1.90) among other ethnic sources.
Other
Due to the gastrointestinal toxicity of pemetrexed administered in combination with cisplatin, severe dehydration was previously observed. Therefore, patients should receive adequate antiemetic therapy before and/or after treatment as well as appropriate hydration therapy.
Serious cardiovascular events, including myocardial infarction and cerebrovascular events, were rarely reported during clinical trials with pemetrexed, usually when co-administered with another cytotoxic agent. The majority of patients reporting these events had known cardiovascular risk factors.
Cases of radiation pneumonitis have been reported in patients who received radiation therapy before, during, or after pemetrexed treatment. Special attention should be paid to these patients and caution should be exercised in the use of radiosensitizing agents. Cases of radiation recall injury have been reported in patients who received radiation therapy in the previous weeks or years.
Pregnant women and nursing mothers
Pregnancy
Depending on the mechanism of action of pemetrexed, fetal harm may result when pregnant women receive pemetrexed. Controlled trials of pemetrexed have not been adequately conducted in pregnant women. In mice, pemetrexed is embryotoxic, fetotoxic and teratogenic. During organogenesis, mice receiving repeated intraperitoneal administration of pemetrexed can cause malformation of the mouse fetus (talus and skull ossification insufficiency; approximately 1/833 of the recommended human intravenous dose in mg/m2) and cleft palate (approximately 1/33 of the recommended human intravenous dose in mg/m2). Embryotoxicity may be manifested by increased embryonic mortality and decreased litter size. If pemetrexed is used in pregnancy, or if the patient becomes pregnant during the use of the drug, the patient should be informed of the potential risk to the fetus. Women of childbearing potential should be advised to use effective contraception during pemetrexed treatment to avoid pregnancy.
Women who are breastfeeding
It is not known whether pemetrexed can be secreted from breast milk. Since many drugs are secreted from breast milk and pemetrexed may cause potentially serious adverse reactions in nursing infants, the decision to discontinue nursing or discontinue the drug should be made after full consideration of the importance of the drug to the mother.
Pediatric Dosage]
The safety and efficacy of pemetrexed in pediatric patients have not been established.
Geriatric Use]
Pemetrexed is known to be excreted in large quantities through the kidneys, and therefore the risk of adverse drug reactions may be elevated in patients with renal impairment. Because elderly patients are more likely to experience decreased renal function, doses should be carefully selected. Renal function monitoring is recommended at the time of pemetrexed administration. Dose reductions are not required in patients 65 years of age or older, except for the dose reduction recommendations given to all patients (see [DOSAGE]).
In clinical trials for first-line treatment of non-small cell lung cancer, 37.7% of pemetrexed plus cisplatin-treated patients were ≥65 years of age, and these patients had more grade 3/4 neutropenia than those younger than 65 years of age (19.9% and 12.2%, respectively). The HR for overall survival time was 0.96 (95% CI: 0.83, 1.10) in patients aged <65 years in the intention-to-treat population and 0.88 (95% CI: 0.74, 1.06) in patients aged 65 years or older.
In clinical trials of maintenance therapy for non-small cell lung cancer, 33.3% of pemetrexed-treated patients were ≥65 years of age, and there was no difference between grade 3/4 adverse events and <65 years of age. The HR for overall survival time was 0.74 (95% CI: 0.58, 0.93) in the intent-to-treat population of patients aged <65 years and 0.88 (95% CI: 0.65, 1.21) in patients aged 65 years or older.
In clinical trials of second-line therapy for non-small cell lung cancer, 29.7% of pemetrexed-treated patients were ≥65 years of age, with more grade 3/4 hypertension than <65 years of age. The HR for overall survival time was 0.95 (95% CI: 0.76, 1.19) in the intent-to-treat population of patients <65 years of age and 1.15 (95% CI: 0.79, 1.68) in patients 65 years of age or older.
In clinical trials in mesothelioma, 36.7% of patients treated with pemetrexed plus cisplatin were ≥65 years of age and had more grade 3/4 malaise, leukopenia, neutropenia, and thrombocytopenia than <65 years of age. The HR for overall survival time was 0.71 (95% CI: 0.53, 0.96) in patients aged <65 years in the intention-to-treat population and 0.85 (95% CI: 0.59, 1.22) in patients aged 65 years or older.
[Drug Interactions].
Non-steroidal anti-inflammatory drugs (NSAIDs)
Ibuprofen
Although ibuprofen (400 mg 4 times daily) may reduce the clearance of pemetrexed, it can be combined with pemetrexed in patients with normal renal function (creatinine clearance ≥80 mL/min). Caution is required when combining with higher doses of ibuprofen (>1600 mg/day). Caution should be exercised when combining ibuprofen with pemetrexed in patients with mild to moderate renal insufficiency (creatinine clearance 45-79 mL/min) (see [Pharmacokinetics]).
Other NSAIDs
In patients with normal renal function (creatinine clearance ≥80 mL/min), caution should be exercised when higher doses of NSAIDs or aspirin are administered concomitantly with pemetrexed.
NSAIDs with a short clearance half-life should be avoided in patients with mild to moderate renal insufficiency for 2 days prior to, on the day of, and 2 days after pemetrexed administration.
Because there is no information on potential interactions of pemetrexed with NSAIDs with longer half-lives, all patients on such NSAIDs should discontinue NSAID administration at least 5 days prior to, on the day of, and 2 days after pemetrexed administration. If concomitant administration of NSAIDs is necessary, patients should be closely monitored for toxicity, particularly myelosuppression, renal and gastrointestinal toxicity.
Nephrotoxic drugs
Pemetrexed is primarily cleared by the kidneys as a prodrug through glomerular filtration and renal tubular secretion. Concomitant use of nephrotoxic drugs (e.g., aminoglycosides, myeloid diuretics, platinum compounds, cyclosporine) may result in delayed clearance of pemetrexed. Concomitant use of substances excreted via the renal tubules (e.g., probenecid) may also result in delayed clearance of pemetrexed. Caution should be exercised when co-administering with these drugs and creatinine clearance should be closely monitored if necessary.
Common interactions for all cytotoxic drugs.
Anticoagulant therapy is often used because of the increased risk of thrombosis in cancer patients. The decision to treat patients with oral anticoagulants requires increased frequency of INR (International Normalized Ratio) monitoring due to the high intraindividual variability of anticoagulation status during disease and the potential for interactions between oral anticoagulants and anticancer therapy.
Live attenuated vaccines.
Immunosuppressed states are more common in cancer patients, so concurrent administration of live attenuated vaccines, in addition to yellow fever vaccines, which are contraindicated, is not recommended and may be a systemic risk for fatal disease.
[Drug overdose].
Pemetrexed overdose has been reported rarely. Reported toxicities include neutropenia, anemia, thrombocytopenia, mucositis, and rash. Expected complications of overdose include myelosuppression, which may manifest as neutropenia, thrombocytopenia, and anemia. In addition, infections with or without fever, diarrhea and mucositis may be seen. If an overdose occurs, the treating physician should take routine supportive treatment measures as needed.
In clinical trials, the use of folinic acid is permitted for the treatment of CTC grade 4 leukopenia of ≥3 days duration, CTC grade 4 neutropenia of ≥3 days duration, and immediate treatment with folinic acid if CTC grade 4 thrombocytopenia, bleeding associated with grade 3 thrombocytopenia, or grade 3 or 4 mucositis occurs. The recommended dose and regimen of intravenous folinic acid: 100 mg/m2 administered intravenously once, followed by folinic acid 50 mg/m2 administered intravenously every 6 hours for 8 days.
It is not known whether pemetrexed can be cleared by dialysis.
Pharmacology and Toxicology
Pharmacological effects
Pemetrexed is a multi-targeted folic acid antagonist that inhibits cell replication by disrupting a key folic acid-dependent metabolic process necessary for cell replication. In vitro studies have shown that pemetrexed acts by inhibiting the activity of thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide nucleotide formyltransferase (GARFT), which are all key folate-dependent enzymes for thymine nucleotide and purine nucleotide biosynthesis. Pemetrexed enters the cell via a reduced folate carrier and a folate-binding protein transport system on the cell membrane. Once inside the cell, pemetrexed is converted to the polyglutamic acid form by the action of folyl polyglutamate synthase. The polyglutamic acid form remains in the cell as a more potent inhibitor of TS and GARFT. Polyglutamylation exhibits a time- and concentration-dependent process in tumor cells and to a relatively lesser extent in normal tissues. The half-life of polyglutamylated metabolites in tumor cells is prolonged, which in turn prolongs the duration of drug action in tumor cells.
Preclinical trials have shown that pemetrexed inhibits the growth of mesothelioma cell lines (MSTO-211H, NCI-H2052) in vitro. Trials using the MSTO-211H mesothelioma cell line demonstrated synergistic effects of pemetrexed in combination with cisplatin.
A population pharmacodynamic analysis was performed using absolute neutrophil count (ANC) in patients receiving pemetrexed monotherapy without supplemental treatment with folic acid and vitamin B12. The severity of hematologic toxicity, as measured by the ANC nadir, correlated with pemetrexed systemic exposure or area under the curve. It was also found in the study that ANC nadir was lower if patients had high cystathionine or homocysteine concentrations at baseline. Supplementation with folic acid and vitamin B12 can reduce both of these concentrations. After multiple cycles of pemetrexed treatment, there was no accumulative effect of pemetrexed exposure on ANC nadir.
Pemetrexed exposure (AUC ) was 38.3- 316.8 μg-hr/mL, and the time to decrease ANC to the nadir was approximately 8 to 9.6 days. In the same exposure range, ANC returned to baseline levels in 4.2 to 7.5 days after the nadir.
Toxicological studies.
Carcinogenicity, Mutagenicity, Fertility Impairment
Carcinogenicity studies have not been conducted with pemetrexed. Pemetrexed was found to be fission-inducing in an in vivo micronucleus test in mouse bone marrow, but it was not mutagenic in various in vitro assays (Ames test, CHO cell analysis). Intravenous administration of ≥0.1 mg/kg/day to male mice (at mg/m2, approximately 1/1666 of the recommended human dose) resulted in decreased fertility, sperm reduction, and testicular atrophy.
See [Precautions] for use in male fertility patients and [Pregnancy and Lactation] for use in female patients.
Pharmacokinetics
Absorption
The pharmacokinetics of pemetrexed after a single dose range of 0.2 to 838 mg/m2 over 10 minutes of intravenous infusion was evaluated in 426 patients with different solid tumor cancers. The total systemic exposure (AUC) and peak plasma concentration (Cmax) of pemetrexed increased in proportion to the dose. The pharmacokinetics of pemetrexed did not change after multiple treatment cycles.
Distribution
The steady-state volume of distribution of pemetrexed was 16.1 liters. In vitro tests have shown that the plasma protein binding of pemetrexed is approximately 81% and is not affected by the degree of renal impairment.
Metabolism and excretion
Pemetrexed is metabolized to a low degree and is mainly cleared by the kidneys from urine, with 70% to 90% of the dose recovered in its original form within the first 24 hours after administration. When renal function decreases, clearance decreases and exposure (AUC) increases. In patients with normal renal function (creatinine clearance of 90 mL/min), the total systemic clearance of pemetrexed was 91.8 mL/min with a clearance half-life of 3.5 hours.
The pharmacokinetics of pemetrexed in specific populations were studied in controlled trials and in approximately 400 patients in single-arm trials.
Age effects
No effect of age on the pharmacokinetics of pemetrexed was observed in the range of 26 to 80 years.
Effect of gender
There were no differences in pemetrexed pharmacokinetics between male and female patients.
Ethnicity effects
The pharmacokinetics of pemetrexed were similar between Caucasian and African-American patients. There are insufficient data to compare pharmacokinetics between other ethnic groups.
Effect of Hepatic Insufficiency
Elevated AST, ALT or total bilirubin have no effect on the pharmacokinetics of pemetrexed. However, it has not been studied in patients with hepatic impairment.
Effects of Renal Insufficiency
One hundred twenty-seven patients with decreased renal function were included in the pharmacokinetic analysis of pemetrexed. When renal function was reduced, plasma clearance of pemetrexed decreased and resulted in elevated systemic exposure. Total systemic exposure (AUC) to pemetrexed was increased by 65%, 54%, and 13% in patients with creatinine clearance of 45, 50, and 80 mL/min, respectively, compared to patients with creatinine clearance of 100 mL/min (see [Precautions] and [Dosage]).
Pediatric Patients
Pediatric patients have not been included in clinical trials.
Effects of Ibuprofen
In patients with normal renal function, ibuprofen 400 mg administered 4 times daily decreased the clearance of pemetrexed by approximately 20% (20% increase in AUC). The effect of higher doses of ibuprofen on the pharmacokinetics of pemetrexed is not known (see [Drug Interactions]).
Effects of aspirin
Administration of low and moderate doses of aspirin (325 mg every 6 hours) did not affect the pharmacokinetics of pemetrexed. The effect of higher doses of aspirin on the pharmacokinetics of pemetrexed is not known.
Effect of cisplatin
Cisplatin did not affect the pharmacokinetics of pemetrexed, nor did pemetrexed affect the pharmacokinetics of total platinum.
Effect of vitamins
The combined use of oral folic acid or intramuscular B12 did not affect the pharmacokinetics of pemetrexed.
Drugs metabolized by cytochrome P450 enzymes
Pemetrexed does not produce clinically significant inhibition of metabolic clearance of drugs metabolized by CYP3A, CYP2D6, CYP2C9 and CYP1A2, as predicted by in vitro human liver microsomal assays.
Storage】Sealed and stored at room temperature.
Package】Packaged in glass bottle, 1 bottle/box
Expiration date】 12 months
Execution Standard
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Manufacturer
Enterprise name: Sichuan Huiyu Pharmaceutical Co.
Production address: Neijiang City, Sichuan Province, west of the west side of Road 5, Industrial Park, Lot B
Postal code: 641000
Telephone number: 0832-8808000
Fax number: 0832-8808111
Inquiry：0832-8808096
Web address: http://www.huiyupharma.com