Medicinal Products

ALIMTA 100 mg

Generic drug of the therapeutic class: Oncology and Hematology
Active ingredients: Pemetrexed
laboratory: Eli Lilly Nederland

Powder for concentrate for solution for infusion IV
Box of 1 vial of powder of 100 mg
All forms

Indication

Malignant pleural mesothelioma

ALIMTA, in combination with cisplatin, is indicated for the treatment of patients with unresectable malignant pleural mesothelioma who have not received prior chemotherapy.

Non-small cell lung cancer

ALIMTA, in combination with cisplatin, is indicated for the first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer, as long as the histology is not predominantly squamous (see section 5.1 ). .

ALIMTA is indicated as monotherapy for the maintenance treatment of locally advanced or metastatic non-small cell lung cancer immediately following platinum-based chemotherapy, provided the histology is not predominantly squamous. in patients whose disease has not progressed (see section 5.1 Pharmacodynamic properties ).

ALIMTA is indicated as monotherapy in the second-line treatment of patients with locally advanced or metastatic non-small cell lung cancer, as long as the histology is not predominantly squamous (see section 5.1 ).

Dosage ALIMTA 100 mg Powder for concentrate for solution for infusion IV Box of 1 vial of powder of 100 mg

Dosage

ALIMTA should be administered only under the supervision of a physician qualified in the use of anticancer chemotherapy.

ALIMTA in combination with cisplatin

The recommended dosage of ALIMTA is 500 mg / m² body surface area, as a 10-minute intravenous infusion, on the first day of each 21-day cycle. The recommended dose of cisplatin is 75 mg / m2 body surface infusion over 2 hours, initiated approximately 30 minutes after completion of the pemetrexed infusion on the first day of each 21-day cycle. Patients should receive adequate anti-emetic therapy and appropriate hydration before and / or after cisplatin infusion (refer to the Summary of Product Characteristics of cisplatin for specific dosing recommendations).

ALIMTA monotherapy

In patients treated for non-small cell lung cancer who have received prior chemotherapy, the recommended dose of ALIMTA is 500 mg / m² body surface area, as a 10-minute intravenous infusion, on the first day of each 21-day cycle. days.

Premedication

To reduce the occurrence and severity of skin reactions, corticosteroid therapy should be given the day before, the same day and the day after pemetrexed administration. The dosage should be equivalent to dexamethasone 4 mg orally twice a day (see Warnings and Precautions ).

To reduce the toxicity of pemetrexed, treated patients should also receive vitamin supplementation (see Warnings and Precautions ). Patients should take folate or a combination of folic acid (350 to 1000 micrograms) orally daily. At least five folic acid doses must be taken within 7 days of the first pemetrexed injection, and patients should continue this supplementation for the full course of treatment and for 21 days after the last pemetrexed injection. Patients should also receive an intramuscular injection of vitamin B 12 (1, 000 micrograms) in the week before the first dose of pemetrexed and once every three cycles. Subsequent injections of vitamin B 12 may take place on the same day as pemetrexed administration.

surveillance

Before each administration of pemetrexed, a complete blood count (NFS) with platelet count should be performed. A biochemical assessment will be carried out before each administration of chemotherapy to evaluate the hepatic and renal functions. Before the beginning of each chemotherapy cycle, the absolute number of neutrophils (PNN) must be greater than or equal to 1 500 cells / mm 3 and the number of platelets greater than or equal to 100 000 cells / mm 3 .

The clearance of creatinine must be greater than or equal to 45 ml / min. The total bilirubin level must be less than or equal to 1.5 times the upper limit of normal. The levels of alkaline phosphatase (AP), aspartate transaminase (AST or SGOT) and alanine transaminase (ALT or SGPT) should be less than or equal to 3 times the upper limit of normal. Alkaline phosphatase, ASAT, and ALAT levels of 5 times the upper limit of normal are acceptable for hepatic metastases.

Dose Adjustments

At the beginning of a new cycle, dose adjustments will be based on the nadir blood count and maximum non-haematological toxicity observed in the previous cycle. The treatment can be deferred the time required for recovery. Upon recovery, patients should be treated again according to the recommendations in Tables 1, 2 and 3, which relate to ALIMTA used as monotherapy and in combination with cisplatin.

Table 1 - Table of modification of doses of ALIMTA (as monotherapy or in combination) and cisplatin - Hematologic toxicities

In nadir: PNN <500 / mm 3 and platelets ≥ 50 000 / mm 3

75% of the previous dose (for ALIMTA and cisplatin)

In nadir: platelets <50 000 / mm 3 regardless of the PNN rate

75% of the previous dose (for ALIMTA and cisplatin)

Nadir: platelets <50, 000 / mm 3 with bleeding a, regardless of the PNN level

50% of the previous dose (for ALIMTA and cisplatin)

a These criteria meet the National Cancer Institute Common Criteria for Toxicity (CTC) ≥ Grade 2 bleeding definition (v2.0, NCI 1998).

For non-hematologic toxicities ≥ Grade 3 (excluding neurotoxicity), ALIMTA therapy should be suspended until resolution at or below the baseline of the patient prior to treatment. Treatment should be continued according to the recommendations in Table 2.

Table 2 - Modification table of doses of ALIMTA (as monotherapy or in combination) and cisplatin - Non-haematological toxicities ab

Dose of ALIMTA

(Mg / m²)

Dose of cisplatin

(Mg / m²)

Any grade 3 or 4 toxicity, except mucositis

75% of the previous dose

75% of the previous dose

Any diarrhea requiring hospitalization (regardless of grade) or grade 3 or 4 diarrhea

75% of the previous dose

75% of the previous dose

grade 3 or 4 mucositis

50% of the previous dose

100% of the previous dose

a Common Criteria for Toxicity (CTC) of the National Cancer Institute (v2.0, NCI 1998)

b Excluding neurotoxicity

In case of neurotoxicity, it is recommended to adjust the doses of ALIMTA and cisplatin as specified in Table 3. Patients should discontinue treatment if grade 3 or 4 neurotoxicity is observed.

Table 3 - Amended dose table for ALIMTA (as monotherapy or combination therapy) and cisplatin - Neurotoxicity

CTC grade a

Dose of ALIMTA (mg / m²)

Dose of cisplatin (mg / m²)

0 - 1

100% of the previous dose

100% of the previous dose

2

100% of the previous dose

50% of the previous dose

a Common Criteria for Toxicity (CTC) of the National Cancer Institute (v2.0, NCI 1998)

Treatment with ALIMTA should be discontinued if the patient has grade 3 or 4 haematological or non-haematological toxicity after 2 dose reductions or immediately if grade 3 or 4 neurotoxicity is observed. Elderly: In clinical trials, there was no evidence of a higher risk of adverse events in patients 65 years of age or older compared to patients younger than 65 years of age. Dose reductions other than those recommended for all patients are not necessary.

Pediatric population

There is no justified use of ALIMTA in the pediatric population in malignant pleural mesothelioma and non-small cell lung cancer.

Patients with renal impairment (standard Cockcroft and Gault formula or glomerular filtration rate measured by the Tc99m-DTPA plasma clearance method): Pemetrexed is essentially eliminated unchanged in the urine. In clinical studies, dose adjustments other than those recommended for all patients were not necessary in patients with creatinine clearance ≥ 45 ml / min. In patients with creatinine clearance <45 ml / min, there is insufficient data; therefore, the use of pemetrexed is not recommended in these patients (see Warnings and Precautions ).

Hepatic impairment: No relationship between AST (SGOT), ALT (SGPT) or total bilirubin levels and the pharmacokinetics of pemetrexed has been identified. However, no specific study was conducted in patients with hepatic impairment with a bilirubin level above 1.5 times the upper limit of normal and / or a transaminase level greater than 3 times the limit. higher than normal (in the absence of liver metastases) or greater than 5 times the upper limit of normal (in case of liver metastases).

Administration mode

For precautions to be taken before handling or administering ALIMTA, see section Instructions for use, handling and disposal .

ALIMTA should be given as an intravenous infusion for 10 minutes on the first day of each 21-day cycle. For instructions on reconstitution and dilution of ALIMTA before administration, see section Instructions for use, handling and disposal .

Against indications

Hypersensitivity to the active substance or to any of the excipients.

Breast-feeding (see section Pregnancy and breast-feeding ).

Concomitant use with yellow fever vaccine (see section 4.5 Interaction with other medicinal products and other forms of interaction ).

Alimta side effects

Tolerance Profile Summary

The most commonly reported adverse events related to pemetrexed, used alone or in combination, are bone marrow depression such as anemia, neutropenia, leukopenia, thrombocytopenia; as well as gastrointestinal toxicities such as anorexia, nausea, vomiting, diarrhea, constipation, pharyngitis, mucositis and stomatitis. Other side effects include: renal toxicity, elevated transaminases, alopecia, fatigue, dehydration, rash, infection / sepsis, and neuropathy. Effects rarely seen include Stevens-Johnson syndrome and Lyell's syndrome.

Tabulated list of adverse effects

The following table presents the frequency and severity of adverse events observed in more than 5% of the 168 patients with mesothelioma included in the arm receiving cisplatin and pemetrexed and 163 patients with mesothelioma included in the arm receiving cisplatin monotherapy. . In both arms of the study, these patients had never received chemotherapy and were supplemented with folic acid and vitamin B 12 .

Side effects

Frequency estimate: Very common (≥ 1/10), Common (≥ 1/100, <1/10), Uncommon (≥ 1/1000, <1/100), Rare (≥ 1/10 000, <1/1 000), Very rare (<1 / 10, 000) and frequency not known (can not be estimated from the available data). Within each group frequency, adverse effects are presented in order of decreasing severity.

Class of

system

member

Frequency

Effect

undesirable*

Pemetrexed / cisplatin

cisplatin

(N = 168)

(N = 163)

Toxicity of all grades

(%)

Grade 3 - 4 toxicity

(%)

Toxicity of all grades

(%)

Grade 3 - 4 toxicity

(%)

Blood and lymphatic system disorders

Very common

Neutropenia / Granulocytopenia

56.0

23.2

13.5

3.1

leukopenia

53.0

14.9

16.6

0.6

Anemia

26.2

4.2

10.4

0.0

thrombocytopenia

23.2

5.4

8.6

0.0

Metabolism and nutrition disorders

Frequent

dehydration

6.5

4.2

0.6

0.6

Nervous system disorders

Very common

Sensory neuropathy

10.1

0.0

9.8

0.6

Frequent

Taste disorder

7.7

0.0 ***

6.1

0.0 ***

Eye disorders

Frequent

Conjunctivitis

5.4

0.0

0.6

0.0

Gastrointestinal disorders

Very common

Diarrhea

16.7

3.6

8.0

0.0

vomiting

56.5

10.7

49.7

4.3

Stomatitis / Pharyngitis

23.2

3.0

6.1

0.0

nausea

82.1

11.9

76.7

5.5

Anorexia

20.2

1.2

14.1

0.6

Constipation

11.9

0.6

7.4

0.6

Frequent

Dyspepsia

5.4

0.6

0.6

0.0

Skin and subcutaneous tissue disorders

Very common

Skin rash

16.1

0.6

4.9

0.0

Alopecia

11.3

0.0 ***

5.5

0.0 ***

Renal and urinary disorders

Very common

Elevation of creatinine

10.7

0.6

9.8

1.2

Decreased creatinine clearance **

16.1

0.6

17.8

1.8

General disorders and administration site conditions

Very common

Tired

47.6

10.1

42.3

9.2

* Refer to National Cancer Institute Common Toxicity Criteria (CTC) version 2 for each grade of toxicity except for the term "Decreased creatinine clearance"

** derived from the term "renal / genitourinary disorders".

*** According to the Common Toxicity Criteria (CTC) criteria of the National Cancer Institute (v2.0, NCI 1998), taste disorder and alopecia should be reported in Grade 1 or 2 only.

In this table, a 5% frequency limit was used for the inclusion of all adverse effects considered to be possibly related to the administration of pemetrexed and cisplatin by the reporter.

Clinically significant CTC toxicities reported in ≥ 1% and ≤ 5% of patients included in the pemetrexed and cisplatin arm included: renal failure, infection, fever, febrile neutropenia, ALT, ASAT and GGT elevations, urticaria and chest pain.

Clinically significant CTC toxicities reported in <1% of patients included in the pemetrexed and cisplatin arm included arrhythmia and motor neuropathy.

The following table presents the frequency and severity of adverse events observed in more than 5% of the 265 patients included in the arm receiving pemetrexed with supplementation with folic acid and vitamin B 12 and the 276 patients included in the arm receiving docetaxel. . All patients had non-small cell lung cancer, locally advanced or metastatic, and had received prior chemotherapy.

Class of organ system Frequency Undesirable effect*

pemetrexed

N = 265

docetaxel

N = 276

Toxicity of all grades

(%)

Grade 3 - 4 toxicity

(%)

Toxicity of all grades

(%)

Grade 3 - 4 toxicity

(%)

Blood and lymphatic system disorders

Very common

Neutropenia / Granulocytopenia

10.9

5.3

45.3

40.2

leukopenia

12.1

4.2

34.1

27.2

Anemia

19.2

4.2

22.1

4.3

Frequent

thrombocytopenia

8.3

1.9

1.1

0.4

Gastrointestinal disorders

Very common

Diarrhea

12.8

0.4

24.3

2.5

Vomiting

16.2

1.5

12.0

1.1

Stomatitis / Pharyngitis

14.7

1.1

17.4

1.1

Nausea

30.9

2.6

16.7

1.8

Anorexia

21.9

1.9

23.9

2.5

Frequent

Constipation

5.7

0.0

4.0

0.0

Hepatobiliary disorders

Frequent

Elevation of SGPT (ALAT)

7.9

1.9

1.4

0.0

Elevation of SGOT (ASAT)

6.8

1.1

0.7

0.0

Skin and subcutaneous tissue disorders

Very common

Rash / Desquamation

14.0

0.0

6.2

0.0

Frequent

itching

6.8

0.4

1.8

0.0

Alopecia

6.4

0.4 **

37.7

2.2 **

General disorders and administration site conditions

Very common

Tired

34.0

5.3

35.9

5.4

Frequent

Fever

8.3

0.0

7.6

0.0

* Refer to Version 2 of the Common Toxicity Criteria (CTC) Criteria of the National Cancer Institute for each grade of toxicity.

** According to the Common Toxicity Criteria (CTC) criteria of the National Cancer Institute (v2.0; NCI 1998), alopecia should be reported in Grade 1 or 2 only. In this table, a 5% frequency limit was used for the inclusion of all adverse effects considered to be possibly related to the administration of pemetrexed by the reporter. Clinically significant CTC toxicities reported in ≥ 1% and ≤ 5% of patients included in the pemetrexed arm included: Neutropenia-free infection, Febrile neutropenia, Allergic / hypersensitivity reaction, Increased creatinine, Motor neuropathy, Neuropathy sensory, erythema multiforme, and abdominal pain. Clinically significant CTC toxicities reported in <1% of patients included in the pemetrexed arm included supraventricular arrhythmias. Clinically significant grade 3 and 4 toxicities were similar between the pooled results of three phase 2 studies of pemetrexed monotherapy (n = 164) and the results of the phase 3 pemetrexed monotherapy study described above., with the exception of neutropenia (respectively 12.8% versus 5.3%) and elevation of alanine transaminase (respectively 15.2% versus 1.9%). These differences are likely due to differences in patient populations, as Phase 2 studies included both breast cancer patients who had never received chemotherapy and breast cancer patients with severe breast cancer. pre-treated with pre-existing liver metastases and / or abnormal liver function test before treatment.

The following table presents the frequency and severity of adverse events considered to be possibly related to the study treatment, seen in more than 5% of the 839 patients with non-small cell lung cancer included in the arm receiving cisplatin and pemetrexed. and 830 patients with non-small cell lung cancer included in the arm receiving cisplatin and gemcitabine. All patients received study therapy as initial treatment for locally advanced or metastatic non-small cell lung cancer, and in both treatment groups, patients were totally supplemented with folic acid and vitamin B 12 .

Class of organ system Frequency Undesirable effect**

Pemetrexed / cisplatin

(N = 839)

Gemcitabine / cisplatin

(N = 830)

Toxicity of all grades (%)

Grade 3 - 4 toxicity

(%)

Toxicity of all grades (%)

Grade 3 - 4 toxicity

(%)

Blood and lymphatic system disorders

Very common

Anemia

33.0 *

5.6 *

45.7 *

9.9 *

Neutropenia / Granulocytopenia

29.0 *

15.1 *

38.4 *

26.7 *

leukopenia

17.8

4.8 *

20.6

7.6 *

thrombocytopenia

10.1 *

4.1 *

26.6 *

12.7 *

Nervous system disorders

Frequent

Sensory neuropathy

8.5 *

0.0 *

12.4 *

0.6 *

Taste disorder

8.1

0.0 ***

8.9

0.0 ***

Gastrointestinal disorders

Very common

nausea

56.1

7.2 *

53.4

3.9 *

vomiting

39.7

6.1

35.5

6.1

Anorexia

26.6

2.4 *

24.2

0.7 *

Constipation

21.0

0.8

19.5

0.4

Stomatitis / Pharyngitis

13.5

0.8

12.4

0.1

Diarrhea without colostomy

12.4

1.3

12.8

1.6

Frequent

Dyspepsia / pyrosis

5.2

0.1

5.9

0.0

Skin and subcutaneous tissue disorders

Very common

Alopecia

11.9 *

0.0 ***

21.4 *

0.5 ***

Frequent

Rash / Desquamation

6.6

0.1

8.0

0.5

Renal and urinary disorders

Very common

Elevation of creatinine

10.1 *

0.8

6.9 *

0.5

General disorders and administration site conditions

Very common

Tired

42.7

6.7

44.9

4.9

* p values ​​of <0.05 comparing pemetrexed / cisplatin to gemcitabine / cisplatin, using the exact Fisher Test.

** Refer to the Common Toxicity Criteria (CTC) criteria of the National Cancer Institute (v2.0, NCI 1998) for each Grade of Toxicity.

*** According to the Common Toxicity Criteria (CTC) criteria of the National Cancer Institute (v2.0, NCI 1998), taste disorder and alopecia should be reported in Grade 1 or 2 only.

In this table, a 5% frequency limit was used for the inclusion of all adverse events considered to be possibly related to the administration of pemetrexed and cisplatin by the reporter. Clinically significant toxicities reported in ≥ 1% and ≤ 5% of patients included in the cisplatin and pemetrexed arm included: increased ASAT, increased ALT, infection, febrile neutropenia, renal failure, pyrexia, dehydration, conjunctivitis, and decreased clearance of creatinine. Clinically significant toxicities reported in <1% of patients included in the cisplatin and pemetrexed arm included: GGT augmentation, chest pain, arrhythmia, and motor neuropathy. Clinically significant toxicities by sex were similar across the entire population of patients receiving pemetrexed plus cisplatin.

The following table presents the frequency and severity of adverse events considered to be possibly related to the study studied, seen in more than 5% of the 800 patients randomized to receive pemetrexed alone and 402 patients randomized to receive placebo in the pemetrexed trial. only given in maintenance (JMEN test: N = 663) and in the test with pemetrexed continued in maintenance (PARAMOUNT test: N = 539). All patients were diagnosed with stage IIIb or IV NSCLC and had previously received platinum-salt chemotherapy. The patients were totally supplemented with folic acid and vitamin B 12 in both treatment arms.

Class of organ system Frequency* Undesirable effect**

pemetrexed ***

(N = 800)

Placebo***

(N = 402)

Toxicity of all grades

(%)

Grade 3 - 4 toxicity

(%)

Toxicity of all grades

(%)

Grade 3 - 4 toxicity

(%)

Blood and lymphatic system disorders

Very common

Anemia

14.6

3.5

4.7

0.5

Frequent

leukopenia

4.9

1.6

0.7

0.2

neutropenia

6.9

3.3

0.2

0.0

Nervous system disorders

Frequent

Sensory neuropathy

6.1

0.5

4.5

0.2

Gastrointestinal disorders

Very common

nausea

15.1

0.6

4.0

0.2

Anorexia

11.9

1.1

3.2

0.0

Frequent

vomiting

7.4

0.1

1.5

0.0

Mucositis / stomatitis

6.0

0.5

1.7

0.0

Hepatobiliary disorders

Frequent

Elevation of SGPT (ALAT)

6.3

0.1

2.2

0.0

Elevation of SGOT (ASAT)

5.4

0.0

1.7

0.0

Skin and subcutaneous tissue disorders

Frequent

Rash / Desquamation

7.6

0.1

3.2

0.0

General disorders and administration site conditions

Very common

Tired

20.8

4.6

10.4

0.5

Frequent

pains

6.6

0.6

4.2

0.0

Abbreviations: ALT = alanine aminotransferase; ASAT = aspartate aminotransferase; CTCAE = Common Criteria for Terminology of Undesirable Events; NCI = National Cancer Institute; SGOT = Serum

Glutamooxaloacetate Transferase; SGPT = Serum Glutamopyruvate Transferase.

* Frequency definition: Very common ≥ 10%; Frequent> 5% and <10%. In this table, a 5% limit was used to include all adverse events considered to be possibly related to the administration of pemetrexed by the reporter.

** Refer to the National Cancer Institute Common Toxicity Criteria (CTC) Criteria (Version 3.0, NCI 2003) for each grade of toxicity. The percentages of the reported effects are presented according to version 3.0 of the CTC criteria.

*** The adverse reaction table combines the results of the trials with pemetrexed in maintenance treatment (JMEN trial: N = 663) and with pemetrexed continued in maintenance treatment (PARAMOUNT trial: N = 539).

Toxicities of all grades according to clinically significant CTC criteria that were reported in ≥ 1% and ≤ 5% of patients who were randomized to the pemetrexed arm include: febrile neutropenia, infection, decreased platelet count, decreased clearance creatinine, diarrhea, constipation, edema, alopecia, elevated creatinine, pruritus / itching, fever (in the absence of neutropenia), ocular surface disease (including conjunctivitis), lacrimal hypersecretion, decreased flow rate of filtration glomerular, dizziness and motor neuropathy. Clinically significant CTC toxicities that have been reported in <1% of patients who have been randomized to the pemetrexed arm include: allergic reaction / hypersensitivity, erythema multiforme, renal failure, supraventricular arrhythmia, and pulmonary embolism. Tolerance was assessed in randomized patients receiving pemetrexed (N = 800). The incidence of adverse events was assessed in maintenance-treated patients who received ≤ 6 cycles of pemetrexed (N = 568), and compared to patients who received> 6 cycles of pemetrexed (N = 232). An increase in the number of adverse events (all grades) was observed during longer exposure; however, there was no statistically significant difference in adverse effects in each of the 3/4/5 Grades. Serious cardiovascular and cerebrovascular effects including myocardial infarction, angina pectoris, stroke, and transient ischemic attack have been uncommonly reported in clinical studies with pemetrexed, usually when combined with another cytotoxic agent. . Most of the patients in whom these events were observed had pre-existing cardiovascular risk factors.

Rare cases of potentially serious hepatitis have been reported in clinical trials with pemetrexed.

The occurrence of pancytopenia has been infrequently reported in clinical trials with pemetrexed.

In clinical trials, cases of colitis (including intestinal and rectal bleeding, sometimes fatal, intestinal perforation, intestinal necrosis and neutropenic colitis) have been infrequently reported in patients treated with pemetrexed.

In clinical trials, cases of interstitial lung disease with respiratory failure, sometimes fatal, have been infrequently reported in patients treated with pemetrexed.

Uncommon cases of edema have been reported in patients treated with pemetrexed.

Radiation esophagitis / oesophagitis has been infrequently reported in clinical trials with pemetrexed.

Sepsis, sometimes fatal, has been reported frequently in clinical trials with pemetrexed.

During postmarketing surveillance, the following side effects have been reported in patients treated with pemetrexed:

Uncommon cases of acute renal failure have been reported with pemetrexed as monotherapy or in combination with other cytotoxic agents (see Warnings and Precautions ).

Infrequent cases of radiation pneumonitis have been reported in patients treated with radiotherapy, either before, during or after pemetrexed chemotherapy (see Warnings and Precautions ).

Rare cases of previously irradiated zone reactivation have been reported in patients previously treated with radiotherapy (see Warnings and Precautions ).

Uncommon cases of peripheral ischemia sometimes leading to necrosis of the extremities have been reported.

Rare cases of bullous disease have been reported such as Stevens-Johnson syndrome and Lyell syndrome, some of which were fatal.

Rarely, haemolytic anemia has been reported in patients treated with pemetrexed.

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