Malignant pleural mesothelioma

PREXET in combination with cisplatin is indicated for the treatment of chemotherapy naive patients with unresectable malignant pleural mesothelioma.

 

Non-small cell lung cancer

Pemetrexed in combination with cisplatin is indicated for the first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) other than predominantly squamous cell histology (see section 5.1).

 

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

 

Pemetrexed is indicated as monotherapy for the second-line treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology (see section 5.1).

PREXET must only be administered under the supervision of a physician qualified in the use of anti-cancer chemotherapy.

 

Posology/frequency and duration of administration:

PREXET solution should be prepared according to instructions given in section 6.6.

 

PREXET in combination with cisplatin:

The recommended dose of PREXET is 500 mg/m² of body surface area administered as an intravenous infusion over 10 minutes on the first day of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m² of body surface area infused over two hours approximately 30 minutes after completion of the pemetrexed infusion on the first day of each 21-day cycle. Patients must receive adequate anti-emetic treatment and appropriate hydration prior to and/or after receiving cisplatin (see also cisplatin Summary of Product Characteristics for specific dosing advice).

 

PREXET as single agent:

In patients treated for non-squamous non-small cell lung cancer after prior chemotherapy, the recommended dose of PREXET is 500 mg/m² body surface area administered as an intravenous infusion over 10 minutes on the first day of each 21-day cycle.

 

Pre-medication regimen:

To reduce the incidence and severity of skin reactions, a corticosteroid should be given the day prior to, on the day of, and the day after pemetrexed administration. The corticosteroid should be equivalent to 4 mg of dexamethasone administered orally twice a day (see section 4.4).

 

Patients should be informed about usage of this product and the supportive vitamins.

 

Monitoring:

Patients receiving pemetrexed should be monitored before each dose with a complete blood count, including a differential leukocyte and thrombocyte count. Prior to each chemotherapy administration, blood chemistry tests should be collected to evaluate renal and hepatic function. Before the start of any cycle of chemotherapy, patients are required to have the following:

 

Absolute neutrophil count (ANC) should be ≥1500 cells/mm³ and platelets should be ≥100000 cells/mm³.

Creatinine clearance should be ≥45 ml/min.

 

The total bilirubin should be ≤1.5-times upper limit of normal. Alkaline phosphatase (AP), aspartate aminotransferase (AST or SGOT), and alanine aminotransferase (ALT or SGPT) should be ≤ 3-times upper limit of normal. Alkaline phosphatase, AST, and ALT ≤5-times upper limit of normal is acceptable if liver has tumor involvement.

 

Dose adjustment:

Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum non-hematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery. Upon recovery, patients should be re-treated using the guidelines in Tables 1, 2, and 3, which are applicable for PREXET used as a single agent or in combination with cisplatin.

 

 

 

TABLE 1 – Dose modification table for PREXET (as single agent or in combination) and cisplatin – Hematologic toxicities

 

Nadir ANC < 500 /mm3 and nadir thrombocyte ≥50,000/mm3	75% of previous dose (both PREXET and cisplatin)
Nadir thrombocyte ≤50,000/mm3 regardless of nadir ANC	75% of previous dose (both PREXET and cisplatin)
Nadir thrombocyte <50,000/mm3 with bleedinga, regardless of nadir ANC	50% of previous dose (both PREXET and cisplatin)

Abbreviations: ANC: Absolute neutrophil count

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

 

If patients develop non-hematologic toxicities ≥Grade 3 (excluding neurotoxicity), PREXET should be withheld until resolution to less than or equal to the patient's pre-therapy value. Treatment should be resumed according to the guidelines in Table 2.

 

TABLE 2 - Dose modification table for PREXET (as single agent or in combination) and cisplatin - Non-Hematologic Toxicities ^{a, b}

 

	Dose of Pemetrexed (mg/m2)	Dose of Cisplatin (mg/m2)
Any Grade 3 or 4 toxicities except mucositis	75% of previous dose	75% of previous dose
Any diarrhea requiring hospitalization (irrespective of grade) or Grade 3 or 4 diarrhea	75% of previous dose	75% of previous dose
Grade 3 or 4 mucositis	50% of previous dose	100% of previous dose

^a National Cancer Institute Common Toxicity Criteria (CTC v2.0; NCI 1998)

^b Excluding neurotoxicity

 

In the event of neurotoxicity, the recommended dose adjustment for PREXET and cisplatin is documented in Table 3. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is observed.

 

TABLE 3 - Dose modification table for PREXET (as single agent or in combination) and cisplatin – Neurotoxicity

 

CTCa Grade	Dose of Pemetrexed (mg/m2)	Dose of Cisplatin (mg/m2)
0 – 1	100% of previous dose	100% of previous dose
2	100% of previous dose	50% of previous dose

^a National Cancer Institute Common Toxicity Criteria (CTC v2.0; NCI 1998)

 

Treatment with PREXET should be discontinued if a patient experiences any hematologic or non-hematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed.

 

 

 

Additional information on special populations:

 

Renal impairment:

(Standard Cockcroft and Gault formula or Glomerular Filtration Rate measured Tc99m-DPTA serum clearance method): Pemetrexed is primarily eliminated unchanged by renal excretion. In clinical studies, patients with creatinine clearance of ≥45 ml/min required no dose adjustments other than those recommended for all patients. There are insufficient data on the use of pemetrexed in patients with creatinine clearance below 45 ml/min; therefore, the use of pemetrexed is not recommended (see section 4.4).

 

Hepatic impairment:

No relationships between AST (SGOT), ALT (SGPT), or total bilirubin and pemetrexed pharmacokinetics were identified. However, patients with hepatic impairment, such as bilirubin >1.5-times the upper limit of normal and/or aminotransferase >3.0-times the upper limit of normal (hepatic metastases absent) or >5.0-times the upper limit of normal (hepatic metastases present), have not been specifically studied.

 

Pediatric population:

Since safety and efficacy have not been investigated in this patient group, use of PREXET in patients less than 18 years of age is not recommended.

 

Geriatric population:

In clinical studies, there has been no indication that patients 65 years of age or older are at increased risk of adverse events compared to patients younger than 65 years old. No dose reductions other than those recommended for all patients are necessary.

 

It is contraindicated in patients with a known hypersensitivity to pemetrexed or to any of the excipients. Breast-feeding should be discontinued during treatment with pemetrexed (see section 4.6). Concomitant use with yellow fever vaccine is contraindicated (see section 4.5).

Pemetrexed can suppress bone marrow function as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia) (see section 4.8). Myelosuppression is usually the dose-limiting toxicity. Patients should be monitored for myelosuppression during therapy and pemetrexed should not be given to patients until absolute neutrophil count (ANC) returns to ≥1,500 cells/mm³ and platelet count returns to ≥100,000 cells/mm³. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum non-hematologic toxicity seen from the previous cycle (see section 4.2).

 

Skin reactions have been reported in patients not pre-treated with a corticosteroid. Pre-treatment with dexamethasone (or equivalent) can reduce the incidence and severity of skin reactions (see section 4.2).

 

An insufficient number of patients has been studied with creatinine clearance of below 45 ml/min. Therefore, the use of pemetrexed in patients with creatinine clearance of <45 ml/min is not recommended (see section 4.2).

 

Patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 ml/min) should avoid taking non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, and acetylsalicylic acid (>1.3 g daily) for 2 days before, on the day of, and 2 days following pemetrexed administration (see section 4.5).

 

In patients with mild to moderate renal insufficiency eligible for pemetrexed therapy, NSAIDs with long elimination half-lives should be interrupted for at least 5 days prior to, on the day of, and at least 2 days following pemetrexed administration (see section 4.5).

 

Serious renal events, including acute renal failure, have been reported with pemetrexed alone or in association with other chemotherapeutic agents. Many of the patients in whom these occurred had underlying risk factors for the development of renal events, including dehydration or pre-existing hypertension or diabetes.

 

The effect of body space fluid, such as pleural effusion or ascites, on pemetrexed is not fully defined. In patients with clinically significant body space fluid, drainage of body space fluid collection prior to pemetrexed treatment should be considered.

 

Due to the gastrointestinal toxicity of pemetrexed given in combination with cisplatin, severe dehydration has been observed. Therefore, patients should receive adequate anti-emetic treatment and appropriate hydration prior to and/or after receiving treatment.

 

Serious cardiovascular events, including myocardial infarction and cerebrovascular events have been uncommonly reported during clinical studies with pemetrexed, usually when given in combination with another cytotoxic agent. Most of the patients in whom these events have been observed had pre-existing cardiovascular risk factors (see section 4.8).

 

Immuno-depressed status is common in cancer patients. As a result, concomitant use of live attenuated vaccines is not recommended (see section 4.3 and 4.5).

 

Pemetrexed can have genetically damaging effects. Sexually mature males are advised not to father a child during the treatment and up to 6 months thereafter. Contraceptive measures or abstinence are recommended. Owing to the possibility of pemetrexed treatment causing irreversible infertility, men are advised to seek counseling on sperm storage before starting treatment.

 

Women of childbearing potential must use effective contraception during treatment with pemetrexed (see section 4.6).

 

Cases of radiation pneumonitis have been reported in patients treated with radiation either prior, during, or subsequent to their pemetrexed therapy. Particular attention should be paid to these patients, and caution exercised with use of other radio-sensitizing agents.

 

Cases of radiation recall have been reported in patients who received radiotherapy weeks or years previously.

 

This medicinal product contains approximately 54 mg of sodium per vial. To be taken into consideration by patients on a controlled sodium diet.

Pemetrexed is mainly eliminated unchanged renally by tubular secretion and to a lesser extent by glomerular filtration. Concomitant administration of nephrotoxic drugs (e.g., aminoglycoside, loop diuretics, platinum compounds, cyclosporine) could potentially result in delayed clearance of pemetrexed. This combination should be used with caution. If necessary, creatinine clearance should be closely monitored.

 

Concomitant administration of substances that are also tubularly secreted (e.g., probenecid, penicillin) could potentially result in delayed clearance of pemetrexed. Caution should be made when these drugs are combined with pemetrexed. If necessary, creatinine clearance should be closely monitored.

 

In patients with normal renal function (creatinine clearance ≥80 ml/min), high doses of non-steroidal anti-inflammatory drugs (NSAIDs, such as ibuprofen > 1600 mg/day) and acetylsalicylic acid at higher doses (≥1.3 g daily) may decrease pemetrexed elimination and, consequently, increase the occurrence of pemetrexed adverse events. Therefore, caution should be made when administering higher doses of NSAIDs or acetylsalicylic acid, concurrently with pemetrexed to patients with normal function (creatinine clearance ≥80 ml/min).

 

In patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 ml/min), the concomitant administration of pemetrexed with NSAIDs (e.g., ibuprofen) or acetylsalicylic acid at higher doses should be avoided for 2 days before, on the day of, and 2 days following pemetrexed administration (see section 4.4). 

 

In the absence of data regarding potential interaction with NSAIDs having longer half-lives such as piroxicam or rofecoxib, the concomitant administration with pemetrexed in patients with mild to moderate renal insufficiency should be interrupted for at least 5 days prior to, on the day of, and at least 2 days following pemetrexed administration (see section 4.4).

 

Pemetrexed undergoes limited hepatic metabolism. Results from in vitro studies with human liver microsomes indicated that pemetrexed would not be predicted to cause clinically significant inhibition of the metabolic clearance of drugs metabolized by CYP3A, CYP2D6, CYP2C9, and CYP1A2.

 

Interactions common to all cytotoxics:

Due to the increased thrombotic risk in patients with cancer, the use of anticoagulation treatment is frequent. The high intra-individual variability of the coagulation status during diseases and the possibility of interaction between oral anticoagulants and anti-cancer chemotherapy require increased frequency of INR (International Normalized Ratio) monitoring, if it is decided to treat the patient with oral anticoagulants.

 

Contraindicated concomitant use: Yellow fever vaccine: Risk of fatal generalized vaccinale disease (see section 4.3).

 

Concomitant use, not recommended: Live attenuated vaccines (except yellow fever, for which concomitant use is contraindicated): Risk of systemic, possibly fatal, disease. The risk is increased in subjects who are already immunosuppressed by their underlying disease. Use an inactivated vaccine where it exists (poliomyelitis) (see section 4.4).

 

Additional information on special populations:

 

Pediatric population:

No interaction studies have been performed.

 

General advice:

Pregnancy Category: D

 

Contraception in males and females

Women of childbearing potential must use effective contraception during treatment with pemetrexed. Pemetrexed can have genetically damaging effects. Sexually mature males are advised not to father a child during the treatment, and up to 6 months thereafter. Contraceptive measures or abstinence are recommended.

 

Pregnancy

Pemetrexed has harmful pharmacological effects on pregnancy and/or the fetus/newborn child. PREXET should not be used during pregnancy unless clearly necessary, after a careful consideration of the needs of the mother and the risk for the fetus (see section 4.4).

 

Lactation

There is insufficient information on the excretion of pemetrexed in human or animal breast milk. Physicochemical and available pharmacodynamic/toxicological data on pemetrexed point to excretion in breast milk and a risk to the suckling child cannot be excluded. PREXET should not be used during breast-feeding (see section 4.3).

 

Fertility

Animal studies have shown reproductive toxicity (see section 5.3). Pemetrexed can have genetically damaging effects. Sexually mature males are advised not to father a child during the treatment and up to 6 months thereafter.

 

Contraceptive measures or abstinence are recommended. Owing to the possibility of pemetrexed treatment causing irreversible infertility, men are advised to seek counseling on sperm storage before starting treatment.

No studies on the effects of pemetrexed on the ability to drive and use machines have been performed. However, it has been reported that pemetrexed may cause fatigue. Therefore patients should be cautioned against driving or operating if this event occurs.

a. Summary of the safety profile

The most commonly reported undesirable effects related to pemetrexed, whether used as monotherapy or in combination, are bone marrow suppression manifested as anaemia, neutropenia, leukopenia, thrombocytopenia; and gastrointestinal toxicities, manifested as anorexia, nausea, vomiting, diarrhoea, constipation, pharyngitis, mucositis, and stomatitis. Other undesirable effects include renal toxicities, increased aminotransferases, alopecia, fatigue, dehydration, rash, infection/sepsis and neuropathy. Rarely seen events include Stevens-Johnson syndrome and Toxic epidermal necrolysis.

 

b. Tabulated summary of adverse reactions

Adverse reactions:

Frequency estimate: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100), rare ((≥1/10,000 to <1/1,000); very rare (<1/10,000), unknown (cannot be estimated from available data).

 

Within each frequency grouping, undesirable effects are presented in order to decreasing seriousness.

 

Mesothelioma study:

The table below provides the frequency and severity of undesirable effects that have been reported in <5% of 168 patients with Mesothelioma who were randomized to receive cisplatin and pemetrexed and 163 patients with Mesothelioma to receive single agent cisplatin.

 

System organ class	Frequency	Event*	Pemetrexed / Cisplatin		Cisplatin
			(N=168)		(N=163)
			All grades toxicity (%)	Grade 3-4 toxicity (%)	All grades toxicity (%)	Grade 3-4 toxicity (%)
Blood and lymphatic system disorders	Very common	Neutrophils/ Granulocytes decreased	56.0	23.2	13.5	3.1
		Leukocytes decreased	53.0	14.9	16.6	0.6
		Hemoglobin decreased	26.2	4.2	10.4	0.0
		Thrombocyte decreased	23.2	5.4	8.6	0.0
Metabolism and nutrition disorders	Common	Dehydration	6.5	4.2	0.6	0.6
Nervous system disorders	Very common	Neuropathy-Sensory	10.1	0.0	9.8	0.6
	Common	Taste disturbance	7.7	0.0***	6.1	0.0***
Eye disorders	Common	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
	Common	Dyspepsia	5.4	0.6	0.6	0.0
Skin and subcutaneous tissue disorders	Very common	Rash	16.1	0.6	4.9	0.0
		Alopecia	11.3	0.0***	5.5	0.0***
Renal and urinary disorders	Very common	Creatinine elevation	10.7	0.6	9.8	1.2
		Creatinine clearance decreased**	16.1	0.6	17.8	1.8
General disorders and administration site conditions	Very common	Fatigue	47.6	10.1	42.3	9.2

*Refer to National Cancer Institute CTC version 2 for each grade of toxicity except the term “creatinine clearance ** decreased”

** which is derived from the term “renal/genitourinary other”.

*** According to National Cancer Institute CTC (v2.0; NCI 1998), taste disturbance and alopecia should only be reported as Grade 1 or 2.

 

Clinically relevant Common Toxicity Criteria (CTC) toxicities that were reported in ≥1% and ≤5% of the patients that were randomly assigned to receive cisplatin and pemetrexed include: Renal failure, infection, pyrexia, febrile neutropenia, increased AST, ALT and GGT, urticaria and chest pain.

 

Clinically relevant CTC toxicities that were reported in <1% of the patients that were randomly assigned to receive cisplatin and pemetrexed include arrhythmia and motor neuropathy.

 

Second-line study:

The table below provides the frequency and severity of undesirable effects that have been reported in >5% of 265 patients randomly assigned to receive single agent pemetrexed and in >5% of 276 patients randomly assigned to receive single agent docetaxel. All patients were diagnosed with locally advanced or metastatic non-small cell lung cancer and received prior chemotherapy.

 

System organ class	Frequency	Event*	Pemetrexed N=265		Docetaxel N=276
			All grades toxicity (%)	Grade 3-4 toxicity (%)	All grades toxicity (%)	Grade 3-4 toxicity (%)
Blood and lymphatic system disorders	Very common	Neutrophils/ Granulocytes decreased	10.9	5.3	45.3	40.2
		Leukocytes decreased	12.1	4.2	34.1	27.2
		Hemoglobin decreased	19.2	4.2	22.1	4.3
	Common	Thrombocyte decreased	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
	Common	Constipation	5.7	0.0	4.0	0.0
Hepatobiliary disorders	Common	SGPT (ALT) elevation	7.9	1.9	1.4	0.0
		SGOT (AST) elevation	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
	Common	Pruritus	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	Fatigue	34.0	5.3	35.9	5.4
	Common	Fever	8.3	0.0	7.6	0.0

*Refer to National Cancer Institute CTC version 2 for each grade of toxicity.

 **According to National Cancer Institute CTC (v2.0; NCI 1998), alopecia should only be reported as Grade 1 or 2.

 

Clinically relevant Common Toxicity Criteria (CTC) toxicities that were reported in ≥1% and <5% of the patients that were randomly assigned to pemetrexed include: Infection without neutropenia, febrile neutropenia, allergic reaction/hypersensitivity, increased creatinine, motor neuropathy, sensory neuropathy, erythema multiforme, and abdominal pain.

 

Clinically relevant CTC toxicities that were reported in <1% of the patients that were randomly assigned to pemetrexed include supraventricular arrhythmias.

 

Clinically relevant Grade 3 and Grade 4 laboratory toxicities were similar between integrated Phase 2 results from three single agent pemetrexed studies (n=164) and the Phase 3 single agent pemetrexed study described above, with the exception of neutropenia (12.8% versus 5.3%, respectively) and alanine aminotransferase elevation (15.2% versus 1.9%, respectively). These differences were likely due to differences in the patient population, since the Phase 2 studies included both chemonaive and heavily pre-treated breast cancer patients with pre-existing liver metastases and/or abnormal baseline liver function tests.

 

First-line study:

The table below provides the frequency and severity of undesirable effects considered possibly related to study drug that have been reported in <5% of 839 patients with non-small cell lung cancer who were randomized to receive cisplatin and pemetrexed and 830 patients with non-small cell lung cancer who were randomized to receive cisplatin and gemcitabine. All patients received study therapy as initial treatment for locally advanced or metastatic non-small cell lung cancer.

System organ class	Frequency	Event**	Pemetrexed/Cisplatin		Gemcitabine/Cisplatin
			(N=839)		(N=830)
			All grades toxicity  (%)	Grade 3-4 toxicity (%)	All grades toxicity (%)	Grade 3-4 toxicity (%)
Blood and lymphatic system disorders	Very common	Hemoglobin decreased	33.0*	5.6*	45.7*	9.9*
		Neutrophils/ Granulocytes decreased	29.0*	15.1*	38.4*	26.7*
		Leukocyte decreased	17.8	4.8*	20.6	7.6*
		Thrombocyte decreased	10.1*	4.1*	26.6*	12.7*
Nervous system disorders	Common	Neuropathy-Sensory	8.5*	0.0*	12.4*	0.6*
		Taste disturbance	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
	Common	Dyspepsia/heartburn	5.2	0.1	5.9	0.0
Skin and subcutaneous tissue disorders	Very common	Alopecia	11.9*	0***	21.4*	0.5***
	Common	Rash / desquamation	6.6	0.1	8.0	0.5
Renal and urinary disorders	Very common	Creatinine	10.1*	0.8	6.9*	0.5
General disorders and administration site conditions	Very common	Fatigue	42.7	6.7	44.9	4.9

 * P-values <0.05 comparing pemetrexed/cisplatin to gemcitabine/cisplatin, using Fisher Exact test.

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

 ***According to National Cancer Institute Common Toxicity Criteria (CTC) (v2.0; NCI 1998), taste disturbance and alopecia should only be reported as Grade 1 or 2.

 

c. Description of selected adverse reactions

Clinically relevant toxicity that was reported in ≥1% and ≤5% of the patients that were randomly assigned to receive cisplatin and pemetrexed include: AST increase, ALT increase, infection, febrile neutropenia, renal failure, pyrexia, dehydration, conjunctivitis, and creatinine clearance decrease.

 

Clinically relevant toxicity that was reported in ≤1% of the patients that were randomly assigned to receive cisplatin and pemetrexed include: GGT increase, chest pain, arrhythmia, and motor neuropathy.

 

Clinically relevant toxicities with respect to gender were similar to the overall population in patients receiving pemetrexed plus cisplatin.

 

Cardiovascular and cerebrovascular events, including myocardial infarction, angina pectoris, cerebrovascular accident and transient ischemic attack have been uncommonly reported during clinical studies with pemetrexed, usually when given in combination with another cytotoxic agent. Most of the patients in whom these events have been observed had pre-existing cardiovascular risk factors.

 

Rare cases of hepatitis, potentially serious, have been reported during clinical studies with pemetrexed.

 

Pancytopenia has been uncommonly reported during clinical trials with pemetrexed.

 

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

 

In clinical trials, cases of interstitial pneumonitis with respiratory insufficiency, sometimes fatal, have been reported uncommonly in patients treated with pemetrexed.

 

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

 

Esophagitis/ radiation esophagitis has been uncommonly reported during clinical trials with pemetrexed.

 

During post marketing surveillance, the following adverse reactions have been reported in patients treated with pemetrexed:

 

Cases of acute renal failure have been reported with pemetrexed alone or in association with other chemotherapeutic agents (see section 4.4).

 

Cases of radiation pneumonitis have been reported in patients treated with radiation either prior, during or subsequent to their pemetrexed therapy (see section 4.4).

 

Cases of radiation recall have been reported in patients who have received radiotherapy previously (see section 4.4).

 

Cases of peripheral ischemia leading to extremity necrosis have been reported.

 

e. Other special populations

Renal impairment:

(Standard Cockcroft and Gault formula or Glomerular Filtration Rate measured Tc99m-DPTA serum clearance method): Pemetrexed is primarily eliminated unchanged by renal excretion. In clinical studies, patients with creatinine clearance of ≥45 ml/min required no dose adjustments other than those recommended for all patients. There are insufficient data on the use of pemetrexed in patients with creatinine clearance below 45 ml/min; therefore, the use of pemetrexed is not recommended (see section 4.4).

 

Hepatic impairment:

No relationships between AST (SGOT), ALT (SGPT), or total bilirubin and pemetrexed pharmacokinetics were identified. However, patients with hepatic impairment, such as bilirubin >1.5-times the upper limit of normal and/or aminotransferase >3.0-times the upper limit of normal (hepatic metastases absent) or >5.0-times the upper limit of normal (hepatic metastases present), have not been specifically studied (see section 4.2).

 

Pediatric population:

Since safety and efficacy have not been investigated in this patient group, use of PREXET in patients less than 18 years of age is not recommended (see section 4.2).

 

Geriatric population:

In clinical studies, there has been no indication that patients 65 years of age or older are at increased risk of adverse events compared to patients younger than 65 years old. No dose reductions other than those recommended for all patients are necessary (see section 4.2).

 

Reporting of suspected adverse reactions

The National Pharmacovigilance and Drug Safety Centre (NPC)

• Fax: +966-11-205-7662

• Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.

• Toll free phone: 8002490000

• E-mail: npc.drug@sfda.gov.sa

• Website: www.sfda.gov.sa/npc

 

Reported symptoms of overdose include neutropenia, anemia, thrombocytopenia, mucositis, sensory polyneuropathy and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia and anemia. In addition, infection with or without fever, diarrhea, and/or mucositis may be seen. In the event of suspected overdose, patients should be monitored with blood counts and should receive supportive therapy as necessary.

Pharmacotherapeutic group     : Folic acid analogues

ATC code                                 : L01BA04

 

PREXET (pemetrexed) is a multi-targeted anti-cancer antifolate agent that exerts its action by disrupting crucial folate-dependent metabolic processes essential for cell replication.

 

In vitro studies have shown that pemetrexed behaves as a multi-targeted antifolate by inhibiting thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), which are key folate-dependent enzymes for the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is transported into cells by both the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is rapidly and efficiently converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are even more potent inhibitors of TS and GARFT. Polyglutamation is a time- and concentration-dependent process that occurs in tumor cells and, to a lesser extent, in normal tissues. Polyglutamated metabolites have an increased intracellular half-life resulting in prolonged drug action in malignant cells.

 

Clinical efficacy:

Mesothelioma:

EMPHACIS, a multi-centre, randomized, single-blind Phase 3 study of pemetrexed plus cisplatin versus cisplatin in chemonaive patients with malignant pleural mesothelioma, has shown that patients treated with pemetrexed and cisplatin had a clinically meaningful 2.8-month median survival advantage over patients receiving cisplatin alone.

 

The primary analysis of this study was performed on the population of all patients randomly assigned to a treatment arm who received study drug (randomized and treated). The results of these analyses of efficacy are summarized in the table below:

 

Efficacy of pemetrexed plus cisplatin combination vs. cisplatin in malignant pleural mesothelioma

	Randomized and treated patients		Fully supplemented patients
Efficacy parameter	Pemetrexed /Cisplatin (N=226)	Cisplatin (N=222)	Pemetrexed /Cisplatin (N=168)	Cisplatin (N=163)
Median overall survival (months) (% 95 CI)	12.1 (10.0-14.4)	9.3 (7.8-10.7)	13.3 (11.4-14.9)	10.0 (8.4-11.9)
Log Rank p-value*	0.020		0.051
Median time to tumor progression (months) (% 95 CI)	5.7 (4.9-6.5)	3.9 (2.8-4.4)	6.1 (5.3-7.0)	3.9 (2.8-4.5)
Log Rank p-value*	0.001		0.008
Time to treatment failure (months) (% 95 CI)	4.5 (3.9-4.9)	2.7 (2.1-2.9)	4.7 (4.3-5.6)	2.7 (2.2-3.1)
Log Rank p-value*	0.001		0.001
Overall response rate** (% 95 CI)	% 41.3 (34.8-48.1)	%16.7 (12.0-22.2)	%45.5 (37.8-53.4)	%19.6 (13.8-26.6)
Fisher’s exact p-value*	< 0.001		< 0.001

Abbreviations: CI=confidence interval

 *p-value refers to comparison between arms

** In the pemetrexed/cisplatin arm, randomized and treated (N=225) and fully supplemented (N=167)

 

A statistically significant improvement of the clinically relevant symptoms (pain and dyspnea) associated with malignant pleural mesothelioma in the pemetrexed/cisplatin arm (212 patients) versus the cisplatin arm alone (218 patients) was demonstrated using the Lung Cancer Symptom Scale. Statistically significant improvements in pulmonary function tests were also observed.

 

Second-line non-small cell lung cancer:

A multi-centre, randomized, open label phase 3 study of pemetrexed versus docetaxel in patients with locally advanced or metastatic non-small cell lung cancer after prior chemotherapy has shown median survival times of 8.3 months for patients treated with pemetrexed (Intent To Treat population (ITT); n=283) and 7.9 months for patients treated with docetaxel (ITT n=288). Prior chemotherapy did not include pemetrexed. An analysis of the impact of non-small cell lung cancer histology on the treatment effect on overall survival was in favor of pemetrexed versus docetaxel for other than predominantly squamous histologies (n=399, 9.3 versus 8.0 months, adjusted HR=0.78; 95% CI=0 .61-1.00, p=0.047) and was in favor of docetaxel for squamous cell carcinoma histology (n=172, 6.2 versus 7.4 months, adjusted HR=1.56; 95% CI=1.08-2.26, p=0.018). There were no clinically relevant differences observed for the safety profile of pemetrexed within the histology subgroups.

 

Efficacy of pemetrexed vs. docetaxel in non-small cell lung cancer - ITT population

	Pemetrexed	Docetaxel
Survival time (months)	(n=283)	(n=288)
Median (m)	8.3	7.9
95% CI for median	(7.0-9.4)	(6.3-9.2)
HR	0.99
95% CI for HR	(.82-1.20)
Non-inferiority p-value (TO)	.226
Progression free survival (months)	(n=283)	(n=288)
Median	2.9	2.9
HR (95% CI)	0.97 (.82-1.16)
Time to treatment failure (TTTF-months)	(n=283)	(n=288)
Median	2.3	2.1
HR (95% CI)	0.84 (.71-.997)
Response (n: qualified for response)	(n=264)	(n=274)
Response rate (%) ( 95% CI)	9.1 (5.9-13.2)	8.8 (5.7-12.8)
Stable disease (%)	45.8	46.4

Abbreviations: CI=confidence interval; HR=hazard ratio; ITT=intent to treat; n=total population size

 

First-line non-small cell lung cancer:

A multi-centre, randomized, open-label, Phase 3 study of pemetrexed plus cisplatin versus gemcitabine plus cisplatin in chemonaive patients with locally advanced or metastatic (Stage IIIb or IV) non-small cell lung cancer showed that pemetrexed plus cisplatin (Intent-To-Treat [ITT] population n=862) met its primary endpoint and showed similar clinical efficacy as gemcitabine plus cisplatin (ITT n=863) in overall survival (adjusted hazard ratio 0.94; 95% CI=0.84-1.05). All patients included in this study had an ECOG performance status 0 or 1.

 

Progression free survival and overall response rate were similar between treatment arms: Median PFS was 4.8 months for pemetrexed plus cisplatin versus 5.1 months for gemcitabine plus cisplatin (adjusted hazard ratio 1.04; 95% CI=0.94-1.15), and overall response rate was 30.6% (95% CI=27.3-33.9) for pemetrexed plus cisplatin versus 28.2% (95% CI=25.0-31.4) for gemcitabine plus cisplatin. PFS data were partially confirmed by an independent review (400/1725 patients were randomly selected for review).

 

The analysis of the impact of non-small cell lung cancer histology on overall survival demonstrated clinically relevant differences in survival according to histology, see table below.

 

Efficacy of Pemetrexed + Cisplatin vs. Gemcitabine + Cisplatin In First-Line Non-small Cell Lung Cancer – ITT Population and Histology Subgroups

 

ITT Population and Histology Subgroups	Median Overall Survival in Months (95% CI)				Adjusted Hazard Ratio (HR) (95% CI)	Superiority p-value
	Pemetrexed + Cisplatin		Gemcitabine + Cisplatin
ITT Population (N=1725)	10.3 (9.8-11.2)	N=862	10.3 (9.6-10.9)	N=863	0.94a (0.84-1.05)	0.259
Adenocarcinoma (N=847)	12.6 (10.7-13.6)	N=436	10.9 (10.2-11.9)	N=411	0.84 (0.71-0.99)	0.033
Large Cell (N=153)	10.4 (8.6- 14.1)	N=76	6.7 (5.5- 9.0)	N=77	0.67 (0.48-0.96)	0.027
Other (N=252)	8.6 (6.8- 10.2)	N=106	9.2 (8.1- 10.6)	N=146	1.08 (0.81-1.45)	0.586
Squamous Cell (N=473)	9.4 (8.4- 10.2)	N=244	10.8 (9.5- 12.1)	N=229	1.23 (1.00-1.51)	0.050

Abbreviations: CI=confidence interval; HR=hazard ratio; ITT=intent to treat; N=total population size

^a Statistically significant for non-inferiority, with the entire confidence interval for HR well below the 1.17645 non-inferiority margin (p<0.001).

 

Kaplan Meier Plots of Overall Survival by Histology

 

There were no clinically relevant differences observed for the safety profile of pemetrexed plus cisplatin within the histology subgroups.

 

Patients treated with pemetrexed and cisplatin required fewer transfusions (16.4% versus 28.9%, p<0.001), red blood cell transfusions (16.1% versus 27.3%, p<0.001) and platelet transfusions (1.8% versus 4.5%, p=0.002). Patients also required lower administration of erythropoietin/darbopoietin (10.4% versus 18.1%, p<0.001), G-CSF/GM-CSF (3.1% versus 6.1%, p=0.004), and iron preparations (4.3% versus 7.0%, p=0.021).

 

Absorption:

The pharmacokinetic properties of pemetrexed following single-agent administration have been evaluated in 426 cancer patients with a variety of solid tumors at doses ranging from 0.2 to 838 mg/m² infused over a 10-minute period. Pemetrexed total systemic exposure (AUC) and maximum plasma concentration increase proportionally with dose. The pharmacokinetics of pemetrexed are consistent over multiple treatment cycles.

 

Distribution:

Pemetrexed has a steady-state volume of distribution of 9 L/m². In vitro studies indicate that pemetrexed is approximately 81% bound to plasma proteins. Binding was not notably affected by varying degrees of renal impairment.

 

Biotransformation:

Pemetrexed undergoes limited hepatic metabolism.

 

Elimination:

Pemetrexed is primarily eliminated in the urine, with 70% to 90% of the administered dose being recovered unchanged in urine within the first 24 hours following administration. Pemetrexed total systemic clearance is 91.8 ml/min and the elimination half-life from plasma is 3.5 hours in patients with normal renal function (creatinine clearance of 90 ml/min). Between patient variability in clearance is moderate at 19.3%.

 

Linearity/non-linearity:

Pemetrexed total area under curve (AUC) and maximum plasma concentration increase proportionally with dose. The pharmacokinetics of pemetrexed are consistent over multiple treatment cycles.

 

Pharmacokinetic/pharmacodynamic relationship(s)

The pharmacokinetic properties of pemetrexed are not influenced by concurrently administered cisplatin.

Administration of pemetrexed to pregnant mice resulted in decreased fetal viability, decreased fetal weight, incomplete ossification of some skeletal structures and cleft palate.

 

Administration of pemetrexed to male mice resulted in reproductive toxicity characterized by reduced fertility rates and testicular atrophy. In a study conducted in beagle dog by intravenous bolus injection for 9 months, testicular findings (degeneration/necrosis of the seminiferous epithelium) have been observed. This suggests that pemetrexed may impair male fertility. Female fertility was not investigated.

 

Pemetrexed was not mutagenic in either the in vitro chromosome aberration test in Chinese hamster ovary cells, or the Ames test. Pemetrexed has been shown to be clastogenic in the in vivo micronucleus test in the mouse.

 

Studies to assess the carcinogenic potential of pemetrexed have not been conducted.

 

Mannitol

Hydrochloric acid

Sodium hydroxide

Pemetrexed is physically incompatible with diluents containing calcium, including lactated Ringer’s injection and Ringer’s injection. In the absence of compatibility studies with other medicines and diluents, this medicinal product must not be mixed with other medicinal products.

Unopened vial: 36 months Reconstituted and diluted medicinal product: When prepared as directed, reconstituted infusion solutions of PREXET contain no antimicrobial preservatives. Chemical and physical in-use stability of infusion solutions of pemetrexed is 24 hours at 2°C to 8°C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not more than 24 hours at 2–8 °C unless reconstitution/dilution has taken place under controlled and validated aseptic conditions.

Chemical and physical in-use stability of infusion solutions of pemetrexed is 24 hours at 2–8 °C. Solution for infusion is stable up to 24 hours at 2–8 °C after reconstitution.

 

Unopened vial:

Store at room temperature below 30°C and in its package.

 

Reconstituted infusion solutions:

For storage conditions after reconstitution of the medicinal product, see section 6.3.

Lyophilized powder in colorless 50 ml Type I glass vial with rubber stopper and flip-off aluminum cap, in protective blister separator, containing 500 mg pemetrexed. Available in packs of 1 vial accompanied by patient information leaflet.

1.   Use aseptic technique during the reconstitution and further dilution of pemetrexed for intravenous infusion administration.

2.   Calculate the dose and the number of PREXET vials needed. Each vial contains an excess of pemetrexed to facilitate delivery of label amount.

3.   Reconstitute 50 ml vials with 20 ml of sodium chloride 9 mg/ml (0.9%) solution for injection, resulting in a solution containing 25 mg/ml pemetrexed. Gently swirl each vial until the powder is completely dissolved. The resulting solution is clear and ranges in color from colorless to yellow or green-yellow without adversely affecting product quality. The pH of the reconstituted solution is between 6.6 and 7.8. Further dilution is required.

4.   The appropriate volume of reconstituted pemetrexed solution must be further diluted to 100 ml with sodium chloride 9 mg/ml (0.9%) solution for injection, and administered as an intravenous infusion over 10 minutes.

5.   Pemetrexed infusion solutions prepared as directed above are compatible with glass infusion bottles, polyvinyl chloride- and polyolefin- lined administration sets and infusion bags.

6.   Parenteral medicinal products must be inspected visually for particulate matter and discoloration prior to administration. If particulate matter is observed, do not administer.

7.   Pemetrexed solutions are for single use only. Any unused medicinal product or waste material must be disposed of in accordance with local requirements.

 

Preparation and administration precautions: As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of pemetrexed infusion solutions. The use of gloves is recommended. If a pemetrexed solution contacts the skin, wash the skin immediately and thoroughly with soap and water. If pemetrexed solutions contact the mucous membranes, flush thoroughly with water. Pemetrexed is not a vesicant. There is not a specific antidote for extravasation of pemetrexed. There have been few reported cases of pemetrexed extravasation, which were not assessed as serious by the investigator. Extravasation should be managed by local standard practice as with other non-vesicants.