Pemetrexed for Injection is indicated for:

Non-Squamous Non-Small Cell Lung Cancer (NSCLC)

·      in combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-squamous, non-small cell lung cancer (NSCLC).

·      in combination with carboplatin and pembrolizumab for the initial treatment of patients with metastatic, non-squamous NSCLC. This indication is approved under accelerated approval based on tumor response rate and progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

·      as a single agent for the maintenance treatment of patients with locally advanced or metastatic, non-squamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

·      as a single agent for the treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy.

Limitations of Use: 

Pemetrexed for Injection is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer.

Mesothelioma

Pemetrexed for Injection is indicated, in combination with cisplatin, for the initial treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery.

4.2.1  Recommended Dosage for Non-Squamous NSCLC

The recommended dose of Pemetrexed for Injection when administered with cisplatin for initial treatment of NSCLC in patients with a creatinine clearance (calculated by Cockcroft- Gault equation) of 45 mL/min or greater is 500 mg/m² as an intravenous infusion over 10 minutes administered prior to cisplatin on Day 1 of each 21-day cycle for up to six cycles in the absence of disease progression or unacceptable toxicity.

The recommended dose of Pemetrexed for Injection for maintenance treatment of NSCLC in patients with acreatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m² as anintravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptabletoxicity after four cycles of platinum-based first-line chemotherapy.

The recommended dose of Pemetrexed for Injection for treatment of recurrent NSCLC in patients with acreatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m² as anintravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity.

The recommended dose of Pemetrexed for Injection when administered with carboplatin and pembrolizumab for the initial treatment of NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation)of 45 mL/min or greater is 500 mg/m² administered as an intravenous infusion over 10 minutes prior tocarboplatin on Day 1 of each 21-day cycle for 4 cycles. Following completion of platinum-based therapy, Pemetrexed for Injection may be administered as maintenance therapy, alone or with pembrolizumab, until disease progression or unacceptable toxicity. Pembrolizumab should be administered prior to Pemetrexed for Injection when given on the same day.

4.2.1  Recommended Dosage for Mesothelioma

The recommended dose of Pemetrexed for Injection when administered with cisplatin in patients with acreatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m² as anintravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity.

4.2.2  Renal Impairment

Pemetrexed for Injection dosing recommendations are provided for patients with a creatinine clearance(calculated by Cockcroft-Gault equation) of 45 mL/min or greater (see section 4.2). There is no recommendeddose for patients whose creatinine clearance is less than 45 mL/min.

4.2.3  Patients with 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.

4.2.4  Premedication and Concomitant Medications to Mitigate Toxicity

Vitamin Supplementation

·      Initiate folic acid 400 mcg to 1000 mcg orally once daily, beginning 7 days before the first dose of Pemetrexed for Injection and continuing until 21 days after the last dose of Pemetrexed for Injection (see section 4.4).

·      Administer vitamin B12 1 mg intramuscularly, 1 week prior to the first dose of Pemetrexed for Injection and every 3 cycles thereafter. Subsequent vitamin B injections may be given the same day as treatment with Pemetrexed for (see section 4.4).

Do not substitute oral vitamin B for intramuscular vitamin B12.

 

Corticosteroids

Administer dexamethasone 4 mg orally twice daily for three consecutive days, beginning the day before each Pemetrexed for Injection administration.

4.2.1    Dosage Modification of Ibuprofen in Patients with Mild to Moderate Renal Impairment Receiving Pemetrexed for Injection

In patients with creatinine clearances between 45 mL/min and 79 mL/min, modify administration of ibuprofen as follows (see section 4.4, section 4.5 and section 5).

·      Avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of Pemetrexed for Injection.

·      Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided.

4.2.2  Dosage Modifications for Adverse Reactions

Obtain complete blood count on Days 1, 8, and 15 of each cycle. Assess creatinine clearance prior to each cycle. Do not administer Pemetrexed for Injection if the creatinine clearance is less than 45 mL/min. Delay initiation of the next cycle of Pemetrexed for Injection until:

·      recovery of non-hematologic toxicity to Grade 0-2,

·      absolute neutrophil count (ANC) is 1500 cells/mm³ or higher, and

·      platelet count is 100,000 cells/mm³ or higher.

Upon recovery, modify the dosage of Pemetrexed for Injection in the next cycle as specified in Table 1.

For dosing modifications for cisplatin, refer to the prescribing information for cisplatin.

Table 1: Recommended Dosage Modifications for Adverse Reactions^a

Toxicity in Most Recent Treatment Cycle	Pemetrexed for Injection Dose Modification for Next Cycle
Myelosuppressive toxicity (see section 4.4)
ANC less than 500/mm3 and platelets greater than or equal to 50,000/mm3 OR Platelet count less than 50,000/mm3without bleeding.	75% of previous dose
Platelet count less than 50,000/mm3 with bleeding	50% of previous dose
Recurrent Grade 3 or 4 myelosuppression after 2 dose reductions	Discontinue
Non-hematologic toxicity
Any Grade 3 or 4 toxicities EXCEPT mucositis or neurologic toxicity OR Diarrhea requiring hospitalization	75% of previous dose
Grade 3 or 4 mucositis	50% of previous dose

Renal toxicity (see section 4.4)	Withhold until creatinine clearance is 45 mL/min or greater
Grade 3 or 4 neurologic toxicity	Permanently discontinue
Recurrent Grade 3 or 4 non-hematologic toxicity after 2 dose reductions	Permanently discontinue
Severe and life-threatening Skin Toxicity (see section 4.4)	Permanently discontinue
Interstitial Pneumonitis (see section 4.4)	Permanently discontinue

 

4.2.1  Preparation for Administration

·       Pemetrexed for Injection is a cytotoxic drug. Follow applicable special handling and disposal procedures.

·       Calculate the dose of Pemetrexed for Injection and determine the number of vials needed.

·       Reconstitute Pemetrexed for Injection to achieve a concentration of 25 mg/mL as follows:

            o     Reconstitute each 500-mg vial with 20 mL of 0.9% Sodium Chloride Injection, USP (preservative-free)

            o     Do not use calcium-containing solutions for reconstitution.

·       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. FURTHER DILUTION IS REQUIRED prior to administration.

·       Store reconstituted, preservative-free product under refrigerated conditions [2-8°C (36- 46°F)] for no longer than 24 hours from the time of reconstitution. Discard vial after 24 hours.

·       Inspect reconstituted product visually for particulate matter and discoloration prior to further dilution. If particulate matter is observed, discard vial.

·       Withdraw the calculated dose of Pemetrexed for Injection from the vial(s) and discard vial with any unused portion.

·       Further dilute Pemetrexed for Injection with 0.9% Sodium Chloride Injection (preservative-free) to achieve a total volume of 100 mL for intravenous infusion.

·       Store diluted, reconstituted product under refrigerated conditions [2-8°C (36-46°F)] for no more than 24 hours from the time of reconstitution. Discard after 24 hours

4.2.1  Elderly

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.

4.2.2     Pediatric population

There is no relevant use of Pemetrexed for Injection in the pediatric population in malignant pleural mesothelioma and non-small cell lung cancer.

 

Pemetrexed for Injection is contraindicated in patients with a history of severe hypersensitivity reaction to pemetrexed (see section 4.8).

Myelosuppression and Increased Risk of Myelosuppression without Vitamin Supplementation

Pemetrexed can suppress bone marrow function as manifested by neutropenia, thrombocytopenia, and anaemia (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 absoluteneutrophil count (ANC) returns to ≥ 1,500 cells/mm³ and platelet count returns to ≥ 100,000 cells/mm³. Dosereductions for subsequent cycles are based on nadir ANC, platelet count, and maximum non-haematologic toxicity seen from the previous cycle (see section 4.2).

Less toxicity and reduction in Grade 3/4 haematologic and non-haematologic toxicities, such as neutropenia, febrile neutropenia, and infection with Grade 3/4 neutropenia, were reported when pre-treatment with folic acid and vitamin B12 was administered. Therefore, all patients treated with pemetrexed must be instructed to take folicacid and vitamin B12 as a prophylactic measure to reduce treatment-related toxicity (see section 4.2).

Renal Function

Pemetrexed for Injection can cause severe, and sometimes fatal, renal toxicity. The incidences of renal failure were found to be up to 2.2% in clinical studies in which patients received Pemetrexed for Injection with cisplatin. The incidence of renal failure in clinical studies in which patients received Pemetrexed for Injection asa single agent ranged from 0.4% to 0.6%.

Determine creatinine clearance before each dose and periodically monitor renal function during treatment withPemetrexed for Injection. Withhold Pemetrexed for Injection in patients with a creatinine clearance of less than 45 mL/minute (see section 4.2).

Bullous and Exfoliative Skin Toxicity

Serious and sometimes fatal, bullous, blistering and exfoliative skin toxicity, including cases suggestive of Stevens-Johnson Syndrome/Toxic epidermal necrolysis can occur with Pemetrexed for Injection. Permanently discontinue Pemetrexed for Injection for severe and life-threatening bullous, blistering or exfoliating skin toxicity.

Interstitial Pneumonitis

Serious interstitial pneumonitis, including fatal cases, can occur with Pemetrexed for Injection treatment. Withhold Pemetrexed for Injection for acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, or fever pending diagnostic evaluation. If pneumonitis is confirmed, permanently discontinue Pemetrexed for Injection.

Radiation Recall

Radiation recall can occur with Pemetrexed for Injection in patients who have received radiation weeks to yearspreviously. Monitor patients for inflammation or blistering in areas of previous radiation treatment. Permanently discontinue Pemetrexed for Injection for signs of radiation recall.

Increased Risk of Toxicity with Ibuprofen in Patients with Renal Impairment

Exposure to Pemetrexed for Injection is increased in patients with mild to moderate renal impairment who take concomitant ibuprofen, increasing the risks of adverse reactions of Pemetrexed for Injection. In patients with creatinine clearances between 45 mL/min and 79 mL/min, avoid administration of ibuprofen for 2 days before,the day of, and 2 days following administration of Pemetrexed for Injection. If concomitant ibuprofen use cannot be avoided, monitor patients more frequently for Pemetrexed for Injection adverse reactions, including myelosuppression, renal, and gastrointestinal toxicity (See section 4.4, section 4.5 and section 5).

Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, Pemetrexed for Injection can cause fetalharm when administered to a pregnant woman. In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic,resulting in developmental delays and increased malformations at doses lower than the recommended human dose of 500 mg/m². Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potentialto use effective contraception during treatment with Pemetrexed for Injection and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Pemetrexed for Injection and for 3 months after the final dose.

 

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, cyclosporin) could potentially result in delayed clearance of pemetrexed. This combination shouldbe used with caution. If necessary, creatinine clearance should be closely monitored.

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

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

In patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79ml/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 pemetrexedadministration (see section 4.4). 

If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression and gastrointestinal toxicity.

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 metabolised 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 Normalised Ratio) monitoring, if it is decided to treat the patient with oral anticoagulants.

Concomitant Use Contraindicated:

Yellow fever vaccine: Risk of fatal generalised 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).

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 childduring the treatment, and up to 6 months thereafter. Contraceptive measures or abstinence are recommended.

Pregnancy

There are no data from the use of pemetrexed in pregnant women; but pemetrexed, like other anti-metabolites, is suspected to cause serious birth defects when administered during pregnancy. Animal studies have shown reproductive toxicity (see section 5.3). Pemetrexed should not be used during pregnancy unless clearlynecessary, after a careful consideration of the needs of the mother and the risk for the foetus (see section 4.4).

Breast-feeding

It is not known whether pemetrexed is excreted in human milk, and adverse reactions on the suckling child cannot be excluded. Breast-feeding must be discontinued during pemetrexed therapy (see section 4.3).

Fertility

Owing to the possibility of pemetrexed treatment causing irreversible infertility, men are advised to seek counselling on sperm storage before starting treatment.

No studies on the effects 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 machines 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

The Table 2 below provides the frequency and severity of undesirable effects that have been reported in >5% of168 patients with mesothelioma who were randomised to receive cisplatin and pemetrexed, and 163 patients with mesothelioma randomised to receive single-agent cisplatin. In both treatment arms, these chemonaive patientswere fully supplemented with folic acid and vitamin B12.

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) and not known (cannot be estimated from available data). 

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

System organclass	Frequency	Event*	Pemetrexed/Cisplatin (N = 168)		Cisplatin(N = 163)
			All gradestoxicity (%)	Grade 3-4toxicity (%)	All gradestoxicity (%)	Grade 3-4toxicity (%)
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
		Haemoglobin decreased	26.2	4.2	10.4	0.0
		Platelets 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
Gastro-intestinal disorders	Very common	Diarrhoea	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 urinarydisorders	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.

 

For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to pemetrexed and cisplatin.

Clinically relevant 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.

Table 3 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 with folic acid and vitamin B12 supplementation, and 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.

Table 3

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
		Haemoglobin decreased	19.2	4.2	22.1	4.3
	Common	Platelets decreased	8.3	1.9	1.1	0.4
Gastrointestinal Disorders	Very common	Diarrhoea	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 andadministration 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.

 

For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to pemetrexed.

Clinically relevant 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 aminotransferaseelevation (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.

Table 4 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 NSCLC who were randomized to receive cisplatin and pemetrexed and 830 patients with NSCLC who were randomized to receive cisplatin and gemcitabine. Allpatients received study therapy as initial treatment for locally advanced or metastatic NSCLC and patients in both treatment groups were fully supplemented with folic acid and vitamin B12.

Table 4

System organ class	Frequency	Event*	Pemetrexed/Cisplatin (N = 839)		Gemcitabine/ Cisplatin (N = 830)
			All grades toxicity (%)	Grade 3-4 toxicity (%)	All grades toxicity (%)	Grade 3-4 toxicity(%)
Blood and lymphatic system disorders	Very common	Haemoglobin decreased	33.0*	5.6*	45.7*	9.9*
		Neutrophils/ Granulocytes decreased	29.0*	15.1*	38.4*	26.7*
		Leukocytes decreased	17.8	4.8*	20.6	7.6*
		Platelets 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
		Diarrhoea 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 urinarydisorders	Very common	Creatinine elevation	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 CTC (v2.0; NCI 1998) for each Grade of Toxicity.

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

 

For the purpose of this table, a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to pemetrexed and cisplatin.

Clinically relevant toxicity that was reported in ≥ 1% and ≤ 5% of the patients that were randomly assigned toreceive 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.

Table 5 below provides the frequency and severity of undesirable effects considered possibly related to study drug that have been reported in > 5% of 800 patients randomly assigned to receive single-agent pemetrexed and402 patients randomly assigned to receive placebo in the single-agent pemetrexed maintenance (JMEN: N= 663) and continuation pemetrexed maintenance (PARAMOUNT: N=539) studies. All patients were diagnosed withStage IIIB or IV NSCLC and had received prior platinum-based chemotherapy. Patients in both study arms were fully supplemented with folic acid and vitamin B12.

Table 5

System organ class	Frequency*	Event**	Pemetrexed*** (N = 800)		Placebo***(N = 402)
			All grades toxicity (%)	Grade 3-4 toxicity (%)	All grades toxicity (%)	Grade 3-4 toxicity (%)
Blood and lymphatic system disorders	Very common	Haemoglobin decreased	18.0	4.5	5.2	0.5
	Common	Leukocytes decreased	5.8	1.9	0.7	0.2
		Neutrophils decreased	8.4	4.4	0.2	0.0
Nervous system disorders	Common	Neuropathy- sensory	7.4	0.6	5.0	0.2
Gastrointestinal disorders	Very common	Nausea	17.3	0.8	4.0	0.2
		Anorexia	12.8	1.1	3.2	0.0
	Common	Vomiting	8.4	0.3	1.5	0.0
		Mucositis/ Stomatitis	6.8	0.8	1.7	0.0
Hepatobiliary disorders	Common	ALT (SGPT) elevation	6.5	0.1	2.2	0.0
		AST (SGOT) elevation	5.9	0.0	1.7	0.0
Skin and subcutaneous tissue disorders	Common	Rash/ desquamation	8.1	0.1	3.7	0.0
	Very common	Fatigue	24.1	5.3	10.9	0.7

General disorders and administration site conditions	Common	Pain	7.6	0.9	4.5	0.0
		Oedema	5.6	0.0	1.5	0.0
Renal Disorders	Common	Renal disorders****	7.6	0.9	1.7	0.0

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = Common Terminology Criteria for Adverse Event; NCI = National Cancer Institute; SGOT = serum glutamic oxaloacetic aminotransferase; SGPT = serum glutamic pyruvic aminotransferase.

*Definition of frequency terms: Very common - ≥ 10%; Common - > 5% and < 10%. For the purpose of this table, a cut off of 5% wasused for inclusion of all events where the reporter considered a possible relationship to pemetrexed.

**Refer to NCI CTCAE Criteria (Version 3.0; NCI 2003) for each grade of toxicity. The reporting rates shown are according to CTCAE version 3.0.

***Integrated adverse reactions table combines the results of the JMEN pemetrexed maintenance (N=663) and PARAMOUNT continuation pemetrexed maintenance (N=539) studies.

**** Combined term includes increased serum/blood creatinine, decreased glomerular filtration rate, renal failure and renal/genitourinary- other.

 

c.  Description of selected adverse reactions

Clinically relevant CTC toxicity of any grade that was reported in ≥1% and ≤5% of the patients that were randomly assigned to pemetrexed include: febrile neutropenia, infection, decreased platelets, diarrhoea, constipation, alopecia, pruritus/itching, fever (in the absence of neutropenia), ocular surface disease (includingconjunctivitis), increased lacrimation, dizziness and motor neuropathy.

Clinically relevant CTC toxicity that was reported in <1% of the patients that were randomly assigned to pemetrexed include: allergic reaction/hypersensitivity, erythema multiforme, supraventricular arrhythmia and pulmonary embolism.

Safety was assessed for patients who were randomised to receive pemetrexed (N=800). The incidence of adverse reactions was evaluated for patients who received ≤6 cycles of pemetrexed maintenance (N=519) and compared to patients who received >6 cycles of pemetrexed (N=281). Increases in adverse reactions (all grades) were observed with longer exposure. A significant increase in the incidence of possibly study-drug-related Grade 3/4 neutropenia was observed with longer exposure to pemetrexed (≤6 cycles: 3.3%, >6 cycles: 6.4%: p=0.046). No statistically significant differences in any other individual Grade 3/4/5 adverse reactions were seen with longer exposure.

Serious cardiovascular and cerebrovascular events, including myocardial infarction, angina pectoris, cerebrovascular accident, and transient ischaemic attack, have been uncommonly reported during clinicalstudies 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, sometimes fatal, 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 oedema have been reported in patients treated with pemetrexed. Oesophagitis/ radiationoesophagitis has been uncommonly reported during clinical trials with pemetrexed.

Sepsis, sometimes fatal, has been commonly reported during clinical trials with pemetrexed. During post-marketingsurveillance, the following adverse reactions have been reported in patients treated with pemetrexed:

Uncommon cases of acute renal failure have been reported with pemetrexed alone or in association with other chemotherapeutic agents (see section 4.4). Nephrogenic diabetes insipidus and renal tubular necrosis have been reported in post marketing setting with an unknown frequency.

Uncommon 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).

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

Uncommon cases of peripheral ischaemia leading sometimes to extremity necrosis have been reported.

Rare cases of bullous conditions have been reported including Stevens-Johnson syndrome and Toxic epidermal necrolysis which in some cases were fatal.

Rarely, immune-mediated haemolytic anaemia has been reported in patients treated with pemetrexed.

Rare cases of anaphylactic shock have been reported.

Erythematous oedema mainly of the lower limbs has been reported with an unknown frequency.

d.  Pediatric population

The safety and effectiveness of Pemetrexed for Injection in pediatric patients have not been established. The safety and pharmacokinetics of Pemetrexed for Injection were evaluated in two clinical studies conducted inpediatric patients with recurrent solid tumors. Pemetrexed for Injection was administered at doses ranging from 400 to 2480 mg/m² intravenously over 10 minutes on Day 1 of a 21-day cycle to 32 pediatric patients with recurrent solid tumors in a dose-finding study. The maximum tolerated dose (MTD) was determined to be 1910 mg/m² (60 mg/kg for patients <12 months old). Pemetrexed for Injection was administered at the MTD every 21 days in an activity-estimating study enrolling 72 patients with relapsed or refractory osteosarcoma, Ewing sarcoma/peripheral primitive neural ectodermal tumor (PNET), rhabdomyosarcoma, neuroblastoma,ependymoma, medulloblastoma/supratentorial PNET, or non-brainstem high grade glioma. Patients in both studies received concomitant vitamin B12 and folic acid supplementation and dexamethasone.

No tumor responses were observed. Adverse reactions observed in pediatric patients were similar to those observed in adults.

Single-dose pharmacokinetics of Pemetrexed for Injection administered at doses ranging from 400 to 2480 mg/m² were evaluated in 22 patients (13 males and 9 females) age 4 to 18 years (average age 12 years). Pemetrexed exposure (AUC and Cmax) appeared to increase proportionally with dose. Average clearance (2.30 L/h/m²) and half-life (2.3 hours) were similar in pediatric patients compared to adults.

e.  Other special population(s)

Geriatric Use

Of the 3,946 patients enrolled in clinical studies of Pemetrexed for Injection, 34% were 65 and over and 4% were75 and over. No overall differences in effectiveness were observed between these patients and younger patients. The incidences of Grade 3-4 anemia, fatigue, thrombocytopenia, hypertension, and neutropenia were higher inpatients 65 years of age and older as compared to younger patients: in at least one of five randomized clinical trials (see section 4.8 and section 5)

Patients with Renal Impairment

Pemetrexed for Injection is primarily excreted by the kidneys. Decreased renal function results in reduced clearance and greater exposure (AUC) to Pemetrexed for Injection compared with patients with normal renal function. (see section 4.4 and section 5).

No dose is recommended for patients with creatinine clearance less than 45 mL/min (see section 4.2)

To reports any side effect(s):

Reporting suspected adverse reactions after authorisation of the medicinal product is important. 

It allows continuedmonitoring of the benefit/risk balance of the medicinal product.

Healthcare professionals are asked to report any suspectedadverse reactions to the competent authority in Saudi Arabia as per details below:

-              The National Pharmacovigilance and Drug Safety Centre (NPC)

o Fax: +966-11-205-7662

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

o   Toll free phone: 8002490000

o   E-mail: npc.drug@sfda.gov.sa

o   Website: www.sfda.gov.sa/npc

To report the Adverse event in other GCC States - Please contact the relevant competent authority

There have been few cases of Pemetrexed overdose. Reported toxicities included neutropenia, anaemia, thrombocytopenia, mucositis, and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia, and anaemia. In addition, infection with or without fever,diarrhoea, and mucositis may be seen. 

If an overdose occurs, general supportive measures should be instituted asdeemed necessary by the treating physician.

Based on animal studies, administration of leucovorin may mitigate the toxicities of Pemetrexed for Injection overdosage. It is not known whether pemetrexed is dialyzable.

Pharmacotherapeutic group: Antineoplastic Agents, ATC code: L01BA04

 

Mechanism of Action

Pemetrexed for Injection is a folate analog metabolic inhibitor that disrupts folate-dependent metabolic processesessential for cell replication. In vitro studies show that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase (GARFT), which are folate dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed istaken into cells by membrane carriers such as the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are inhibitors of TS and GARFT.

Pharmacodynamic effect

Pemetrexed inhibited the in vitro growth of mesothelioma cell lines (MSTO-211H, NCI- H2052) and showed synergistic effects when combined with cisplatin.

Based on population pharmacodynamic analyses, the depth of the absolute neutrophil counts (ANC) nadir correlates with the systemic exposure to pemetrexed and supplementation with folic acid and vitamin B12. There is no cumulative effect of pemetrexed exposure on ANC nadir over multiple treatment cycles.

Clinical efficacy and safety

 Non-Squamous NSCLC Mesothelioma

EMPHACIS, a multi-centre, randomised, single-blind Phase 3 study of Pemetrexed for Injection plus cisplatin versus cisplatin in chemonaive patients with malignant pleural mesothelioma, has shown that patients treatedwith Pemetrexed for Injection and cisplatin had a clinically meaningful 2.8-month median survival advantageover patients receiving cisplatin alone.

During the study, low-dose folic acid and vitamin B12 supplementation was introduced to patients' therapy to reduce toxicity. The primary analysis of this study was performed on the population of all patients randomly assigned to a treatment arm who received study drug (randomised and treated). A subgroup analysis wasperformed on patients who received folic acid and vitamin B12 supplementation during the entire course of study therapy (fully supplemented). The resultsof these analyses of efficacy are summarised in the Table 6 below.

Table 6: Efficacy of Pemetrexed for Injection plus cisplatin vs. cisplatin in malignant pleural mesothelioma

	Randomised and treated patients		Fully supplemented patients
Efficacy parameter	Pemetrexed for Injection/Cisplatin (N = 226)	Cisplatin (N = 222)	Pemetrexed for Injection/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	5.7	3.9	6.1	3.9
tumour progression
(months) (95% CI)	(4.9-6.5)	(2.8-4.4)	(5.3-7.0)	(2.8-4.5)
Log rank p-value*	0.001		0.008
Time to treatment	4.5	2.7	4.7	2.7
failure (months) (95% CI)	(3.9-4.9)	(2.1-2.9)	(4.3-5.6)	(2.2-3.1)
Log rank p-value*	0.001		0.001
Overall response	41.3%	16.7%	45.5%	19.6%
rate** (95% CI)	(34.8-48.1)	(12.0-22.2)	(37.8-53.4)	(13.8-26.6)
Fisher's exact p- value*	<0.001		<0.001

Abbreviation: CI = confidence interval.

*p-value refers to comparison between arms.

** In the Pemetrexed for Injection Pemetrexed for Injection /cisplatin arm, randomized and treated (N=225) and fully supplemented (N=167).

 

A statistically significant improvement of the clinically relevant symptoms (pain and dyspnoea) associated withmalignant pleural mesothelioma in the Pemetrexed for Injection

/cisplatin arm (212 patients) versus the cisplatin arm alone (218 patients) was demonstrated using the Lung Cancer Symptom Scale. Statistically significant differences in pulmonary function tests were also observed. Theseparation between the treatment arms was achieved by improvement in lung function in the Pemetrexed for Injection /cisplatin arm and deterioration of lung function over time in the control arm.

There are limited data in patients with malignant pleural mesothelioma treated with Pemetrexed for Injection alone. Pemetrexed for Injection at a dose of 500mg/m² was studied as a single agent in 64 chemonaive patientswith malignant pleural mesothelioma. The overall response rate was 14.1%.

NSCLC, second-line treatment

A multi-centre, randomised, open-label Phase 3 study of Pemetrexed for Injection versus docetaxel in patientswith locally advanced or metastatic NSCLC after prior chemotherapy has shown median survival times of 8.3months for patients treated with Pemetrexed for Injection (Intent-To-Treat [ITT] population N = 283) and 7.9months for patients treated with docetaxel (ITT N = 288). Prior chemotherapy did not include Pemetrexed for Injection. An analysis of the impact of NSCLC histology on the treatment effect on overall survival was in favour of Pemetrexed for Injection versus docetaxel for other than predominantly squamous histologies (N =399, 9.3 versus 8.0 months, adjusted hazard ratio (HR) = 0.78; 95% CI = 0.61-1.00, p =

0.047) and was in favour 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 for Injection within the histology subgroups.

Limited clinical data from a separate randomized, Phase 3, controlled trial, suggest that efficacy data (overall survival, progression-free survival) for pemetrexed are similar between patients previously pre-treated with docetaxel (N = 41) and patients who did not receive previous docetaxel treatment (N = 540).

Table 7: Efficacy of Pemetrexed for Injection vs. Docetaxel in NSCLC - ITT population

	Pemetrexed for Injection	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	(0.82-1.20)
•  Non-inferiority p-value (HR)	0.226
Progression-freesurvival (months) •  Median •  HR (95% CI)	(N = 283)	(N = 283)
	2.9
		2.9
	0.97 (0.82-1.16)
Response (n: qualified for	(N = 264)	(N = 274)
response)	9.1 (5.9-13.2)	8.8 (5.7-12.8)
•  Response rate (%) (95% CI)	45.8	46.4
•  Stable disease (%)
Abbreviations: CI = confidence interval; HR = hazard ratio; ITT = intent-to-treat; N = total population size.

 

NSCLC, first-line treatment

A multi-centre, randomised, open-label, Phase 3 study of Pemetrexed for Injection plus cisplatin versus gemcitabine plus cisplatin in chemonaive patients with locally advanced or metastatic (Stage IIIbor IV) non-small cell lung cancer (NSCLC) showed that Pemetrexed for Injection 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 (HR) 0.94; 95% CI= 0.84-1.05). All patients included in this study had an ECOG performance status 0 or 1.

The primary efficacy analysis was based on the ITT population. Sensitivity analyses of main efficacy endpointswere also assessed on the Protocol Qualified (PQ) population. The efficacy analyses using PQ population are consistent with the analyses for the ITT population and support the non-inferiority of AC versus GC.

Progression-free survival (PFS) and overall response rate were similar between treatment arms: median PFS was4.8 months for Pemetrexed for Injection plus cisplatin versus 5.1 months for gemcitabine plus cisplatin (adjusted hazard ratio (HR) 1.04; 95% CI= 0.94-1.15), and overall response rate was 30.6% (95% CI= 27.3- 33.9) forPemetrexed for Injection plus cisplatin versus 28.2% (95% CI= 25.0-31.4) for gemcitabine plus cisplatin. PFSdata were partially confirmed by an independent review (400/1725 patients were randomly selected for review). The analysis of the impact of NSCLC histology on overall survival demonstrated clinically relevant differences in survival according to histology, see table below.

Table 8: Efficacy of Pemetrexed for Injection + 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 for Injection + Cisplatin		Gemcitabine + Cisplatin
ITT population	10.3	N = 862	10.3	N = 863	0.94a	0.259
(N = 1725)	(9.8-11.2)		(9.6 – 10.9)		(0.84-1.05)
Adenocarcinoma	12.6	N = 436	10.9	N = 411	0.84	0.033
(N = 847)	(10.7-13.6)		(10.2-11.9)		(0.71–0.99)
Large cell	10.4	N = 76	6.7	N = 77	0.67	0.027
(N = 153)	(8.6 – 14.1)		(5.5 – 9.0)		(0.48–0.96)
Other	8.6	N = 106	9.2	N = 146	1.08	0.586
(N = 252)	(6.8 – 10.2)		(8.1 – 10.6)		(0.81–1.45)
Squamous cell	9.4	N = 244	10.8	N = 229	1.23	0.050
(N = 473)	(8.4 – 10.2)		(9.5 – 12.1)		(1.00–1.51)
Abbreviations: CI = confidence interval; 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 noninferiority margin (p < 0.001).

 

        

Figure 1: Kaplan-Meier plots of overall survival by histology

 

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

Patients treated with Pemetrexed for Injection 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).

NSCLC, maintenance treatment

JMEN

A multi-centre, randomised, double-blind, placebo-controlled Phase 3 study (JMEN), compared the efficacy andsafety of maintenance treatment with Pemetrexed for Injection plus best supportive care (BSC) (N = 441) withthat of placebo plus BSC (N = 222) in patients with locally advanced (Stage IIIB) or metastatic (Stage IV) Non-Small Cell Lung Cancer (NSCLC) who did not progress after 4 cycles of first-line doublet therapy containing Cisplatin or Carboplatin in combination with Gemcitabine, Paclitaxel, or Docetaxel. First-line doublet therapy containing Pemetrexed for Injection was not included. All patients included in this study had an ECOG performance status 0 or 1. Patients received maintenance treatment until disease progression. Efficacy and safety were measured from the time of randomisation after completion of first-line (induction) therapy. Patients received a median of 5 cycles of maintenance treatment with Pemetrexed for Injection and 3.5 cycles of placebo.A total of 213 patients (48.3%) completed ≥ 6 cycles and a total of 103 patients (23.4%) completed ≥ 10 cycles of treatment with Pemetrexed for Injection.

The study met its primary endpoint and showed a statistically significant improvement in PFS in the Pemetrexed for Injection arm over the placebo arm (N = 581, independently reviewed population; median of 4.0 months and2.0 months, respectively) (hazard ratio = 0.60, 95% CI

= 0.49-0.73, p < 0.00001). The independent review of patient scans confirmed the findings of the investigatorassessment of PFS. The median OS for the overall population (N = 663) was

13.4 months for the Pemetrexed for Injection arm and 10.6 months for the placebo arm, hazard ratio = 0.79 (95% CI= 0.65-0.95, p = 0.01192).

Consistent with other Pemetrexed for Injection studies, a difference in efficacy according to NSCLC histologywas observed in JMEN. For patients with NSCLC other than predominantly squamous cell histology (N = 430, independently reviewed population) median PFS was 4.4 months for the Pemetrexed for Injection arm and 1.8months for the placebo arm, hazard ratio

= 0.47 (95% CI = 0.37-0.60, p = 0.00001). The median OS for patients with NSCLC other than predominantly squamous cell histology (N = 481) was 15.5 months for the Pemetrexed for Injection arm and 10.3 months for the placebo arm, hazard ratio = 0.70 (95% CI = 0.56- 0.88, p = 0.002). Including the induction phase, the median OS for patients with NSCLC other than predominantly squamous cell histology was 18.6 months for thePemetrexed for Injection arm and 13.6 months for the placebo arm, hazard ratio = 0.71 (95% CI = 0.56-0.88, p = 0.002).

The PFS and OS results in patients with squamous cell histology suggested no advantage for Pemetrexed for Injection over placebo.

 

 

 

 

 

 

 

 

Figure 2: JMEN: Kaplan-Meier plots of progression-free survival (PFS) and overall survival Pemetrexed for Injection versus placebo in patients with NSCLC other than predominantly squamous cell histology:

 

PARAMOUNT

A multi-centre, randomised, double-blind, placebo-controlled Phase 3 study (PARAMOUNT), compared the efficacy and safety of continuation maintenance treatment with Pemetrexed for Injection plus BSC (N = 359)with that of placebo plus BSC (N = 180) in patients with locally advanced (Stage IIIB) or metastatic (Stage IV) NSCLC other than predominantly squamous cell histology who did not progress after 4 cycles of first-line doublet therapy of Pemetrexed for Injection in combination with cisplatin. Of the 939 patients treated with Pemetrexed for Injection plus cisplatin induction, 539 patients were randomised to maintenance treatment with pemetrexed or placebo. Of the randomised patients, 44.9% had a complete/partial response and 51.9% had a response of stable disease to Pemetrexed for Injection plus cisplatin induction. Patients randomised to maintenance treatment were required to have an ECOG performance status 0 or 1. The median time from the start of Pemetrexed for Injection plus cisplatin induction therapy to the start of maintenance treatment was 2.96 months on both the pemetrexed arm and the placebo arm. Randomised patients received maintenance treatment until disease progression. Efficacy and safety were measured from the time of randomisation after completion of first-line (induction) therapy. Patients received a median of 4 cycles of maintenance treatment with Pemetrexed for Injection and 4 cycles of placebo. A total of 169 patients (47.1%) completed ≥ 6 cycles maintenance treatment with Pemetrexed for Injection, representing at least 10 total cycles of Pemetrexed for Injection.

The study met its primary endpoint and showed a statistically significant improvement in PFS in the Pemetrexed for Injection arm over the placebo arm (N = 472, independently reviewed population; median of 3.9 months and2.6 months, respectively) (hazard ratio = 0.64, 95% CI

= 0.51-0.81, p = 0.0002). The independent review of patient scans confirmed the findings of the investigator assessment of PFS. For randomised patients, as measured from the start of Pemetrexed for Injection pluscisplatin first-line induction treatment, the median investigator- assessed PFS was 6.9 months for the Pemetrexed for Injection arm and 5.6 months for the placebo arm (hazard ratio = 0.59, 95% CI = 0.47-0.74).

Following Pemetrexed for Injection plus cisplatin induction (4 cycles), treatment with Pemetrexed for Injection was statistically superior to placebo for OS (median 13.9 months versus 11.0 months, hazard ratio = 0.78,95%CI=0.64-0.96, p=0.0195). At the time of this final survival analysis, 28.7% of patients were alive or lost to follow up on the Pemetrexed for Injection arm versus 21.7% on the placebo arm.

The relative treatment effect of Pemetrexed for Injection was internally consistent across subgroups (including disease stage, induction response, ECOG PS, smoking status, gender, histology and age) and similar to thatobserved in the unadjusted OS and PFS analyses. The 1 year and 2 year survival rates for patients on Pemetrexed for Injection were 58% and 32% respectively, compared to 45% and 21% for patients on placebo. From the startof Pemetrexed for Injection plus cisplatin first-line induction treatment, the median OS of patients was 16.9 months for the Pemetrexed for Injection arm and 14.0 months for the placebo arm (hazard ratio= 0.78, 95% CI=0.64-0.96). The percentage of patients that received post-study treatment was 64.3% for Pemetrexed for Injection and 71.7% for placebo.

PARAMOUNT: Kaplan-Meier plot of progression-free survival (PFS) and Overall Survival (OS) for continuation Pemetrexed for Injection maintenance versus placebo in patients with NSCLC other than predominantly squamous cell histology (measured from randomisation)

 

 

 

 

 

 

 

Figure 3: The Pemetrexed for Injection maintenance safety profiles from the two studies JMEN and PARAMOUNT were similar.

 

Absorption

The pharmacokinetics of pemetrexed when Pemetrexed for Injection was administered as a single agent in doses ranging from 0.2 to 838 mg/m² infused over a 10-minute period have been evaluated in 426 cancer patients witha variety of solid tumors. Pemetrexed total systemic exposure (AUC) and maximum plasma concentration(Cmax) increased proportionally with increase of dose. The pharmacokinetics of pemetrexed did not change over multiple treatment cycles.

Distribution

Pemetrexed has a steady-state volume of distribution of 16.1 liters. In vitro studies indicated that pemetrexed is 81% bound to plasma proteins.

Elimination

The total systemic clearance of pemetrexed is 91.8 mL/min and the elimination half-life of pemetrexed is 3.5 hours in patients with normal renal function (creatinine clearance of 90 mL/min). As renal function decreases, the clearance of pemetrexed decreases and exposure (AUC) of pemetrexed increases.

Metabolism

Pemetrexed is not metabolized to an appreciable extent.

Excretion

Pemetrexed is primarily eliminated in the urine, with 70% to 90% of the dose recovered unchanged within the first 24 hours following administration. In vitro studies indicated that pemetrexed is a substrate of OAT3 (organicanion transporter 3), a transporter that is involved in the active secretion of pemetrexed.

Specific Populations

Age (26 to 80 years) and sex had no clinically meaningful effect on the systemic exposure of pemetrexed based on population pharmacokinetic analyses.

Racial Groups

The pharmacokinetics of pemetrexed were similar in Whites and Blacks or African Americans. Insufficient data are available for other ethnic groups.

Patients with Hepatic Impairment

Pemetrexed has not been formally studied in patients with hepatic impairment. No effect of elevated AST, ALT,or total bilirubin on the PK of pemetrexed was observed in clinical studies. 

Patients with Renal Impairment 

Pharmacokinetic analyses of pemetrexed included 127 patients with impaired renal function. Plasma clearance ofpemetrexed decreases as renal function decreases, with a resultant increase in systemic exposure. Patients withcreatinine clearances of 45, 50, and 80 mL/min had 65%,

54%, and 13% increases, respectively in systemic exposure (AUC) compared to patients with creatinine clearance of 100 mL/min (see section 4.2 and section 4.4)

Third-Space Fluid

The pemetrexed plasma concentrations in patients with various solid tumors with stable, mild to moderate third-space fluid were comparable to those observed in patients without third space fluid collections. The effect of severe third space fluid on pharmacokinetics is not known.

Drug Interaction Studies

Drugs Inhibiting OAT3 Transporter

Ibuprofen, an OAT3 inhibitor, administered at 400 mg four times a day decreased the clearance of pemetrexed and increased its exposure (AUC) by approximately 20% in patients with normal renal function (creatinine clearance >80 mL/min).

In Vitro Studies

Pemetrexed is a substrate for OAT3. Ibuprofen, an OAT3 inhibitor inhibited the uptake of pemetrexed in OAT3-expressing cell cultures with an average [Iu]/IC50 ratio of 0.38. In vitro data predict that at clinically relevant concentrations, other NSAIDs (naproxen, diclofenac, celecoxib) would not inhibit the uptake of pemetrexed by OAT3 and would not increase the AUC of pemetrexed to a clinically significant extent (see section 4.5).

Pemetrexed is a substrate for OAT4. In vitro, ibuprofen and other NSAIDs (naproxen, diclofenac, celecoxib) are not inhibitors of OAT4 at clinically relevant concentrations.

Aspirin

Aspirin, administered in low to moderate doses (325 mg every 6 hours), does not affect the pharmacokinetics of pemetrexed.

Cisplatin

Cisplatin does not affect the pharmacokinetics of pemetrexed and the pharmacokinetics of total platinum are unaltered by pemetrexed.

Vitamins

Neither folic acid nor vitamin B12 affect the pharmacokinetics of pemetrexed.

Drugs Metabolized by Cytochrome P450 Enzymes

In vitro studies suggest that pemetrexed does not inhibit the clearance of drugs metabolized by CYP3A, CYP2D6, CYP2C9, and CYP1A2.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in an in vivomicronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, Chinese Hamster Ovary cell assay).

Pemetrexed administered intraperitoneally at doses of ≥0.1 mg/kg/day to male mice (approximately 0.006 timesthe recommended human dose based on BSA) resulted in reduced fertility, hypospermia, and testicular atrophy.

Mannitol 

Hydrochloric Acid

SodiumHydroxide

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

Unopened vial :24 months Reconstituted and infusion solutions When prepared as directed, reconstituted and infusion solutions of Pemetrexed contain no antimicrobial preservatives. Chemical and physical in-use stability of reconstituted and infusion solutions of pemetrexed were demonstrated for 24 hours at refrigerated temperature. 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 not be longer than 24 hours at 2°C to 8°C(36-46°F).

Store below 30°C

The product is packed as (20 mL fill volume) Pemetrexed Disodium equivalent to 500 mg of Pemetrexed in 50mL USP Type I clear glass lyo vial, stoppered with 20 mm grey Chlorobutyl rubber stoppers and sealed with 20 mm aluminium flip-off seals.

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

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

3.   Reconstitute 500mg vials with 20ml of sodium chloride 9mg/ml (0.9%) solution for injection, withoutpreservative, resulting in a solution containing 25mg/ml pemetrexed. Gently swirl each vial until the powder is completely dissolved. The resulting solution is clear and ranges in colour from colourless 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 100ml with sodium chloride 9mg/ml (0.9%) solution for injection, without preservative, and administered as an intravenous infusion over 10 minutes.

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

6.    Parenteral medicinal products must be inspected visually for particulate matter and discolouration 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 anti-cancer agents, care should be exercised in the handling and preparation of pemetrexed infusion solutions. The use of gloves isrecommended. If a pemetrexed solution contacts the skin, wash the skin immediately and thoroughly with soapand water. If pemetrexed solutions contact the mucous membranes, flush thoroughly with water. Pemetrexed isnot a vesicant. There is not a specific antidote for extravasation of pemetrexed. There have been few reportedcases 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.