Pemetrexed Krka - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Pemetrexed Krka 100 mg powder for concentrate for solution for infusion

Pemetrexed Krka 500 mg powder for concentrate for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Pemetrexed Krka 100 mg powder for concentrate for solution for infusion

Each vial contains 100 mg pemetrexed (as pemetrexed disodium hemipentahydrate).

After reconstitution (see section 6.6), each vial contains 25 mg/ml pemetrexed.

Excipient with known effect

Each vial contains approximately 11 mg (0.48 mmol) sodium.

Pemetrexed Krka 500 mg powder for concentrate for solution for infusion

Each vial contains 500 mg pemetrexed (as pemetrexed disodium hemipentahydrate).

After reconstitution (see section 6.6), each vial contains 25 mg/ml pemetrexed.

Excipient with known effect

Each vial contains approximately 54 mg (2.35 mmol) sodium.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder for concentrate for solution for infusion (powder for concentrate).

White to either light yellow or green yellow lyophilized cake or powder.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Malignant pleural mesothelioma

Pemetrexed Krka in combination with cisplatin is indicated for the treatment of chemotherapy naïve patients with unresectable malignant pleural mesothelioma.

Non-small cell lung cancer

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

Pemetrexed Krka 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 Krka 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).

4.2 Posology and method of administration

Posology

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

Pemetrexed Krka in combination with cisplatin

The recommended dose of Pemetrexed Krka is 500 mg/m2 of body surface area (BSA) 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 BSA 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).

Pemetrexed Krka as single agent

In patients treated for non-small cell lung cancer after prior chemotherapy, the recommended dose of Pemetrexed Krka is 500 mg/m2 BSA 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).

To reduce toxicity, patients treated with pemetrexed must also receive vitamin supplementation (see section 4.4). Patients must take oral folic acid or a multivitamin containing folic acid (350 to 1,000 micrograms) on a daily basis. At least five doses of folic acid must be taken during the seven days preceding the first dose of pemetrexed, and dosing must continue during the full course of therapy and for 21 days after the last dose of pemetrexed. Patients must also receive an intramuscular injection of vitamin B12 (1,000 micrograms) in the week preceding the first dose of pemetrexed and once every three cycles thereafter. Subsequent vitamin B12 injections may be given on the same day as pemetrexed.

Monitoring

Patients receiving pemetrexed should be monitored before each dose with a complete blood count, including a differential white cell count (WCC) and platelet 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 > 100,000 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 tumour involvement.

Dose adjustments

Dose adjustments at the start of a subsequent cycle should be based on nadir haematologic counts or maximum non-haematologic 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 Pemetrexed Krka used as a single agent or in combination with cisplatin.

Table 1 – Dose modification table for Pemetrexed Krka (as single agent or in combination) and cisplatin – Haematologic toxicities
Nadir ANC < 500/mm3 and nadir platelets > 50,000/mm3	75% of previous dose (both Pemetrexed Krka and cisplatin)
Nadir platelets < 50,000/mm3 regardless of nadir ANC	75% of previous dose (both Pemetrexed Krka and cisplatin)
Nadir platelets < 50,000/mm3 with bleedinga,	50% of previous dose (both Pemetrexed Krka and

regardless of nadir ANC	cisplatin)
aThese criteria meet the National Cancer Institute Common Toxicity Criteria (CTC v2.0; NCI 1998) definition of > CTC Grade 2 bleeding.

If patients develop non-haematologic toxicities > Grade 3 (excluding neurotoxicity), Pemetrexed Krka 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 Pemetrexed Krka (as single agent or in combination) and cisplatin – Non-haematologic toxicities a, b
	Dose of Pemetrexed Krka (mg/m2)	Dose for cisplatin (mg/m2)
Any Grade 3 or 4 toxicities except mucositis	75% of previous dose	75% of previous dose
Any diarrhoea requiring hospitalisation (irrespective of grade) or Grade 3 or 4 diarrhoea	75% of previous dose	75% of previous dose
Grade 3 or 4 mucositis	50% of previous dose	100% of previous dose
aNational Cancer Institute Common Toxicity Criteria (CTC v2.0; NCI 1998) b Excluding neurotoxicity

In the event of neurotoxicity, the recommended dose adjustment for Pemetrexed Krka 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 Pemetrexed Krka (as single agent or in combination) and cisplatin – Neurotoxicity
CTC aGrade	Dose of Pemetrexed Krka (mg/m2)	Dose for cisplatin (mg/m2)
0–1	100% of previous dose	100% of previous dose
2	100% of previous dose	50% of previous dose
aNational Cancer Institute Common Toxicity Criteria (CTC v2.0; NCI 1998)

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

Special  populations

Elderly

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

Paediatric population

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

Patients with renal impairment (standard cockcroft and gault formula or glomerular filtration rate measured 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).

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.

Method of administration

Pemetrexed Krka is for intravenous use. Pemetrexed Krka should be administered as an intravenous infusion over 10 minutes on the first day of each 21-day cycle.

For precautions to be taken before handling or administering Pemetrexed Krka and for instructions on reconstitution and dilution of Pemetrexed Krka before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Breast-feeding (see section 4.6).

Concomitant yellow fever vaccine (see section 4.5).

4.4 Special warnings and precautions for use

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 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-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 pretreatment with folic acid and vitamin B12 was administered. Therefore, all patients treated with pemetrexed must be instructed to take folic acid and vitamin B12 as a prophylactic measure to reduce treatment-related toxicity (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. Nephrogenic diabetes insipidus and renal tubular necrosis were also reported in post marketing setting with pemetrexed alone or with other chemotherapeutic agents. Most of these events resolved after pemetrexed withdrawal. Patients should be regularly monitored for acute tubular necrosis, decreased renal function and signs and symptoms of nephrogenic diabetes insipidus (e.g. hypernatraemia).

The effect of third-space fluid, such as pleural effusion or ascites, on pemetrexed is not fully defined. A Phase 2 study of pemetrexed in 31 solid tumour patients with stable third-space fluid demonstrated no difference in pemetrexed dose normalized plasma concentrations or clearance compared to patients without third-space fluid collections. Thus, drainage of third-space fluid collection prior to pemetrexed treatment should be considered, but may not be necessary.

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 preexisting cardiovascular risk factors (see section 4.8).

Immunodepressed 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 counselling 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 radiosensitising agents.

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

Excipients

Pemetrexed Krka 100 mg powder for concentrate for solution for infusion

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially “sodium-free”.

Pemetrexed Krka 500 mg powder for concentrate for solution for infusion

This medicinal product contains 54 mg sodium per vial, equivalent to 2.7% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

4.5 Interaction with other medicinal products and other forms of interaction

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 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 reactions. 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 dose 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). 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).

4.6 Fertility, pregnancy and lactation

Women of childbearing potential / 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

There are no data from the use of pemetrexed in pregnant women but pemetrexed, like other antimetabolites, 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 clearly necessary, after a careful consideration of the needs of the mother and the risk for the foetus (see section 4.4).

Breast-feeding

It is unknown whether pemetrexed is excreted in human milk, and adverse reactions on the breast-feeding 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.

4.7 Effects on ability to drive and use machines

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.

4.8 Undesirable effects

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.

Tabulated list of adverse reactions

The table 4 lists the adverse drug events regardless of causality associated with pemetrexed used either as a monotherapy treatment or in combination with cisplatin from the pivotal registration studies (JMCH, JMEI, JMBD, JMEN and PARAMOUNT) and from the post marketing period.

ADRs are listed by MedDRA body system organ class. The following convention has been used for classification of frequency: 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 the available data).

Table 4. Frequencies of all grades adverse drug events regardless of causality from the pivotal registration studies: JMEI (PEMETREXED vs Docetaxel), JMDB (PEMETREXED and Cisplatin versus GEMZAR and Cisplatin, JMCH (PEMETREXED plus Cisplatin versus Cisplatin), JMEN and PARAMOUNT (Pemetrexed plus Best Supportive Care versus Placebo plus Best Supportive Care) and from post-marketing period.

System Organ Class (MedDRA)	Very common	Common	Uncommon	Rare	Very rare	Not known
Infections and infestations	Infectiona Pharyngitis	Sepsisb			Dermo-hypodermiti s
Blood and lymphatic system disorders	Neutropeni a Leukopenia Haemoglob in decreased	Febrile neutropenia Platelet count decreased	Pancytopenia	Autoimmu ne haemolytic anaemia
Immune System disorders		Hypersensitivity		Anaphylact ic shock
Metabolism and nutrition		Dehydration

disorders
Nervous system disorders		Taste disorder Peripheral motor neuropathy Peripheral sensory neuropathy Dizziness	Cerebrovascu lar accident Ischaemic stroke Haemorrhage intracranial
Eye disorders		Conjunctivitis Dry eye Lacrimation increased Keratoconjunctiv itis sicca Eyelid oedema Ocular surface disease
Cardiac disorders		Cardiac failure Arrhythmia	Angina Myocardial infarction Coronary artery disease Arrhythmia supraventricu lar
Vascular disorders			Peripheral ischaemiac
Respiratory, thoracic and mediastinal disorders			Pulmonary embolism Interstitial pneumonitisbd
Gastrointestinal disorders	Stomatitis Anorexia Vomiting Diarrhoea Nausea	Dyspepsia Constipation Abdominal pain	Rectal haemorrhage Gastrointestina l haemorrhage Intestinal perforation Oesophagitis Colitise
Hepatobiliar y disorders		Alanine aminotransferase increased Aspartate aminotransferase increased		Hepatitis
Skin and subcutaneou s tissue disorders	Rash Skin exfoliation	Hyperpigmentati on Pruritus Erythema multiforme Alopecia Urticaria		Erythema	Stevens-Johnson syndromeb Toxic epidermal necrolysisb Pemphigoid Dermatitis bullous Acquired epidermoly sis bullosa

					Erythematous oedemaf Pseudocellu -litis Dermatitis Eczema Prurigo
Renal and urinary disorders	Creatinine clearance decreased Blood creatinine increasede	Renal failure Glomerular filtration rate decreased				Nephro g-enic diabetes insipidu s Renal tubular necrosis
General disorders and administrati on site conditions	Fatigue	Pyrexia Pain Oedema Chest pain Mucosal inflammation
Investigatio ns		Gamma-glutamyltransfera se increased
Injury, poisoning and procedural complicatio ns			Radiation oesophagitis Radiation pneumonitis	Recall phenomenon

a

b

with and without neutropenia in some cases fatal

c sometimes leading to extremity necrosis d with respiratory insufficiency

e seen only in combination with cisplatin

f mainly of the lower limbs

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

Reported symptoms of overdose include neutropenia, anaemia, thrombocytopenia, mucositis, sensory polyneuropathy, 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/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. The use of calcium folinate/folinic acid in the management of pemetrexed overdose should be considered.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antineoplastic agents, folic acid analogues, ATC code: L01BA04.

Pemetrexed Krka (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 tumour 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.

The European Medicines Agency has waived the obligation to submit the results of studies with pemetrexed in all subsets of the paediatric population in the granted indications (see section 4.2).

Clinical efficacy

Mesothelioma

EMPHACIS, a multi-centre, randomised, 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.

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 was performed on patients who received folic acid and vitamin B12 supplementation during the entire course of study therapy (fully supplemented). The results of these analyses of efficacy are summarised in the table below.

Table 5. Efficacy of pemetrexed plus cisplatin vs. cisplatin in malignant pleural mesothelioma

	Randomised 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-valuea	0.020		0.051
Median time to tumour 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-valuea	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-valuea	0.001		0.001
Overall response rateb (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-valuea	<0.001		<0.001
Abbreviation: CI = confidence interval. a p-value refers to comparison between arms. b 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 dyspnoea) 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 differences in pulmonary function tests were also observed. The separation between the treatment arms was achieved by improvement in lung function in the pemetrexed/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 alone. Pemetrexed at a dose of 500 mg/m2 was studied as a single agent in 64 chemonaive patients with 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 versus docetaxel in patients with locally advanced or metastatic NSCLC after prior chemotherapy has shown median survival times of 8.3 months for patients treated with pemetrexed (Intent-To-Treat [ITT] population 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 NSCLC histology on the treatment effect on overall survival was in favour of pemetrexed 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 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 6. Efficacy of pemetrexed vs. docetaxel in NSCLC – ITT population

	Pemetrexed	Docetaxel
Survival time (months) • Median (m) • 95% CI for median • HR • 95% CI for HR • Non-inferiority p-value (HR)	(N=283) 8.3 (7.0–9.4)	(N=288) 7.9 (6.3–9.2)
	0.99 (0.82–1.20) 0.226
Progression-free survival (months) • Median • HR (95% CI)	(N=283) 2.9	(N=288) 2.9
	0.97 (0.82–1.16)
Time to treatment failure (TTTF – months) • Median • HR (95% CI)	(N=283) 2.3	(N=288) 2.1
	0.84 (0.71–0.997)
Response (n: qualified for response) • Response rate (%) (95% CI) • Stable disease (%)	(N=264) 9.1 (5.9–13.2) 45.8	(N=274) 8.8 (5.7–12.8) 46.4
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 plus cisplatin versus gemcitabine plus cisplatin in chemonaive patients with locally advanced or metastatic (Stage IIIb or IV) non-small cell lung cancer (NSCLC) 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 (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 endpoints were 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 was 4.8 months for pemetrexed 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) 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 NSCLC histology on overall survival demonstrated clinically relevant differences in survival according to histology, see table below.

Table 7. Efficacy of pemetrexed + cisplatin vs. gemcitabine + cisplatin in first-line non-small celllung 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; 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

1.0

0.9

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0.1

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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).

NSCLC, maintenance treatment

JMEN

A multi-centre, randomised, double-blind, placebo-controlled Phase 3 study (JMEN), compared the efficacy and safety of maintenance treatment with pemetrexed plus best supportive care (BSC) (N=441) with that 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 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 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.

The study met its primary endpoint and showed a statistically significant improvement in PFS in the pemetrexed arm over the placebo arm (N=581, independently reviewed population; median of 4.0 months and 2.0 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 investigator assessment of PFS. The median OS for the overall population (N=663) was 13.4 months for the pemetrexed 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 studies, a difference in efficacy according to NSCLC histology was 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 arm and 1.8 months 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 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 the pemetrexed 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 over placebo.

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

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

Progression-Free Survival                 ­Overall Survival

PARAMOUNT

A multi-centre, randomised, double-blind, placebo-controlled Phase 3 study (PARAMOUNT), compared the efficacy and safety of continuation maintenance treatment with pemetrexed 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 in combination with cisplatin. Of the 939 patients treated with pemetrexed 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 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 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 and 4 cycles of placebo. A total of 169 patients (47.1%) completed > 6 cycles maintenance treatment with pemetrexed, representing at least 10 total cycles of pemetrexed.

The study met its primary endpoint and showed a statistically significant improvement in PFS in the pemetrexed arm over the placebo arm (N=472, independently reviewed population; median of 3.9 months and 2.6 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 plus cisplatin first-line induction treatment, the median investigator-assessed PFS was 6.9 months for the pemetrexed arm and 5.6 months for the placebo arm (hazard ratio = 0.59, 95% CI=0.47–0.74).

Following pemetrexed plus cisplatin induction (4 cycles), treatment with pemetrexed 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 arm versus 21.7% on the placebo arm. The relative treatment effect of pemetrexed was internally consistent across subgroups (including disease stage, induction response, ECOG PS, smoking status, gender, histology and age) and similar to that observed in the unadjusted OS and PFS analyses. The 1 year and 2 year survival rates for patients on pemetrexed were 58% and 32% respectively, compared to 45% and 21% for patients on placebo. From the start of pemetrexed plus cisplatin first-line induction treatment, the median OS of patients was 16.9 months for the pemetrexed 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 and 71.7% for placebo.

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

Progression-Free Survival

The pemetrexed maintenance safety profiles from the two studies JMEN and PARAMOUNT were similar.

5.2 Pharmacokinetic properties

The pharmacokinetic properties of pemetrexed following single-agent administration have been evaluated in 426 cancer patients with a variety of solid tumours at doses ranging from 0.2 to 838 mg/m2 infused over a 10-minute period. 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. Pemetrexed undergoes limited hepatic metabolism. 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. In vitro studies indicate that pemetrexed is actively secreted by OAT3 (organic anion transporter).

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

The pharmacokinetic properties of pemetrexed are not influenced by concurrently administered cisplatin. Oral folic acid and intramuscular vitamin B12 supplementation do not affect the pharmacokinetics of pemetrexed.

5.3 Preclinical safety data

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

Administration of pemetrexed to male mice resulted in reproductive toxicity characterised 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.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Mannitol

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment) (E524)

6.2 Incompatibilities

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.

6.3 Shelf life

Unopened vial

3 years

Reconstituted and diluted solution

Chemical and physical in-use stability of reconstituted and infusion solutions of pemetrexed were demonstrated for 24 hours at 2°C to 8°C (and 25°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 not be longer than 24 hours at 2°C to 8°C.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

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

6.5 Nature and contents of container

Pemetrexed Krka 100 mg powder for concentrate for solution for infusion

• 10 ml vial (transparent type I glass) with bromobutyl rubber stopper and aluminium cap with tear off part made of polypropylene (embossed with sign “FLIP OFF”): containing 100 mg pemetrexed. Pack of 1 vial is available in a box.

Pemetrexed Krka 500 mg powder for concentrate for solution for infusion

• 50 ml vial (transparent type I glass) with bromobutyl rubber stopper and aluminium cap with tear off part made of polypropylene (embossed with sign “FLIP OFF”): containing 500 mg pemetrexed. Pack of 1 vial is available in a box.

6.6 Special precautions for disposal and other handling

• 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 Krka vials needed. Each 100 mg vial contains an excess of pemetrexed to facilitate delivery of label amount.

• 3. Pemetrexed Krka 100 mg powder for concentrate for solution for infusion

Reconstitute 100 mg vials with 4.2 ml of sodium chloride 9 mg/ml (0.9%) solution for injection, without preservative, resulting in a solution containing 25 mg/ml pemetrexed.

Pemetrexed Krka 500 mg powder for concentrate for solution for infusion

Reconstitute 500 mg vials with 20 ml of sodium chloride 9 mg/ml (0.9%) solution for injection, without preservative, 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 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 100 ml with sodium chloride 9 mg/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 should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

KRKA, d.d., Novo mesto, Smarjeska cesta 6, 8501 Novo mesto, Slovenia

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/18/1283/001

EU/1/18/1283/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 22 May 2018