Ciambra - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

CIAMBRA 100 mg powder for concentrate for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One vial of powder contains 100 mg of pemetrexed (as pemetrexed disodium hemipentahydrate).

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

Excipient with known effect

Each vial contains approximately 11 mg sodium.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder for concentrate for solution for infusion.

White to almost white lyophilised powder.

The pH of the reconstituted solution is between 6.6 and 7.8.

The Osmolality of the reconstituted solution is 230–270 mOsmol/kg.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Malignant pleural mesothelioma

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

Non-small cell lung cancer

CIAMBRA 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).

CIAMBRA 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).

CIAMBRA 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

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

Posology

CIAMBRA in combination with cisplatin

The recommended dose of CIAMBRA 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).

CIAMBRA as single agent

In patients treated for non-small cell lung cancer after prior chemotherapy, the recommended dose of CIAMBRA 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 1000 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 (1000 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. AP, 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 retreated using the guidelines in Tables 1, 2 and 3, which are applicable for CIAMBRA used as a single agent or in combination with cisplatin.

Table 1 – Dose modification table for CIAMBRA (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 CIAMBRA and cisplatin)
Nadir platelets <50,000 /mm3 regardless of nadir ANC	75 % of previous dose (both CIAMBRA and cisplatin)
Nadir platelets <50,000/mm3 with bleedinga, regardless of nadir ANC	50% of previous dose (both CIAMBRA and cisplatin)

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

If patients develop non-haematologic toxicities > Grade 3 (excluding neurotoxicity), CIAMBRA 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 CIAMBRA (as single agent or in combination) and cisplatin- Non-haematologic toxicities a, b
	Dose of CIAMBRA (mg/m 2)	Dose for cisplatin (mg/m 2)
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 CIAMBRA 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 CIAMBRA (as single agent or in combination) and cisplatin – Neurotoxicity
CTC aGrade	Dose of CIAMBRA (mg/m 2)	Dose for cisplatin (mg/m 2)
0 – 1	100 % of previous dose	100 % of previous dose
2	100 % of previous dose	50 % of previous dose

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

Treatment with CIAMBRA 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 Population

Elderly

In clinical studies, there has been no indication that patients 65 years of age or older are at increased risk of adverse reactions 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 CIAMBRA 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

CIAMBRA is for intravenous use. CIAMBRA 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 CIAMBRA, see section 6.6.

For instructions on reconstitution and dilution of CIAMBRA 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 ANC returns to > 1500 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 pre-treatment 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 normalised 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 antiemetic treatment and appropriate hydration prior to and/or after receiving treatment.

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

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.

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

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 medicinal products (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 medicinal products 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 NSAIDs (such as ibuprofen > 1600 mg/day) and acetylsalicylic acid at higher dose (> 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 medicines 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 anticancer chemotherapy require increased frequency of International Normalised Ratio (INR) 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 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 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 not known 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

Pemetrexed may have a minor influence on the ability to drive and use machines. Fatigue may occur following administration of Pemetrexed (see section 4.8).

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 (>1/1000 to

<1/100), rare (>1/10,000 to <1/1000), very rare (<1/10,000) and not known (cannot be estimated from 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-hypodermit is
Blood and lymphatic system disorders	Neutropenia Leukopenia Haemoglobin decreased	Febrile neutropenia Platelet count decreased	Pancytopenia	Autoimmune haemolytic anaemia
Immune System disorders		Hypersensitivity		Anaphylac-tic shock
Metabolism and nutrition disorders		Dehydration
Nervous system disorders		Taste disorder Peripheral motor neuropathy Peripheral sensory neuropathy Dizziness	Cerebrovascul ar accident Ischaemic stroke Haemorrhage intracranial
Eye disorders		Conjunctivitis Dry eye Lacrimation increased Keratoconjunc tivitis sicca Eyelid oedema Ocular surface disease
Cardiac disorders		Cardiac failure Arrhythmia	Angina Myocardial infarction Coronary artery disease Arrhythmia supraventricul ar
Vascular disorders			Peripheral ischaemiac
Respiratory, thoracic and			Pulmonary embolism

mediastinal disorders			Interstitial pneumonitis“
Gastrointestinal disorders	Stomatitis Anorexia Vomiting Diarrhoea Nausea	Dyspepsia Constipation Abdominal pain	Rectal haemorrhage Gastrointestina l haemorrhage Intestinal perforation Oesophagitis Colitis e
Hepatobiliary disorders		Aalanine aminotransfera se increased Aspartate aminotransfera se increased		Hepatitis
Skin and subcutaneous tissue disorders	Rash Skin exfoliation	Hyperpigment ation Pruritus Erythema multiforme Alopecia Urticaria		Erythema	Stevens-Johnson syndromeb Toxic epidermal necrolysisb Pemphigoi d Dermatitis bullous Acquired epidermoly sis bullosa Erythematous oedemaf Pseudocell u-litis Dermatitis Eczema Prurigo
Renal and urinary disorders	Creatinine clearance decreased Blood creatinine increasede	Renal failure Glomerular filtration rate decreased				Nephrogenic diabetes insipidus Renal tubular necrosis
General disorders and administration site conditions	Fatigue	Pyrexia Pain Oedema Chest pain Mucosal inflammation
Investigations		Gamma-glutamyltransf erase increased

Injury, poisoning and procedural complications

Radiation oesophagitis Radiation pneumonitis

Recall phenomenon

with and without neutropenia

in some cases fatal

sometimes leading to extremity necrosis with respiratory insufficiency

seen only in combination with cisplatin 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

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

CIAMBRA (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 multitargeted 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 active substance action in malignant cells.

Clinical efficacy

Mesothelioma

EMPHACIS, a multicentre, 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 the medicinal product (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:

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-value*	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-value*	0.001		0.008
Time to treatment failure (months) (95 % CI)	4.5 (3.9 – 4.9)	2.7 (2.1 – 2.9)	4.7 (4.3 – 5.6)	2.7 (2.2 – 3.1)
Log Rank p-value*	0.001		0.001
Overall response rate** (95 % CI)	41.3 % (34.8 – 48.1)	16.7 % (12.0 – 22.2)	45.5 % (37.8 – 53.4)	19.6 % (13.8 – 26.6)
Fisher’s exact p-value*	< 0.001		< 0.001

Abbreviation: CI = confidence interval

• * p-value refers to comparison between arms.

• * * In the pemetrexed /cisplatin arm, randomised 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 multicentre, 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 population (ITT) n = 283) and 7.9 months for patients treated with docetaxel (ITT n = 288). Prior chemotherapy did not include pemetrexed. An analysis of the impact of 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 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 randomised, 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).

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)              (­n=288) 8.3                       ­7.9 (7.0 – 9.4)                (­6.3 – 9.2) 0.99 (0.82 – 1.20) 0.226
Progression free survival (months) □ Median □ HR (95 % CI)	(n=283)              (­n=288) 2.9                      2­.9 0.97 (0.82 – 1.16)
Time to treatment failure (TTTF – months) □ Median □ HR (95 % CI)	(n=283)              (­n=288) 2.3                      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 multicentre, 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) NSCLC showed that pemetrexed plus cisplatin (ITT population

n = 862) met its primary endpoint and showed similar clinical efficacy as gemcitabine plus cisplatin (ITT n = 863) in overall survival (adjusted hazard ratio 0.94; 95% CI = 0.84–1.05). All patients included in this study had an ECOG performance status 0 or 1.

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 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.

Efficacy of pemetrexed + cisplatin vs. gemcitabine + cisplatin in first-line non-small cell lung cancer – ITT population and histology subgroups.

ITT population and histology subgroups	Median overall survival in months (95% CI)				Adjusted hazard ratio (HR) (95% CI)	Superiority p-value
	Pemetrexed + cisplatin		Gemcitabine + cisplatin
ITT population (N = 1725)	10.3 (9.8 – 11.2)	N=862	10.3 (9.6 – 10.9)	N=863	0.94a (0.84 – 1.05)	0.259
Adenocarcinoma (N=847)	12.6 (10.7 – 13.6)	N=436	10.9 (10.2 – 11.9)	N=411	0.84 (0.71–0.99)	0.033

Large cell (N=153)	10.4 (8.6 – 14.1)	N=76	6.7 (5.5 – 9.0)	N=77	0.67 (0.48–0.96)	0.027
Other (N=252)	8.6 (6.8 – 10.2)	N=106	9.2 (8.1 – 10.6)	N=146	1.08 (0.81–1.45)	0.586
Squamous cell (N=473)	9.4 (8.4 – 10.2)	N=244	10.8 (9.5 – 12.1)	N=229	1.23 (1.00–1.51)	0.050

Abbreviations: CI = confidence interval; ITT = intent-to-treat; N = total population size.

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

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 multicentre, 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) (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:

PARAMOUNT

A multicentre, 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)

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

The European Medicines Agency has waived the obligation to submit the results of studies with the reference medicinal product containing pemetrexed in all subsets of the paediatric population in the granted indications (see section 4.2 for information on paediatric use).

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 (E 421)

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

6.2 Incompatibilities

Pemetrexed is physically incompatible with diluents containing calcium, including lactated Ringer’s injection and Ringer’s injection This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

Unopened vial

2 years

Reconstituted and infusion solutions

Chemical and physical in-use stability of the infusion solution of pemetrexed was demonstrated for 24 hours at 2°C-8°C or 15–25°C. The reconstituted solution should be used immediately to prepare the infusion solution. From a microbiological point of view, the infusion solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2°C to 8°C or 15°C to 25°C.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

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

6.5 Nature and contents of container

Type I glass vial with chlorobutyl rubber stopper and an aluminium seal with flip off cap. The vial is covered with a shrink-wrapped plastic sleeve. Each 10 ml vial contains 100 mg of pemetrexed (as pemetrexed disodium hemipentahydrate).

Pack of 1 vial.

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 CIAMBRA vials needed. Each vial contains an excess of pemetrexed to facilitate delivery of label amount.

• 3. 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. 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 or discolouration is observed, do not administer.

• 7. Pemetrexed solutions are for single use only. Any unused medicinal product or waste material

must be disposed of in accordance with local requirements.

Preparation and administration precautions

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

7. MARKETING AUTHORISATION HOLDER

Menarini International Operations Luxembourg S.A.

• 1, Avenue de la Gare

L-1611, Luxembourg

Luxembourg

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/15/1055/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 2 December 2015

Date of latest renewal: