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PEMETREXED DR. REDDYS 100 MG POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION

Active substance(s): PEMETREXED DITROMETHAMINE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Pemetrexed Dr. Reddy’s 100 mg Powder For Concentrate For Solution For Infusion

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains 100 mg of pemetrexed (as pemetrexed ditromethamine
dihydrate).
After reconstitution (see section 6.6), each vial contains 25 mg/ml of
pemetrexed.
For the full list of excipients see section 6.1.

3

PHARMACEUTICAL FORM
Powder for concentrate for solution for infusion.
White to either light yellow or green-yellow lyophilised cake or powder.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Malignant pleural mesothelioma
Pemetrexed in combination with cisplatin is indicated for the treatment of
chemotherapy naïve patients with unresectable malignant pleural
mesothelioma.
Non-small cell lung cancer
Pemetrexed in combination with cisplatin is indicated for the first line
treatment of patients with locally advanced or metastatic non-small cell lung
cancer other than predominantly squamous cell histology (see section 5.1).
Pemetrexed is indicated as monotherapy for the maintenance treatment of
locally advanced or metastatic non-small cell lung cancer other than
predominantly squamous cell histology in patients whose disease has not

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

4.2

Posology and method of administration
Posology:
Pemetrexed must only be administered under the supervision of a physician
qualified in the use of anti-cancer chemotherapy.
Pemetrexed in combination with cisplatin
The recommended dose of Pemetrexed 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 as single agent
In patients treated for non-small cell lung cancer after prior chemotherapy, the
recommended dose of Pemetrexed is 500 mg/m2 BSA administered as an
intravenous infusion over 10 minutes on the first day of each 21-day cycle.
Premedication 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.
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 retreated using the guidelines
in Tables 1, 2 and 3, which are applicable for Pemetrexed used as a single
agent or in combination with cisplatin.
Table 1 - Dose modification table for Pemetrexed (as single agent or in
combination) and cisplatin – Haematologic toxicities
Nadir ANC < 500 /mm3 and nadir platelets 75 % of previous dose (both
Pemetrexed and cisplatin)
≥ 50,000 / mm3
3
75 % of previous dose (both
Nadir platelets < 50,000 / mm
regardless of nadir ANC
Pemetrexed and cisplatin)
3
Nadir platelets < 50,000 / mm with
50 % of previous dose (both
bleedinga, regardless of nadir ANC
Pemetrexed 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), Pemetrexed 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 (as single agent or in
combination) and cisplatin– Non-haematologic toxicities
a, b
Dose of Pemetrexed
Dose for cisplatin
(mg/m2)
(mg/m2)
Any Grade 3 or 4 toxicities
75 % of previous dose
75 % of previous dose
except mucositis
Any diarrhoea requiring
75 % of previous dose
75 % of previous dose
hospitalisation (irrespective of
grade) or grade 3 or 4
diarrhoea.
Grade 3 or 4 mucositis

50 % of previous dose

100 % of previous dose

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

100 % of previous dose

50 % of previous dose

a National Cancer Institute Common Toxicity Criteria (CTC v2.0; NCI 1998)
Treatment with Pemetrexed 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.
Elderly: In clinical studies, there has been no indication that patients 65 years
of age or older are at increased risk of adverse events compared to patients
younger than 65 years old. No dose reductions other than those recommended
for all patients are necessary.
Paediatric population
There is no relevant use of Pemetrexed 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:

For Precautions to be taken before handling or administering Pemetrexed, see
section 6.6.
Pemetrexed should be administered as an intravenous infusion over 10 minutes
on the first day of each 21-day cycle. For instructions on reconstitution and
dilution of Pemetrexed 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 ≥ 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 nonhaematologic 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 aspirin (> 1.3 g daily) for 2 days before, on
the day of, and 2 days following pemetrexed administration (see section 4.5).
In patients with mild to moderate renal insufficiency eligible for pemetrexed
therapy NSAIDs with long elimination half-lives should be interrupted for at
least 5 days prior to, on the day of, and at least 2 days following pemetrexed
administration (see section 4.5).

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

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 aspirin at higher dose (> 1.3 g daily) may decrease
pemetrexed elimination and, consequently, increase the occurrence of
pemetrexed adverse events. Therefore, caution should be made when
administering higher doses of NSAIDs or aspirin, 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 aspirin 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 anticancer 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
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).
Breastfeeding
It is not known whether pemetrexed is excreted in human milk and adverse
reactions on the suckling child cannot be excluded. Breast-feeding must be
discontinued during pemetrexed therapy (see section 4.3).
Fertility
Owing to the possibility of pemetrexed treatment causing irreversible
infertility, men are advised to seek counselling on sperm storage before
starting treatment.

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.
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 Yellow Card Scheme, website:
www.mhra.gov.uk/yellowcard.
Tabulated list of adverse reactions
The table below provides the frequency and severity of undesirable effects that
have been reported in > 5 % of 168 patients with mesothelioma who were
randomised to receive cisplatin and pemetrexed and 163 patients with
mesothelioma randomised to receive single agent cisplatin. In both treatment
arms, these chemonaive patients were fully supplemented with folic acid and
vitamin B12.
Adverse reactions
Frequency estimate: Very common (≥1/10), Common (≥1/100 and <1/10),
Uncommon (≥1/1000 and <1/100), Rare (≥1/10,000 and <1/1000), Very rare
(<1/10,000) and not known (cannot be estimated from available dataspontaneous reports).
Within each frequency grouping, undesirable effects are presented in order of
decreasing seriousness.
System
organ
class

Frequency

Blood and
lymphatic
system
disorders

Very
common

Metabolism
and nutrition
disorders

Common

Event*

Neutrophils/
Granulocytes
decreased
Leukocytes
decreased
Haemoglobin
decreased
Platelets
decreased
Dehydration

Pemetrexed/cisplatin
(N = 168)
Grade
All
grades
3-4
toxicity
toxicity
(%)
(%)
56.0
23.2

Cisplatin
(N = 163)
Grade
All
grades
3-4
toxicity
toxicity
(%)
(%)
13.5
3.1

53.0

14.9

16.6

0.6

26.2

4.2

10.4

0.0

23.2

5.4

8.6

0.0

6.5

4.2

0.6

0.6

Nervous
system
disorders

Very
common

NeuropathySensory

10.1

0.0

9.8

0.6

Common

Taste
disturbance
Conjunctivitis

7.7

0.0***

6.1

0.0***

5.4

0.0

0.6

0.0

Eye disorders

Common

Gastrointestinal
disorders

Very
common

Skin and
subcutaneous
tissue disorders
Renal and
urinary
disorders

General
Disorders and
administration
site conditions

16.7
56.5
23.2

3.6
10.7
3.0

8.0
49.7
6.1

0.0
4.3
0.0

Common

Diarrhoea
Vomiting
Stomatitis/
Pharyngitis
Nausea
Anorexia
Constipation
Dyspepsia

82.1
20.2
11.9
5.4

11.9
1.2
0.6
0.6

76.7
14.1
7.4
0.6

5.5
0.6
0.6
0.0

Very
common

Rash
Alopecia

16.1
11.3

0.6
0.0***

4.9
5.5

0.0
0.0***

Very
common

Creatinine
elevation

10.7

0.6

9.8

1.2

Creatinine
clearance
decreased**
Fatigue

16.1

0.6

17.8

1.8

47.6

10.1

42.3

9.2

Very
common

*Refer to National Cancer Institute CTC version 2 for each grade of toxicity
except the term “creatinine clearance decreased”
** which is derived from the term “renal/genitourinary other”.
*** According to National Cancer Institute CTC (v2.0; NCI 1998), taste
disturbance and alopecia should only be reported as Grade 1 or 2.
For the purpose of this table a cut off of 5 % was used for inclusion of all
events where the reporter considered a possible relationship to pemetrexed and
cisplatin.
Clinically relevant CTC toxicities that were reported in ≥ 1 % and < 5 % of
the patients that were randomly assigned to receive cisplatin and pemetrexed
include: renal failure, infection, pyrexia, febrile neutropenia, increased AST,
ALT, and GGT, urticaria and chest pain.
Clinically relevant CTC toxicities that were reported in < 1 % of the patients
that were randomly assigned to receive cisplatin and pemetrexed include
arrhythmia and motor neuropathy.
The table below provides the frequency and severity of undesirable effects that
have been reported in > 5 % of 265 patients randomly assigned to receive
single agent pemetrexed with folic acid and vitamin B12 supplementation and

276 patients randomly assigned to receive single agent docetaxel. All patients
were diagnosed with locally advanced or metastatic non-small cell lung cancer
and received prior chemotherapy.

System organ
class

Frequency Event*

Blood and
lymphatic
system disorders

Very
common

Common
Gastrointestinal
disorders

Hepatobiliary
disorders
Skin and subcutaneous tissue
disorders

Very
common

Common
Common

Very
common
Common

Neutrophils/
Granulocytes
decreased
Leukocytes
decreased
Haemoglobin
decreased
Platelets
decreased
Diarrhoea
Vomiting
Stomatitis/
Pharyngitis
Nausea
Anorexia
Constipation
SGPT (ALT)
elevation
SGOT (AST)
elevation
Rash/
desquamation
Pruritus
Alopecia
Fatigue

Pemetrexed
N = 265
Grade 3 –
All
4 toxicity
grades
(%)
toxicity
(%)
10.9
5.3
12.1

4.2

19.2

4.2

8.3

1.9

12.8
16.2
14.7

0.4
1.5
1.1

30.9
21.9
5.7
7.9

2.6
1.9
0.0
1.9

6.8

1.1

14.0

0.0

6.8
6.4
34.0

0.4
0.4**
5.3

Docetaxel
N = 276
Grade 3 –
All
4 toxicity
grades
(%)
toxicity
(%
45.
40.2
3
34.
1
22.
1
1.
1
24.
12.
3
0
17.
4
16.
7
23.
9
4.
0
1.
4
0.
7
6.
2
1.
8
37.
7
35.
9
7.
6

General
Very
disorders and
Common
Common
Fever
8.3
0.0
administration
site conditions
*Refer to National Cancer Institute CTC version 2 for each grade of toxicity.
**According to National Cancer Institute CTC (v2.0; NCI 1998), alopecia
should only be reported as Grade 1 or 2.
For the purpose of this table a cut off of 5 % was used for inclusion of all
events where the reporter considered a possible relationship to pemetrexed.
Clinically relevant CTC toxicities that were reported in ≥ 1 % and < 5 % of the
patients that were randomly assigned to pemetrexed include: infection without
neutropenia, febrile neutropenia, allergic reaction/hypersensitivity, increased
creatinine, motor neuropathy, sensory neuropathy, erythema multiforme, and
abdominal pain.

27.2
4.3
0.4
2.5
1.1
1.1
1.8
2.5
0.0
0.0
0.0
0.0
0.0
2.2**
5.4
0.0

Clinically relevant CTC toxicities that were reported in < 1 % of the patients
that were randomly assigned to pemetrexed include supraventricular
arrhythmias.
Clinically relevant Grade 3 and Grade 4 laboratory toxicities were similar
between integrated Phase 2 results from three single agent pemetrexed studies
(n = 164) and the Phase 3 single agent pemetrexed study described above, with
the exception of neutropenia (12.8 % versus 5.3 %, respectively) and alanine
aminotransferase elevation (15.2 % versus 1.9 %, respectively). These
differences were likely due to differences in the patient population, since the
Phase 2 studies included both chemonaive and heavily pre-treated breast
cancer patients with pre-existing liver metastases and/or abnormal baseline
liver function tests.
The table below provides the frequency and severity of undesirable effects
considered possibly related to study drug that have been reported in >5% of
839 patients with NSCLC who were randomized to receive cisplatin and
pemetrexed and 830 patients with NSCLC who were randomized to receive
cisplatin and gemcitabine. All patients received study therapy as initial
treatment for locally advanced or metastatic NSCLC and patients in both
treatment groups were fully supplemented with folic acid and vitamin B12.

System organ
class

Frequency

Event**

Pemetrexed/
cisplatin
(N = 839)
All
grades
toxicity
(%)

Blood and
lymphatic
system
disorders

Nervous
system
disorders
Gastrointestinal
disorders

Very
common

Common

Very
common

Hemoglobin
decreased
Neutrophils/
Granulocytes
decreased
Leukocytes
decreased
Platelets decreased
Neuropathysensory
Taste disturbance
Nausea
Vomiting
Anorexia
Constipation
Stomatitis/
Pharyngitis

Grade
3-4
toxicity
(%)

Gemcitabine/
cisplatin
(N = 830)
All
grades
toxicity
(%)

Grade
3-4
toxicity
(%)

33.0*

5.6*

45.7*

9.9*

29.0*

15.1*

38.4*

26.7*

17.8

4.8*

20.6

7.6*

10.1*
8.5*

4.1*
0.0*

26.6*
12.4*

12.7*
0.6*

8.1
56.1
39.7
26.6
21.0
13.5

0.0***
7.2*
6.1
2.4*
0.8
0.8

8.9
53.4
35.5
24.2
19.5
12.4

0.0***
3.9*
6.1
0.7*
0.4
0.1

Common
Skin and
subcutaneous
tissue disorders
Renal and
urinary
disorders
General
disorders and
administration
site conditions

Very
common
Common
Very
common
Very
common

Diarrhoea
without
Dyspepsia/
Heartburn
Alopecia

12.4

1.3

12.8

1.6

5.2

0.1

5.9

0.0

11.9*

0***

21.4*

0.5***

Rash/desquamation
Creatinine
elevation

6.6
10.1*

0.1
0.8

8.0
6.9*

0.5
0.5

Fatigue

42.7

6.7

44.9

4.9

*P-values <0.05 comparing pemetrexed/cisplatin to gemcitabine/cisplatin,
using Fisher Exact test.
**Refer to National Cancer Institute CTC (v2.0; NCI 1998) for each Grade of
Toxicity.
***According to National Cancer Institute CTC (v2.0; NCI 1998), taste
disturbance and alopecia should only be reported as Grade 1 or 2.
For the purpose of this table, a cut-off of 5% was used for inclusion of all
events where the reporter considered a possible relationship to pemetrexed and
cisplatin.
Clinically relevant toxicity that was reported in ≥ 1% and ≤ 5% of the patients
that were randomly assigned to receive cisplatin and pemetrexed include: AST
increase, ALT increase, infection, febrile neutropenia, renal failure, pyrexia,
dehydration, conjunctivitis, and creatinine clearance decrease. Clinically
relevant toxicity that was reported in < 1% of the patients that were randomly
assigned to receive cisplatin and pemetrexed include: GGT increase, chest
pain, arrhythmia, and motor neuropathy.
Clinically relevant toxicities with respect to gender were similar to the overall
population in patients receiving pemetrexed plus cisplatin.
The table below provides the frequency and severity of undesirable effects
considered possibly related to study drug that have been reported in > 5% of
800 patients randomly assigned to receive single agent pemetrexed and 402
patients randomly assigned to receive placebo in the single-agent pemetrexed
maintenance (JMEN: N=663) and continuation pemetrexed maintenance
(PARAMOUNT: N=539) studies. All patients were diagnosed with Stage IIIB
or IV NSCLC and had received prior platinum-based chemotherapy. Patients
in both study arms were fully supplemented with folic acid and vitamin B12.
System organ
Pemetrexed***
Placebo***
Frequency*
Event**
class
(N =800)
(N =402)

All
grades
toxicity
(%)

Blood and
Lymphatic system
disorders

Nervous system
disorders
Gastrointestinal
disorders

Hepatobiliary
disorders

Very
common
Common

Common
Very
common
Common
Common

Skin and
Subcutaneous
tissue disorders

Common

General
disorders and
administration site
conditions
Renal Disorders

Very
common
Common

Hemoglobin
decreased
Leukocytes
decreased
Neutrophils
decreased
Neuropathysensory
Nausea
Anorexia
Vomiting
Mucositis/
stomatitis
ALT (SGPT)
elevation
AST (SGOT)
elevation

Grade
3/4
toxicity
(%)

All
grades
toxicity
(%)

Grade
3/4
toxicity
(%)

18.0

4.5

5.2

0.5

5.8

1.9

0.7

0.2

8.4

4.4

0.2

0.0

7.4
17.3
12.8
8.4
6.8

0.6
0.8
1.1
0.3
0.8

5.0
4.0
3.2
1.5
1.7

0.2
0.2
0.0
0.0
0.0

6.5

0.1

2.2

0.0

5.9

0.0

1.7

0.0

Rash/
desquamation

8.1

0.1

3.7

0.0

Fatigue

24.1

5.3

10.9

0.7

Pain
7.6
0.9
4.5
Edema
5.6
0.0
1.5
Common
7.6
0.9
1.7
Renal
disorders***
Abbreviations: ALT = alanine aminotransferase; AST = aspartate
aminotransferase; CTCAE = Common Terminology Criteria for Adverse
Event; NCI = National Cancer Institute; SGOT = serum glutamic oxaloacectic
aminotransferase; SGPT = serum glutamic pyruvic aminotransferase.
* Definition of frequency terms: Very common - ≥ 10%; Common - > 5%
and < 10%. For the purpose of this table, a cutoff of 5% was used for
inclusion of all events where the reporter considered a possible relationship to
pemetrexed.
** Refer to NCI CTCAE Criteria (Version 3.0; NCI 2003) for each grade of
toxicity. The reporting rates shown are according to CTCAE version 3.0.
*** Integrated adverse reactions table combines the results of the JMEN
pemetrexed maintenance (N=663) and PARAMOUNT continuation
pemetrexed maintenance (N=539) studies.

0.0
0.0
0.0

**** Combined term includes increased serum/blood creatinine, decreased
glomerular filtration rate, renal failure and renal/genitourinary- other.
Clinically relevant CTC toxicity of any grade that was reported in ≥ 1% and ≤
5% of the patients that were randomly assigned to pemetrexed include: febrile
neutropenia, infection, decreased platelets, diarrhoea, constipation, alopecia,
pruritis/itching, fever (in the absence of neutropenia), ocular surface disease
(including conjunctivitis), increased lacrimation, dizziness and motor
neuropathy.
Clinically relevant CTC toxicity that was reported in < 1% of the patients that
were randomly assigned to pemetrexed include: allergic
reaction/hypersensitivity, erythema multiforme, supraventricular arrhythmia
and pulmonary embolism.
Safety was assessed for patients who were randomised to receive pemetrexed
(N=800). The incidence of adverse reactions was evaluated for patients who
received ≤ 6 cycles of pemetrexed maintenance (N=519), and compared to
patients who received > 6 cycles of pemetrexed (N=281). Increases in adverse
reactions (all grades) were observed with longer exposure. A significant
increase in the incidence of possibly study-drug-related Grade 3/4 neutropenia
was observed with longer exposure to pemetrexed (≤6 cycles: 3.3%, > 6
cycles: 6.4%; p=0.046). No statistically significant differences in any other
individual Grade 3/4/5 adverse reactions were seen with longer exposure.
Serious cardiovascular and cerebrovascular events, including myocardial
infarction, angina pectoris, cerebrovascular accident and transient ischaemic
attack have been uncommonly reported during clinical studies with
pemetrexed, usually when given in combination with another cytotoxic agent.
Most of the patients in whom these events have been observed had pre-existing
cardiovascular risk factors.
Rare cases of hepatitis, potentially serious, have been reported during clinical
studies with pemetrexed. Pancytopenia has been uncommonly reported during
clinical trials with pemetrexed.
In clinical trials, cases of colitis (including intestinal and rectal bleeding,
sometimes fatal, intestinal perforation, intestinal necrosis and typhlitis) have
been reported uncommonly in patients treated with pemetrexed.
In clinical trials, cases of interstitial pneumonitis with respiratory
insufficiency, sometimes fatal, have been reported uncommonly in patients
treated with pemetrexed.
Uncommon cases of oedema have been reported in patients treated with
pemetrexed. Oesophagitis/ radiation oesophagitis has been uncommonly
reported during clinical trials with pemetrexed.
Sepsis, sometimes fatal, has been commonly reported during clinical trials
with pemetrexed. During post marketing surveillance, the following adverse
reactions have been reported in patients treated with pemetrexed:

Uncommon cases of acute renal failure have been reported with pemetrexed
alone or in association with other chemotherapeutic agents (see section 4.4).
Uncommon cases of radiation pneumonitis have been reported in patients
treated with radiation either prior, during or subsequent to their pemetrexed
therapy (see section 4.4).
Rare cases of radiation recall have been reported in patients who have received
radiotherapy previously (see section 4.4).
Uncommon cases of peripheral ischaemia leading sometimes to extremity
necrosis have been reported. Rare cases of bullous conditions have been
reported including Stevens-Johnson syndrome and Toxic epidermal necrolysis
which in some cases were fatal.
Rarely, haemolytic anaemia has been reported in patients treated with
pemetrexed. Rare cases of anaphylactic shock have been reported.

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 PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Folic acid analogues, ATC code: L01BA04
Pemetrexed is a multi-targeted anti-cancer antifolate agent that exerts its action
by disrupting crucial folate-dependent metabolic processes essential for cell
replication.
Mechanism of action
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 drug action in malignant cells.
Clinical efficacy and safety:
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 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:
Efficacy of Pemetrexed plus cisplatin vs. cisplatin in malignant pleural
mesothelioma
Randomized and
Fully
treated
supplemented
patients Cisplatin
patients Cisplatin
Efficacy parameter
Pemetrexed/
Pemetrexed/
cisplatin
cisplatin
(N = 222)
(N = 163)
(N = 226)
(N = 168)
Median overall survival (months)
12.1
9.
13.3
10.
3
0
(95 % CI)
(10.0 - 14.4)
(11.4 - 14.9)
(7.8
(8.4
Log Rank p-value*
0.020
0.051
Median time to tumour progression
5.7
3.
6.1
3.
9
9
(months)
(95 %
(4.9 – 6.5)
(5.3 - 7.0)
CI) Rank p-value*
Log
0.001 (2.8 0.008 (2.8 Time to treatment failure (months)
4.5
2.
4.7
2.
7
7
(95 % CI)
(3.9 – 4.9)
(4.3 - 5.6)
Log Rank p-value*
0.001 (2.1 0.001 (2.2 Overall response rate**
41.3 %
16.7
45.5 %
19.6
%
%
(95 % CI)
(34.8 - 48.1)
(37.8 - 53.4)
Fisher’s exact p-value*
< 0.001 (12.0 –
< 0.001 (13.8 Abbreviation: CI = confidence interval
* p-value refers to comparison between arms.
** In the Pemetrexed/cisplatin arm, randomized and treated (N = 225) and
fully supplemented (N = 167)
A statistically significant improvement of the clinically relevant symptoms
(pain and 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 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 randomized, Phase 3, controlled trial,
suggest that efficacy data (overall survival, progression free survival) for
pemetrexed are similar between patients previously pretreated 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
(n = 283)
(n = 288)
(months)
8.3
7.9
Median (m)
(7.0 - 9.4)
(6.3 95 % CI for median
0.99
9.2)
(0.82 - 1.20)
HR
0.226
95 % CI for HR
(n = 283)
(n = 288)
Progression free survival (months)
Median
2.9
2.9
HR (95 % CI)
0.97 (0.82 – 1.16)
(n = 283)
(n = 288)
Time to treatment failure (TTTF –
2.3
2.1
months)
0.84 (0.71 - 0.997)
Median
Response (n: qualified for response)
(n = 264)
(n = 274)
Response rate (%) (95 % CI)
9.1 (5.9 8.8 (5.7 13.2)
12.8)
Stable disease (%)
45.8
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) 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 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 noninferiority 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 = 27.333.9) 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.
Median overall survival in
Adjusted
Superiority
months
hazard
Gemcitabine
p-value
ratio
Pemetrexed +
+
(HR)
cisplatin
cisplatin
(95% CI)
a
ITT population
10.3
N=862
10.3
N=863
0.259
0.94
(N = 1725)
(9.8 – 11.2)
(9.6 – 10.9)
(0.84 – 1.05)
Adenocarcinoma
N=436
N=411
0.033
12.6
10.9
0.84
(N=847)
(10.7 –
(10.2 –
(0.71–
Large cell
10.4
N=76
6.7
N=77
0.027
0.67
(N=153)
(8.6 – 14.1)
(5.5 – 9.0)
(0.48–
Other
8.6
N=106
9.2
N=146
0.586
1.08
(N=252)
(6.8 – 10.2)
(8.1 – 10.6)
(0.81–
Squamous cell
9.4
N=244
10.8
N=229
0.050
1.23
(N=473)
(8.4 – 10.2)
(9.5 – 12.1)
(1.00–
Abbreviations: CI = confidence interval; ITT = intent-to-treat; N = total
population size.
ITT population
and histology
subgroups

a Statistically significant for noninferiority, with the entire confidence interval
for HR well below the 1.17645 noninferiority margin (p <0.001).
Kaplan Meier plots of overall survival by histology

There were no clinically relevant differences observed for the safety profile of
Pemetrexed plus cisplatin within the histology subgroups.
Patients treated with Pemetrexed and cisplatin required fewer transfusions
(16.4% versus 28.9%, p<0.001), red blood cell transfusions (16.1% versus
27.3%, p<0.001) and platelet transfusions (1.8% versus 4.5%, p=0.002).
Patients also required lower administration of erythropoietin/darbopoietin
(10.4% versus 18.1%, p<0.001), G-CSF/GM-CSF (3.1% versus 6.1%,
p=0.004), and iron preparations (4.3% versus 7.0%, p=0.021).
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) 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:

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.
Paediatric population
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).

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 10minute period.
Distribution
Pemetrexed has a steady-state volume of distribution of 9 l/ m2. In vitro studies
indicate that pemetrexed is approximately 81 % bound to plasma proteins.
Binding was not notably affected by varying degrees of renal impairment.
Biotransformation
Pemetrexed undergoes limited hepatic metabolism.
Elimination
Pemetrexed is primarily eliminated in the urine, with 70 % to 90 % of the
administered dose being recovered unchanged in urine within the first 24 hours
following administration. 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 %.

Linearity/non-linearity
Pemetrexed total systemic exposure (AUC) and maximum plasma
concentration increase proportionally with dose. The pharmacokinetics of
pemetrexed are consistent over multiple treatment cycles.
Pharmacokinetic/pharmacodynamic relationships
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 PARTICULARS

6.1

List of excipients
Mannitol
Ttrometamol
Hydrochloric acid (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
When prepared as directed, reconstituted and infusion solutions of pemetrexed
contain no antimicrobial preservatives. Chemical and physical in-use stability
of reconstituted and infusion solutions of pemetrexed were demonstrated for
24 hours at refrigerated temperature (2 °C − 8 °C) and room temperature (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
Unopened vial
This medicinal product does not require any special storage conditions.
For storage conditions after reconstitution of the medicinal product, see section
6.3.

6.5

Nature and contents of container
Type I glass vial with rubber stopper containing 100 mg of pemetrexed.
Pack of 1 vial.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
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 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 glucose 50 mg/ml (5 %) solution for
infusion (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 either 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 glucose 50 mg/ml (5 %) solution for infusion (without
preservative), and administered as an intravenous infusion over 10 minutes.

5. Pemetrexed infusion solutions prepared as directed above are compatible with
polyvinyl chloride and polyolefin lined administration sets and infusion bags.
6. Parenteral medicinal products must be inspected visually for particulate matter and
discolouration prior to administration. If particulate matter is observed, do not
administer.
7. Pemetrexed solutions are for single use only. Any unused medicinal product or
waste material must be disposed of in accordance with local requirements.

Preparation and administration precautions: As with other potentially toxic
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.
Any unused medicinal product or waste material should be disposed of in
accordance with local requirements.

7

MARKETING AUTHORISATION HOLDER
Dr. Reddy’s Laboratories (UK) Ltd.
6 Riverview Road
Beverley
East Yorkshire
HU17 0LD
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 08553/0562

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
01/07/2016

10

DATE OF REVISION OF THE TEXT
01/07/2016

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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