4. Clinical particulars
4.1 Therapeutic indications
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Malignant Pleural Mesothelioma:
ALIMTA in combination with cisplatin is indicated for the treatment of chemotherapy naïve patients with unresectable malignant pleural mesothelioma.
Non-small cell lung cancer:
ALIMTA 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).
ALIMTA 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
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Malignant pleural mesothelioma:
In patients treated for malignant pleural mesothelioma, tALIMTA in combination with cisplatin: The recommended dose of ALIMTA 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).
Non‑small cell lung cancer:
ALIMTA as single agent: In patients treated for non‑small cell lung cancer, after prior chemotherapy the recommended dose of ALIMTA is 500 mg/m2 BSA administered as an intravenous infusion over 10 minutes on the first day of each 21‑day cycle.
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Nadir platelets <50,000/mm3 with bleedinga, regardless of nadir ANC.
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50% of previous dose (both drugs).
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4.4 Special warnings and precautions for use
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In the Phase 3 mesothelioma trial, overall lLess 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).
4.5 Interaction with other medicinal products and other forms of interaction
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Concomitant use not recommended: Live attenuated vaccines (except yellow fever, for which concomitant use is contra-indicated): 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).
4.8 Undesirable effects
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Nervous
System
Disorders
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Very
Common
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Neuropathy-
Sensory
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10.1
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0.0
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9.8
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0.6
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Common
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Taste disturbance
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7.7
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0.0***
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6.1
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0.0***
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Skin and Subcutaneous
Tissue Disorders
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Very Common
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Rash
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16.1
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0.6
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4.9
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0.0
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Alopecia
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11.3
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0.0***
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5.5
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0.0***
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Very common - ≥ 10 %; Common is normally defined as - ≥ 1 % and < 10 %. 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 % (common) 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 % (uncommon) of the patients that were randomly assigned to receive cisplatin and pemetrexed include arrhythmia and motor neuropathy.
*Refer to National Cancer Institute CTC version 2 for each grade of toxicity.
Very common - ≥ 10 %; Common is normally defined as - ≥ 1 % and < 10 %. 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 % (common) of the patients that were randomly assigned to pemetrexed include: infection without neutropenia, febrile neutropenia, allergic reaction/hypersensitivity, increased creatinine, motor neuropathy, sensory neuropathy, erythema multiforme, and abdominal pain.
Clinically relevant CTC toxicities that were reported in < 1 % (uncommon) of the patients that were randomly assigned to pemetrexed include supraventricular arrhythmias.
Added:
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.
Very common - ≥10%; common is normally defined as ≥ 1 % and < 10 %. 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% (common) 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% (uncommon) 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.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
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A multicentre, randomised, open label phase 3 study of ALIMTA 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 ALIMTA (Intent To Treat population n = 283) and 7.9 months for patients treated with docetaxel (ITT n = 288). An analysis of the impact of NSCLC histology on the treatment effect on overall survival was in favour of ALIMTA 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 ALIMTA within the histology subgroups.
Limited clinical data from a separate randomized, Phase 3, controlled trial, suggest that efficacy data (overall survival, progression free survival) for pemetrexed are similar between patients previously pre treated with docetaxel (n=41) and patients who did not receive previous docetaxel treatment (n=540).
Added:
A multicentre, randomised, open-label, Phase 3 study of ALIMTA 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 ALIMTA 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 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 ALIMTA 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 ALIMTA 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 ALIMTA + Cisplatin vs. Gemcitabine + Cisplatin in First-Line Non-Small Cell Lung Cancer – ITT Population and Histology Subgroups.
Kaplan Meier Plots of Overall Survival by Histology
*GRAPHS HERE*
There were no clinically relevant differences observed for the safety profile of ALIMTA plus cisplatin within the histology subgroups.
Patients treated with ALIMTA and cisplatin required fewer transfusions (16.4% versus 28.9%, p<0.001), red blood cell transfusions (16.1% versus 27.3%, p<.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<.001), G-CSF/GM-CSF (3.1% versus 6.1%, p=0.004), and iron preparations (4.3% versus 7.0%, p=0.021).
6. PHARMACEUTICAL PARTICULARS
6.5 Nature and contents of container
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Not all pack sizes may be marketed.
10. DATE OF REVISION OF THE TEXT
New date
08 April 2008