Pemtori Iv 100 and 500 mg Powder for solution for infusion

The treatment of patients with malignant pleural mesothelioma in combination with cisplatin.
In combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic non-small cell lung cancer other than that predominantly squamous cell histology.
Monotherapy for the treatment of patients with locally advanced or metastatic adenocarcinoma of the lung after prior chemotherapy.
Monotherapy for the maintenance treatment of locally advanced or metastatic adenocarcinoma of the lung in patients whose disease has not progressed immediately following standard chemotherapy.

PEMTORI IV should only be administered under the supervision of a medical practitioner qualified in the use of anti-cancer chemotherapy.
Malignant pleural mesothelioma:
Combination use with cisplatin:
Adults: The recommended dose of PEMTORI IV is 500 mg/m2 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 infused over 2 hours approximately 30 minutes after completion of PEMTORI IV infusion on the first day of each 21-day cycle. Patients should receive appropriate hydration prior to and/or after receiving cisplatin.
Adenocarcinoma of the lung:
Single medicine use:
Adults: In patients treated for adenocarcinoma of the lung, the recommended dose of PEMTORI IV is 500 mg/m2 administered as an intravenous infusion over 10 minutes on the first day of each 21-day cycle.
Combination use with cisplatin:
Adults: In patients treated for non-small cell lung cancer, the recommended dose of PEMTORI IV is 500 mg/m2 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 infused over 2 hours approximately 30 minutes after completion of the PEMTORI IV infusion on the first day of each 21-day cycle. Patients should receive appropriate hydration prior to and/or after receiving cisplatin.
Pre-medication regimen:
A corticosteroid should be given the day prior to, on the day of, and the day after PEMTORI IV administration in order to reduce the incidence and severity of skin reactions. The corticosteroid should be equivalent to 4 mg of dexamethasone administered orally twice a day (see section 4.4). Patients treated with PEMTORI IV should also receive vitamin supplementation in order to reduce toxicity (see section 4.4). Oral folic acid or a multivitamin containing folic acid (350 to 1000 mcg) must be taken on a daily basis. At least 5 daily doses of folic acid must be taken during the 7 days preceding the first dose of PEMTORI IV, continued during the full course of therapy and for 21 days after the last dose of PEMTORI IV. In the week preceding the first dose of PEMTORI IV and every 3 cycles thereafter patients must receive an intramuscular injection of vitamin B12 (1000 mcg).
Monitoring:
Monitoring, in the form of a with a full blood count, including a differential and platelet count should be undertaken in patients before each dose of PEMTORI IV, with periodic blood chemistry tests being collected to evaluate renal and hepatic function. Absolute neutrophil count (ANC) should be u2265 1500 cells/mm3 and platelets should be u2265 100 000 cells/mm3 prior to the start of each cycle.
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 may be re-treated using the guidelines in Tables 1, 2 and 3 below, which are applicable for PEMTORI IV used as a single medicine or in combination with cisplatin.

• Hypersensitivity to pemetrexed or to any of the ingredients of PEMTORI IV (see section 6.1)
• Concomitant yellow fever vaccine (see section 4.5)

PEMTORI IV can suppress bone marrow function as manifested by neutropenia, thrombocytopenia, anaemia or pancytopenia (see section 4.8). Myelosuppression is usually the dose-limiting toxicity. Patients should be monitored for myelosuppression during therapy and PEMTORI IV should not be given to patients until absolute neutrophil count (ANC) returns to u2265 1500 cells/mm3 and platelet count returns to u2265 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).
In patients with mesothelioma, less overall toxicity and reduction in Grade 3/4 haematologic and non-haematologic toxicities such as neutropenia, febrile neutropenia and infection with Grade 3/4 neutropenia occur when pre-treatment with folic acid and vitamin B12 are administered. Therefore, patients treated with PEMTORI IV 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 can occur 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).
Patients with creatinine clearance < 45 ml/min have not been studied in sufficient numbers when treated with pemetrexed, as contained in PEMTORI IV. Therefore, the use of PEMTORI IV in these patients is not recommended (see section 4.2).
Non-steroidal anti-inflammatory drugs (NSAIDs) with short-elimination half-lives, such as ibuprofen and acetylsalicylic acid, should be avoided for at least 2 days prior to, on the day of, and at least 2 days after administration of PEMTORI IV in those patients with mild to moderate renal insufficiency (creatinine clearance from 45 u2013 79 ml/min).
All patients eligible for PEMTORI IV therapy should avoid taking NSAIDs with long elimination half-lives at least 5 days prior to, on the day of, and at least 2 days after PEMTORI IV administration (see section 4.5).
Serious renal events, including acute renal failure, have been reported with pemetrexed alone or in association with other chemotherapeutic medicines. The majority of 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 have also been reported with pemetrexed alone or with other chemotherapeutic medicines. 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. The administration of pemetrexed in solid tumour patients with normal renal function and with stable third space fluid demonstrates 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 administration of PEMTORI IV in patients with normal renal function should be considered, but may not be necessary.
Serious cardiovascular events, including myocardial infarction and cerebrovascular events, have been reported rarely when pemetrexed, as contained in PEMTORI IV is given in combination with another cytotoxic medicine, or in patients with cardiovascular risk factors (see section 4.8).
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.
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 as in PEMTORI IV is primarily eliminated unchanged renally by tubular secretion and to a lesser extent by glomerular filtration. Pemetrexed is actively secreted by OAT3 (organic anion transporter 3). Concomitant administration of nephrotoxic medicines, (e.g. aminoglycoside, loop diuretics, platinum compounds, cyclosporin), could result in delayed clearance of pemetrexed. This combination should be used with caution. If necessary, creatinine clearance should be closely monitored.
Concomitant administration of medicines that are tubularly secreted (e.g. probenecid, penicillin) could potentially result in delayed clearance of pemetrexed. Caution should be made during concomitant use of PEMTORI IV with these medicines. If necessary, creatinine clearance should be closely monitored.
Although NSAIDS in moderate doses can be administered with PEMTORI IV in patients with normal renal function (creatinine clearance u2265 80 ml/min), caution should be used when administering NSAIDS concurrently with PEMTORI IV to patients with mild to moderate renal insufficiency (creatinine clearance 45 u2013 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 between pemetrexed as in PEMTORI IV and NSAIDs with longer half-lives (e.g. piroxicam) patients with mild to moderate renal insufficiency taking these NSAIDs should interrupt dosing for at least 5 days before, on the day of, and at least 2 days after PEMTORI IV administration. If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression and gastrointestinal toxicity.
Acetylsalicylic acid, administered in low to moderate doses (325 mg orally every 6 hours) does not affect the pharmacokinetics of pemetrexed as in PEMTORI IV. The pharmacokinetics of pemetrexed as in PEMTORI IV are not influenced by concurrently administered cisplatin or carboplatin. Similarly, the pharmacokinetics of total platinum are unaltered by PEMTORI IV pemetrexed. Oral folic acid and intramuscular vitamin B12 supplementation do not affect the pharmacokinetics of pemetrexed as in PEMTORI IV. Pemetrexed as in PEMTORI IV undergoes limited hepatic metabolism and is not expected 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 such as PEMTORI IV require increased frequency of INR (International Normalised Ratio) monitoring, if it is decided to treat the patient with oral anticoagulants.

Women of childbearing potential / Contraception in males and females:
PEMTORI IV therapy may cause teratogenicity and other reproductive adverse events due to its genotoxic nature. In males, PEMTORI IV may cause DNA damage in the sperm, potentially resulting in adverse events in the embryo or foetus of a female sexual partner. In females, PEMTORI IV may directly affect the embryo or foetus; or may cause DNA damage in the oocytes.
Male patients should be advised to use highly effective contraception while receiving treatment with PEMTORI IV, until the end of relevant systemic exposure to this product, including its potential genotoxic metabolites (i.e., five half-lives after the last dose, which is 40 days) plus 90 days (i.e., 60 - 75 days for sperm production plus 10 - 14 days for the transport to the epididymis) giving 130 days (4 months and 10 days) after the last dose.
Women of childbearing potential, that is female patients using PEMTORI IV and female sexual partners of male patients receiving PEMTORI IV, should be advised to use highly effective contraception until the end of relevant systemic exposure to PEMTORI IV, including its potential genotoxic metabolites (i.e., five half-lives after the last dose, which is 40 days) plus 6 months (which covers the growth and maturation phase of folliculogenesis). This gives a total of 7 months and 10 days.
Pregnancy:
Safety in pregnancy has not been established. There is no data on the use of pemetrexed as in PEMTORI IV in pregnant women. Animal studies have shown reproductive toxicity such as birth defects and other defects on the development of the foetus, the course of gestation and peri- and post-development. The potential risk for humans is unknown. Therefore, the use of PEMTORI IV should be avoided during pregnancy due to the potential hazard to the foetus. Women should also be advised to avoid becoming pregnant while being treated with PEMTORI IV.
Breastfeeding:
Safety during lactation has not been established. It is not known whether pemetrexed is excreted in human milk. Therefore, breast feeding is not recommended during PEMTORI IV therapy.
Fertility:
Owing to the possibility of pemetrexed treatment causing irreversible infertility, men are advised to seek counselling on sperm storage before starting treatment with PEMTORI IV.

PEMTORI IV may cause fatigue. Patients should be cautioned against driving or operating machinery.

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 effects:
In combination with cisplatin supplemented with folic acid and vitamin B12 (malignant pleural mesothelioma):

Signs and symptoms:
Reported symptoms of overdose include neutropenia, anaemia, thrombocytopenia, mucositis, sensory neuropathy 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.
Management of overdose:
In the event of suspected overdose, patients should be monitored with blood counts and should receive supportive therapy as necessary. The use of leucovorin (calcium folinate / folinic acid) in the management of PEMTORI IV overdosage should be considered.