Ontrex

Ontrex

pemetrexed

Manufacturer:

Oncogen Pharma

Distributor:

Pharmaniaga Marketing
Full Prescribing Info
Contents
Pemetrexed.
Description
Each 500mg vial contains 500mg of pemetrexed (as pemetrexed disodium 2.5 Hydrate).
Each vial must be reconstituted with 20ml of 0.9% sodium chloride injection resulting in 25mg/ml solution. The appropriate volume of required dose is removed from the vial and further diluted to 100ml with sodium chloride injection.
Excipients/Inactive Ingredients: Mannitol, Hydrochloric acid, Sodium hydroxide.
Action
Pharmacotherapeutic Group: Folic acid analogues. ATC Code: L01BA04.
Pharmacology: Pharmacodynamics: Pemetrexed is a multi-targeted anti-cancer antifolate agent that exerts its action by disrupting crucial folate- dependent metabolic processes essential for cell replication.
In vitro studies have shown that pemetrexed behaves as a multi-targeted antifolate by inhibiting thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), which are key folate- dependent enzymes for the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is transported into cells by both the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is rapidly and efficiently converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are even more potent inhibitors of TS and GARFT. Polyglutamation is a time- and concentration-dependent process that occurs in tumour cells and, to a lesser extent, in normal tissues.
Polyglutamated metabolites have an increased intracellular half-life resulting in prolonged drug action in malignant cells.
Pharmacokinetics: The pharmacokinetic properties of pemetrexed following single-agent administration have been evaluated in cancer patients with a variety of solid tumours at doses ranging from 0.2 to 838mg/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 91.8ml/min and the elimination half-life from plasma is 3.5 hours in patients with normal renal function (creatinine clearance of 90ml/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.
Indications/Uses
Malignant Pleural Mesothelioma: ONTREX in combination with cisplatin is indicated for the treatment of chemotherapy naive patients with unresectable malignant pleural mesothelioma.
Non-small Cell Lung Cancer: ONTREX in combination with cisplatin is indicated for the first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) other than predominantly squamous cell histology.
ONTREX 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.
ONTREX 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.
Dosage/Direction for Use
Posology: ONTREX must only be administered under the supervision of a physician qualified in the use of anti-cancer chemotherapy.
ONTREX must only be prepared according to the instructions provided in Special precautions for disposal and other handling under Cautions for Usage.
ONTREX in combination with cisplatin: The recommended dose of ONTREX is 500mg/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 75mg/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.
ONTREX as single agent: In patients treated for non-small cell lung cancer after prior chemotherapy, the recommended dose of ONTREX is 500mg/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 4mg of dexamethasone administered orally twice a day (see Precautions).
To reduce toxicity, patients treated with pemetrexed must also receive vitamin supplementation (see Precautions). Patients must take oral folic acid or a multivitamin containing folic acid (350 to 1,000 micrograms) on a daily basis. At least five doses of folic acid must be taken during the seven days preceding the first dose of pemetrexed, and dosing must continue during the full course of therapy and for 21 days after the last dose of pemetrexed. Patients must also receive an intramuscular injection of vitamin B12 (1,000 micrograms) in the week preceding the first dose of pemetrexed and once every three cycles thereafter. Subsequent vitamin B12 injections may be given on the same day as pemetrexed.
Monitoring: Patients receiving pemetrexed should be monitored before each dose with a complete blood count, including a differential white cell count (WCC) and platelet count. Prior to each chemotherapy administration, blood chemistry tests should be collected to evaluate renal and hepatic function. Before the start of any cycle of chemotherapy, patients are required to have the following: absolute neutrophil count (ANC) should be ≥ 1,500 cells/mm3 and platelets should be ≥ 100,000 cells/mm3.
Creatinine clearance should be ≥ 45ml/min.
The total bilirubin should be ≤ 1.5-times upper limit of normal. Alkaline phosphatase (AP), aspartate aminotransferase (AST or SGOT), and alanine aminotransferase (ALT or SGPT) should be ≤ 3-times upper limit of normal. Alkaline phosphatase, AST, and ALT ≤ 5-times upper limit of normal is acceptable if liver has tumour involvement.
Dose Adjustments: Dose adjustments at the start of a subsequent cycle should be based on nadir haematologic counts or maximum non- haematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery. Upon recovery, patients should be re-treated using the guidelines in Tables 1, 2, and 3, which are applicable for ONTREX used as a single agent or in combination with cisplatin. (See Table 1.)

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If patients develop non-haematologic toxicities ≥ Grade 3 (excluding neurotoxicity), ONTREX 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. (See Table 2.)

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In the event of neurotoxicity, the recommended dose adjustment for ONTREX and cisplatin is documented in Table 3. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is observed. (See Table 3.)

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Treatment with ONTREX 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: 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: ONTREX is not recommended for use in patients under 18 years of age, as safety and efficacy have not been established in this group of patients.
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. Patients with creatinine clearance of ≥ 45ml/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 45ml/min; therefore, the use of pemetrexed is not recommended (see Precautions).
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.
Route of Administration: Intravenous (IV).
Overdosage
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.
Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in Description.
Breast-feeding (see Use of Pregnancy & Lactation).
Concomitant yellow fever vaccine (see Interactions).
Special Precautions
Pemetrexed can suppress bone marrow function as manifested by neutropenia, thrombocytopenia, and anaemia (or pancytopenia) (see Adverse Reactions). Myelosuppression is usually the dose-limiting toxicity. Patients should be monitored for myelosuppression during therapy and pemetrexed should not be given to patients until absolute neutrophil count (ANC) returns to ≥ 1,500 cells/mm3 and platelet count returns to ≥ 100,000 cells/mm3. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum non-haematologic toxicity seen from the previous cycle (see Dosage & Administration).
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 Dosage & Administration).
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 Dosage & Administration).
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).
An insufficient number of patients has been studied with creatinine clearance of below 45ml/min. Therefore, the use of pemetrexed in patients with creatinine clearance of <45ml/min is not recommended (see Dosage & Administration).
Patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79ml/min) should avoid taking non- steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, and acetylsalicylic acid (>1.3g daily) for 2 days before, on the day of, and 2 days following pemetrexed administration (see Interactions).
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 Interactions).
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. Thus, drainage of third-space fluid collection prior to pemetrexed treatment should be considered, but may not be necessary. Due to the gastrointestinal toxicity of pemetrexed given in combination with cisplatin, severe dehydration has been observed. Therefore, patients should receive adequate anti-emetic treatment and appropriate hydration prior to and/or after receiving treatment.
Serious cardiovascular events, including myocardial infarction and cerebrovascular events, have been uncommonly reported 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 Adverse Reactions).
Immunodepressed status is common in cancer patients. As a result, concomitant use of live attenuated vaccines is not recommended (see Interactions).
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 Use in Pregnancy & Lactation).
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 the use of other radiosensitising agents.
Effect 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.
Use In Pregnancy & 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. 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 Precautions).
Breast-feeding: 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 Contraindications).
Fertility: Owing to the possibility of pemetrexed treatment causing irreversible infertility, men are advised to seek counselling on sperm storage before starting treatment.
Adverse Reactions
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.
Nephrogenic diabetes insipidus and renal tubular necrosis also have been reported in post marketing setting with an unknown frequency.
Tabulated list of adverse reactions of Pemetrexed in Combination with Cisplatin: (See Table 4.)

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Tabulated list of adverse reactions of Pemetrexed: (See Table 5.)

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Drug Interactions
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 ≥ 80ml/min), high doses of non-steroidal anti-inflammatory drugs (NSAIDs, such as ibuprofen > 1600mg/day) and acetylsalicylic acid at higher doses (≥ 1.3g 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 acetylsalicylic acid, concurrently with pemetrexed to patients with normal function (creatinine clearance ≥ 80ml/min).
In patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79ml/min), the concomitant administration of pemetrexed with NSAIDs (e.g., ibuprofen) or acetylsalicylic acid at higher doses should be avoided for 2 days before, on the day of, and 2 days following pemetrexed administration (see Precautions).
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 Precautions). If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression and gastrointestinal toxicity.
Pemetrexed undergoes limited hepatic metabolism. Pemetrexed would not be predicted to cause clinically significant inhibition of the metabolic clearance of drugs metabolised by CYP3A, CYP2D6, CYP2C9, and CYP1A2.
Interactions Common to all Cytotoxics: Due to the increased thrombotic risk in patients with cancer, the use of anticoagulation treatment is frequent. The high intra-individual variability of the coagulation status during diseases and the possibility of interaction between oral anticoagulants and anti-cancer chemotherapy require increased frequency of INR (International Normalised Ratio) monitoring, if it is decided to treat the patient with oral anticoagulants.
Concomitant Use Contraindicated: Yellow fever vaccine: Risk of fatal generalised vaccinale disease (see Contraindications).
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 Precautions).
Caution For Usage
Special precautions for disposal and other handling: 1. Use aseptic technique during the reconstitution and further dilution of ONTREX for intravenous infusion administration.
2. Calculate the dose of ONTREX and determine the number of vials needed. Vials contain 500 mg of ONTREX. The vials contain an excess of ONTREX to facilitate delivery of label amount.
3. Reconstitute each 500-mg vial with 20 ml of 0.9% Sodium Chloride Injection (preservative free). Reconstitution of vial gives 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 color from colorless to yellow or green-yellow without adversely affecting product quality. The pH of the reconstituted ONTREX solution is between 6.6 and 7.8. FURTHER DILUTION IS REQUIRED.
4. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter is observed, do not administer.
5. An appropriate quantity of the reconstituted ONTREX solution must be further diluted into a solution of 0.9% Sodium Chloride Injection (preservative free), so that the total volume of solution is 100 ml. ONTREX is administered as an intravenous infusion over 10 minutes.
6. Chemical and physical stability of reconstituted and infusion solutions of ONTREX were demonstrated for up to 24 hours following initial reconstitution, when stored refrigerated. When prepared as directed, reconstitution and infusion solutions of ONTREX contain no antimicrobial preservatives. Discard any unused portion.
Reconstitution and further dilution prior to intravenous infusion is only recommended with 0.9% Sodium Chloride Injection (preservative free). ONTREX is physically incompatible with diluents containing calcium, including Lactated Ringer's Injection and Ringer's Injection and therefore these should not be used. Coadministration of ONTREX with other drugs and diluents has not been studied, and therefore is not recommended. ONTREX is compatible with standard polyvinyl chloride (PVC) administration sets and non-PVC multilayer film intravenous bags.
Preparation and administration precautions: As with other potentially toxic anti-cancer 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.
CAUTION: CYTOTOXIC AGENT.
CONTROLLED MEDICINE.
Incompatibilities: Pemetrexed is physically incompatible with diluents containing calcium, including lactated Ringer's injection and Ringer's injection. In the absence of other compatibility studies this medicinal product must not be mixed with other medicinal products.
Storage
Unopened vial: ONTREX 500mg powder for concentrate for solution for infusion should be stored below 30°C (86°F).
For storage conditions after reconstitution of the medicinal product, see Shelf-Life as follows.
Shelf-Life: Unopened vial 500mg: 2 years.
Reconstituted and infusion solutions: Chemical and physical stability of reconstituted and infusion solutions of ONTREX 500mg powder for concentrate for solution for infusion were demonstrated for up to 24 hours following initial reconstitution, when stored refrigerated, 2° to 8°C (36° to 46°F). When prepared as directed, reconstituted and infusion solutions of ONTREX 500mg powder for concentrate for solution for infusion contain no antimicrobial preservatives. Discard unused portion.
ONTREX 500mg powder for concentrate for solution for infusion is not light sensitive.
ATC Classification
L01BA04 - pemetrexed ; Belongs to the class of antimetabolites, folic acid analogues. Used in the treatment of cancer.
Presentation/Packing
Powd for infusion (vial) 500 mg x 1's.
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