Pexitaz

Pexitaz is a white to either light yellow or green yellow lyophilized solid, intended to be used as an intravenous infusion.
Each vial contains Pemetrexed Disodium equivalent to Pemetrexed 100/500 mg, Excipients q.s.
After reconstitution, each ml contains 25 mg of Pemetrexed.

Clinical Pharmacology: Pemetrexed is an antifolate containing the pyrrolopyrimidine based nucleus.
Mechanism of Action: 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 inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), all folate dependent enzymes involved in 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 converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are inhibitors of TS and GARFT. Polyglutamation is a time and concentration dependent process that occurs in tumor 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.
Preclinical studies have shown that pemetrexed inhibits the in vitro growth of mesothelioma cell lines (MSTO-211H, NCI-H2052). Studies with the MSTO211H mesothelioma cell line showed synergistic effects when pemetrexed was combined concurrently with cisplatin.
Pharmacokinetics: The pharmacokinetics of pemetrexed administered as a single agent in doses ranging from 0.2 to 838 mg/m² infused over a 10 minute period have been evaluated in 426 cancer patients with a variety of solid tumors. Pemetrexed undergoes limited metabolism in the liver. 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.
Pemetrexed is primarily eliminated in the urine, with 70% to 90% of the dose recovered unchanged within the first 24 hours following administration. The total systemic clearance of pemetrexed is 91.8 mL/min and the elimination half life of pemetrexed is 3.5 hours in patients with normal renal function (creatinine clearance of 90 mL/min). The clearance decreases, and exposure (AUC) increases, as renal function decreases. Pemetrexed total systemic exposure (AUC) and maximum plasma concentration (C_max) increase proportionally with dose. Between patient variability in clearance is moderate at 19.3%.
The pharmacokinetics of pemetrexed do not change over multiple treatment cycles. Pemetrexed has a steady state volume of distribution of 16.1 liters. In vitro studies indicate that pemetrexed is approximately 81% bound to plasma proteins. Binding is not affected by degree of renal impairment.
No effect of age on the pharmacokinetics of pemetrexed was observed over a range of 26 to 80 years. Pediatric patients were not included in clinical trials. The pharmacokinetics of pemetrexed were not different in male and female patients.
There was no effect of elevated AST (SGOT), ALT (SGPT), or total bilirubin on the pharmacokinetics of pemetrexed. However, studies of hepatically impaired patients have not been conducted. Pharmacokinetic analyses of pemetrexed included 127 patients with reduced renal function. Plasma clearance of pemetrexed decreases as renal function decreases, with a resultant increase in systemic exposure. Patients with creatinine clearances of 45, 50, and 80 mL/min had 65%, 54%, and 13% increases, respectively in pemetrexed total systemic exposure (AUC) compared to patients with creatinine clearance of 100 mL/ min.
Cisplatin does not affect the pharmacokinetics of pemetrexed and the pharmacokinetics of total platinum are unaltered by pemetrexed. Coadministration of oral folic acid or intramuscular vitamin B₁₂ does not affect the pharmacokinetics of pemetrexed.

Malignant Pleural Mesothelioma: Pexitaz in combination with cisplatin is indicated for the treatment of chemotherapy naive patients with unresectable malignant pleural mesothelioma.
Non-small cell lung cancer: Pexitaz 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.
Pexitaz 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.

For intravenous use only.
In combination with cisplatin: The recommended dose of Pexitaz is 500 mg/m² of body surface area (BSA) administered as an intravenous infusion over 10 minutes on Day 1 of each 21 day cycle. The recommended dose of cisplatin is 75 mg/m² BSA infused over 2 hours beginning approximately 30 minutes after the end of Pexitaz administration on Day 1 of each 21 day cycle. Patients should receive adequate antiemetic treatment and appropriate hydration prior to and/or after receiving cisplatin.
As a single agent: In patients treated for non-small cell lung cancer after prior chemotherapy, the recommended dose of Pexitaz is 500 mg/m² BSA administered as an intravenous infusion over 10 minutes on Day 1 of each 21 day cycle.
Premedication Regimen: Corticosteroid: Skin rash has been reported more frequently in patients not pretreated with a corticosteroid. Pretreatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction. In clinical trials, dexamethasone 4 mg was given by mouth twice daily the day before, the day of, and the day after Pexitaz administration.
Vitamin Supplementation: To reduce toxicity, patients treated with Pexitaz must be instructed to take a low dose oral folic acid preparation or multivitamin with folic acid on a daily basis. At least 5 daily doses of folic acid must be taken during the 7 day period preceding the first dose of Pexitaz; and dosing should continue during the full course of therapy and for 21 days after the last dose of Pexitaz. Patients must also receive one (1) intramuscular injection of vitamin B12 during the week preceding the first dose of Pexitaz and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as Pexitaz. In clinical trials, the dose of folic acid studied ranged from 350 to 1,000 mcg, and the dose of vitamin B12 was 1,000 mcg. The most commonly used dose of oral folic acid in clinical trials was 400 mcg.
Laboratory Monitoring and Dose Reduction Recommendations: Complete blood cell counts, including platelet counts, should be performed on all patients receiving Pexitaz. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is ≥1,500 cells/mm³, the platelet count is ≥100,000 cells/mm³, and creatinine clearance is ≥45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function.
Dose Reduction Recommendations: Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic 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 1-3, which are suitable for using Pexitaz as a single agent or in combination with cisplatin. (See Table 1.)

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If patients develop nonhematologic toxicities (excluding neurotoxicity) ≥Grade 3 (except Grade 3 transaminase elevations), Pexitaz should be withheld until resolution to less than or equal to the patient's pre-therapy value. Treatment should be resumed according to guidelines in Table 2. (See Table 2.)

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In the event of neurotoxicity, the recommended dose adjustments for Pexitaz and cisplatin are described in Table 3. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced. (See Table 3.)

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Pexitaz therapy should be discontinued if a patient experiences any hematologic or nonhematologic Grade 3 or 4 toxicity after 2 dose reductions (except Grade 3 transaminase elevations) or immediately if Grade 3 or 4 neurotoxicity is observed.
Elderly Patients: No effect of age on the pharmacokinetics of pemetrexed was observed over a range of 26 to 80 years. 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. Hence, no dose reductions other than those recommended for all patients are necessary for patients ≥65 years of age.
Pediatric use: Pexitaz is not recommended for use in children, as safety and efficacy have not been established in children.
Hepatic impairment: Pemetrexed is not extensively metabolized by the liver. There was no effect of elevated AST (SGOT), ALT (SGPT), or total bilirubin on the pharmacokinetics of pemetrexed. There is limited clinical experience in patients with hepatic impairment. Patients with bilirubin >1.5 times the upper limit of normal were excluded from clinical trials of pemetrexed. Patients with transaminase >3.0 times the upper limit of normal were routinely excluded from clinical trials if they had no evidence of hepatic metastases. Patients with transaminase from 3 to 5 times the upper limit of normal were included in the clinical trial of pemetrexed if they had hepatic metastases. Dose adjustments based on hepatic impairment experienced during treatment with Pexitaz are provided in Table 2.
Renal impairment: Pemetrexed is known to be primarily excreted by the kidney. Decreased renal function will result in reduced clearance and greater exposure (AUC) to pemetrexed compared with patients with normal renal function. Cisplatin coadministration with pemetrexed has not been studied in patients with moderate renal impairment. In clinical studies, patients with creatinine clearance ≥45 mL/min required no dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to make dosage recommendations for this group of patients. Therefore, Pexitaz should not be administered to patients whose creatinine clearance is <45 mL/min using the standard Cockcroft and Gault formula (below) or GFR measured by Tc99m-DPTAserum clearance method: See equation.

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Caution should be exercised when administering Pexitaz concurrently with NSAIDs to patients whose creatinine clearance is <80 mL/min.
Preparation and Administration Precautions: As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion solutions of Pexitaz. The use of gloves is recommended. If a solution of Pexitaz contacts the skin, wash the skin immediately and thoroughly with soap and water. If Pexitaz contacts the mucous membranes, flush thoroughly with water. Several published guidelines for handling and disposal of anticancer agents are available. Pexitaz is not a vesicant.
There is no specific antidote for extravasation of pemetrexed. To date, there have been few reported cases of pemetrexed extravasation, which were not assessed as serious by the investigator. Pexitaz extravasation should be managed with local standard practice for extravasation as with other non-vesicants.
Preparation for Intravenous Infusion Administration: 1. Use aseptic technique during the reconstitution and further dilution of Pexitaz for intravenous infusion administration.
2. Calculate the dose of Pexitaz and determine the number of vials needed. Vials contain either 100 mg or 500 mg of Pexitaz. The vials contain an excess of Pexitaz to facilitate delivery of label amount.
3. Reconstitute each 100 mg vial with 4.2 mL of 0.9% Sodium Chloride Injection (preservative free). Reconstitute 500 mg vial with 20 mL of 0.9% Sodium Chloride Injection (preservative free). Reconstitution of either size vial gives a solution containing 25 mg/mL Pexitaz. 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 Pexitaz 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. If particulate matter is observed, do not administer.
5. An appropriate quantity of the reconstituted Pexitaz 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. Pexitaz is administered as an intravenous infusion over 10 minutes.
6. Chemical and physical stability of reconstituted and infusion solutions of Pexitaz were demonstrated for up to 24 hours following initial reconstitution, when stored at refrigerated or ambient room temperature and lighting. When prepared as directed, reconstitution and infusion solutions of Pexitaz 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). Pexitaz 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 pemetrexed for injection with other drugs and diluents has not been studied, and therefore is not recommended.

There have been few cases of pemetrexed overdose. Reported toxicities included neutropenia, anemia, thrombocytopenia, sensory polyneuropathy, mucositis, and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia, and anemia. In addition, infection with or without fever, diarrhea, and mucositis may be seen. If an overdose occurs, patients should be monitored with blood counts and general supportive measures should be instituted as deemed necessary by the treating physician. The use of calcium folinate/folinic acid in the management of pemetrexed overdose should be considered.
In clinical trials, leucovorin was permitted for NCI CTC Grade 4 leukopenia lasting ≥3 days, CTC Grade 4 neutropenia lasting ≥3 days, and immediately for CTC Grade 4 thrombocytopenia, bleeding associated with Grade 3 thrombocytopenia, or Grade 3 or 4 mucositis. The following intravenous doses and schedules of leucovorin were recommended for intravenous use: 100 mg/m², intravenously once, followed by leucovorin, 50 mg/m², intravenously every 6 hours for 8 days.
The ability of pemetrexed to be dialyzed is unknown.

In patients who have a history of severe hypersensitivity reaction to pemetrexed or to any other ingredient used in the formulation.
Concomitant yellow fever vaccine.

Pemetrexed is primarily eliminated unchanged by renal excretion. No dosage adjustment is needed in patients with creatinine clearance ≥45 mL/min. Insufficient numbers of patients have been studied with creatinine clearance <45 mL/min to give a dose recommendation. Therefore, pemetrexed should not be administered to patients whose creatinine clearance is <45 mL/min. It has been reported that a patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B₁₂ died of drug related toxicity following administration of pemetrexed alone.
Pemetrexed can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia); myelosuppression is usually the dose limiting toxicity. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum nonhematologic toxicity seen in the previous cycle. Complete blood cell counts, including platelet counts and periodic chemistry tests, should be performed on all patients receiving pemetrexed. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is ≥1,500 cells/ mm, the platelet count is ≥100,000 cells/mm³, and creatinine clearance is ≥45 mL/min.
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. All patients eligible for pemetrexed therapy should avoid taking NSAIDs with long elimination half-lives for at least 5 days prior to, on the day, and at least 2 days following pemetrexed administration.
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.
Patients treated with pemetrexed must be instructed to take folic acid and vitamin B₁₂ as a prophylactic measure to reduce treatment related hematologic and GI toxicity. In clinical studies, less overall toxicity and reductions in Grade 3/4 hematologic and nonhematologic toxicities such as neutropenia, febrile neutropenia, and infection with Grade 3/4 neutropenia were reported when pretreatment with folic acid and vitamin B₁₂ was administered.
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.
Pemetrexed should be administered under the supervision of a qualified physician experienced in the use of antineoplastic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available. Treatment related adverse events of pemetrexed seen in clinical trials have been reversible. Skin rash has been reported more frequently in patients not pretreated with a corticosteroid in clinical trials. Pretreatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction.
The effect of third space fluid, such as pleural effusion and ascites, on pemetrexed is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to pemetrexed administration.
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.
Immunodepressed status is common in cancer patients. As a result, concomitant use of live attenuated vaccines (except yellow fever, which is contra-indicated) is not recommended.
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.
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: 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.

Pemetrexed may cause fetal harm when administered to a pregnant woman. Pemetrexed was fetotoxic and teratogenic in animal studies. There are no studies of pemetrexed in pregnant women. Patients should be advised to avoid becoming pregnant. If pemetrexed is used during pregnancy, or if the patient becomes pregnant while taking pemetrexed, the patient should be apprised of the potential hazard to the fetus.
It is not known whether pemetrexed or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from pemetrexed, it is recommended that nursing be discontinued if the mother is treated with pemetrexed.

The adverse events reported with the use of pemetrexed include neutropenia, leukopenia, anemia, thrombocytopenia, ALT elevation, AST elevation, decrease creatinine clearance, creatinine elevation, renal failure, thrombosis, embolism, cardiac ischemia, nausea, vomiting, constipation, anorexia, stomatitis, pharyngitis, diarrhea without colostomy, dehydration, dysphagia, esophagitis, odynophagia, dyspnea, chest pain, hypertension, sensory neuropathy, mood alteration, depression, infection without neutropenia, infection with grade 3 or grade 4 neutropenia, febrile neutropenia, allergic reaction, hypersensitivity, rash, desquamation, conjunctivitis, taste disturbance, pyrexia, fatigue, fever, edema, myalgia, alopecia, dyspepsia, urticaria, arrhythmias, motor neuropathy, pruritis, erythema multiforme, abdominal pain, heart burn, GGT increase, arthralgia and other constitutional symptoms.
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.
The following adverse events have been identified during post-marketing use of pemetrexed. These events have occurred with pemetrexed when used as a single agent and in combination therapies. These events included rare cases of colitis, interstitial pneumonitis, acute renal failure and radiation recall.

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 nonsteroidal anti-inflammatory drugs (NSAIDs, such as ibuprofen >1,600 mg/day) and aspirin at higher dosage (≥1.3 g daily) may decrease pemetrexed elimination and, consequently, increase the occurrence of pemetrexed adverse events. Therefore, caution is advised when administering higher doses of NSAIDs or aspirin at higher dosage 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 dosage should be avoided for 2 days before, on the day of, and 2 days following pemetrexed administration.
In the absence of data regarding potential interaction with NSAIDs having longer half-lives, such as piroxicam or rofecoxib, the concomitant administration with pemetrexed should be avoided for at least 5 days prior to, on the day, and at least 2 days following pemetrexed administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, 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. No studies were conducted to determine the cytochrome P450 isozyme induction potential of pemetrexed, because pemetrexed used as recommended (once every 21 days) would not be expected to cause any significant enzyme induction.
Due to the increased thrombotic risk in patients with cancer, the use of anticoagulation treatment is frequent. The high intraindividual 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 of pemetrexed with yellow fever vaccine is contraindicated due to the risk of fatal generalised vaccinale disease.
Concomitant use of pemetrexed with live attenuated vaccines (except yellow fever vaccine, which is not contraindicated) is not recommended due to the 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).
Cisplatin does not affect the pharmacokinetics of pemetrexed and the pharmacokinetics of total platinum are unaltered by pemetrexed.
Coadministration of oral folic acid or intramuscular vitamin B₁₂ does not affect the pharmacokinetics of pemetrexed.

Incompatibilities: Reconstitution and further dilution prior to intravenous infusion is only recommended with 0.9% Sodium Chloride Injection. Pemetrexed is physically incompatible with diluents containing calcium, including Lactated Ringer's Injection and Ringer's Injection. Coadministration of pemetrexed for injection with other drugs and diluents has not been studied, and therefore is not recommended.

Storage & Handling: Store below 30°C. Administer infusion solution within 24 hours after initial reconstitution. Discard unused portion.

Cytotoxic Chemotherapy

L01BA04 - pemetrexed ; Belongs to the class of antimetabolites, folic acid analogues. Used in the treatment of cancer.

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