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PEMETREXED

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Pemetrexed is an antifolate antineoplastic agent that disrupts folate-dependent metabolic processes essential for cell replication.

Specific Substances

    1) Pemetrexed disodium
    2) Pemetrexed disodico
    3) CAS 137281-23-3 (pemetrexed)
    4) CAS 150399-23-8 (pemetrexed disodium)
    1.2.1) MOLECULAR FORMULA
    1) C20-H19-N5-Na2-O6.7H2O (Prod Info ALIMTA(R) injection, 2004)

Available Forms Sources

    A) FORMS
    1) Pemetrexed is available as 100 mg and 500 mg single-use vials for injection (Prod Info ALIMTA(R) intravenous injection powder, 2013).
    B) USES
    1) Pemetrexed is used alone or in combination with cisplatin to treat locally advanced or metastatic non-small cell lung cancer in patients. It is also used in combination with cisplatin to treat malignant pleural mesothelioma in patients whose disease is unresectable or who are not candidates for curative surgery (Prod Info ALIMTA(R) intravenous injection powder, 2013).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Pemetrexed is used alone or in combination with cisplatin to treat locally advanced or metastatic non-small cell lung cancer in patients. It is also used in combination with cisplatin to treat malignant pleural mesothelioma in patients whose disease is unresectable or who are not candidates for curative surgery.
    B) PHARMACOLOGY: Pemetrexed is an folate analog metabolic inhibitor that exerts its antineoplastic activity by disrupting folate-dependent metabolic processes required for cell replication. In in vitro studies, pemetrexed inhibited 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.
    C) EPIDEMIOLOGY: Inadvertent iatrogenic overdose may occur, but is rare.
    D) WITH THERAPEUTIC USE
    1) Myelosuppression is the dose-limiting toxicity with pemetrexed therapy. Anemia, leukopenia, neutropenia, thrombocytopenia, immune-mediated hemolytic anemia, and febrile neutropenia have been reported. The most common adverse effects are nausea, anorexia, and fatigue. Other adverse effects include chest pain, hypertension, vomiting, constipation, diarrhea, stomatitis, rash/desquamation, alopecia, edema, Stevens-Johnson syndrome, toxic epidermal necrolysis, radiation recall syndrome, pancreatitis, colitis, elevated liver enzymes, hypersensitivity reactions, rhabdomyolysis, myalgia, arthralgia, sensory neuropathy, dyspnea, pneumonitis, fever, and infection.
    E) WITH POISONING/EXPOSURE
    1) Pemetrexed administration, in doses of 600 mg/m(2) or greater, have resulted in neutropenia, anemia, thrombocytopenia, nausea, vomiting, diarrhea, and rash. Other possible overdose effects may include infection (with or without fever) and mucositis.
    0.2.20) REPRODUCTIVE
    A) Pemetrexed is classified as FDA pregnancy category D. Animal studies have shown that administration of pemetrexed to mice resulted in increased embryo-fetal deaths, reduced litter sizes, and fetal malformations.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Myelosuppression may occur. Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery. Monitor patient for signs of bleeding.
    D) Monitor for clinical evidence of infection, with particular attention to odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    E) Monitor serum electrolytes, CK, renal function, and hepatic enzymes.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Treat persistent nausea and vomiting with several antiemetics of different classes. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia, or hemorrhage. Leucovorin has been administered to patients with pemetrexed toxicity. An optimal dose of leucovorin after pemetrexed overdose is unknown. In clinical trials, patients who developed severe hematologic toxicity received an initial dose of leucovorin 100 mg/m(2) IV, followed by 50 mg/m(2) IV every 6 hours for 8 days. Severe nausea and vomiting may respond to a combination of agents from different drug classes.
    C) INTRATHECAL INJECTION
    1) No clinical reports available, information derived from experience with other antineoplastics. Immediately drain at least 20 ml CSF; drainage of up to 70 ml has been tolerated in adults. Follow with CSF exchange (remove serial 20 ml aliquots CSF and replace with equivalent volumes of warmed, preservative free saline). For large overdoses, consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline through ventricular catheter, drain fluid from lumbar catheter; typical volumes 80 mL/hr). Albumin (5%) has also been used for perfusion, may be useful because of high protein binding. Dexamethasone 4 mg intravenously every 6 hours to prevent arachnoiditis.
    D) DECONTAMINATION
    1) Gastrointestinal decontamination is not recommended; administered via the parenteral route.
    E) AIRWAY MANAGEMENT
    1) Endotracheal intubation and mechanical ventilation may rarely be required in patients with severe respiratory distress or allergic reactions.
    F) MYELOSUPPRESSION
    1) Administer colony stimulating factors as these patients are at significant risk for developing severe neutropenia. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours. Monitor CBC with differential for evidence of bone marrow suppression. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage. Patients with severe neutropenia should be in protective isolation.
    G) NEUTROPENIA
    1) Prophylactic therapy with a fluoroquinolone should be considered in high risk patients with expected prolonged (more than 7 days), and profound neutropenia (ANC 100 cells/mm(3) or less).
    H) FEBRILE NEUTROPENIA
    1) If fever (38.3 C) develops during neutropenic phase (ANC 500 cells/mm(3) or less), cultures should be obtained and empiric antibiotics started. HIGH RISK PATIENT (anticipated neutropenia of 7 days or more; unstable; significant comorbidities): IV monotherapy with either piperacillin-tazobactam; a carbapenem (meropenem or imipenem-cilastatin); or an antipseudomonal beta-lactam agent (eg, ceftazidime or cefepime). LOW RISK PATIENT (anticipated neutropenia of less than 7 days; clinically stable; no comorbidities): oral ciprofloxacin and amoxicillin/clavulanate.
    I) RHABDOMYOLYSIS
    1) Administer sufficient 0.9% saline to maintain urine output of 2 to 3 mL/kg/hr. Monitor input and output, serum electrolytes, CK, and renal function. Diuretics may be necessary to maintain urine output. Urinary alkalinization is NOT routinely recommended.
    J) NAUSEA AND VOMITING
    1) Treat severe nausea and vomiting with agents from several different classes. For example: dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol).
    K) STOMATITIS
    1) Treat mild mucositis with bland oral rinses with 0.9% saline, sodium bicarbonate, and water. For moderate cases with pain, consider adding a topical anesthetic (eg, lidocaine, benzocaine, dyclonine, diphenhydramine, or doxepin). Treat moderate to severe mucositis with topical anesthetics and systemic analgesics. Patients with mucositis and moderate xerostomia may receive sialagogues (eg, sugarless candy/mints, pilocarpine/cevimeline, or bethanechol) and topical fluorides to stimulate salivary gland function. Consider prophylactic antiviral and antifungal agents to prevent infections. Topical oral antimicrobial mouthwashes, rinses, pastilles, or lozenges may be used to decrease the risk of infection. Palifermin is indicated to reduce the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support. In patients with a pemetrexed overdose, administer palifermin 60 mcg/kg/day IV bolus injection starting 24 hours after the overdose for 3 consecutive days.
    L) ENHANCED ELIMINATION
    1) There is no information regarding the effectiveness of hemodialysis or hemoperfusion for the removal of pemetrexed from plasma; however, due to its high protein binding (81%) and large volume of distribution, it is anticipated that hemodialysis would be ineffective.
    M) PREVENTIVE PROCEDURE
    1) Daily folic acid (350 to 1000 mcg/day orally) and vitamin B12 (1000 mcg intramuscularly every 9 weeks) supplementation before, during, and after therapy for reduction or prevention of drug toxicity. Oral dexamethasone to reduce incidence or severity of skin rashes.
    N) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no data to support home management. All exposures should be evaluated in a healthcare facility.
    2) OBSERVATION CRITERIA: All patients should be sent to a healthcare facility for observation. If patients are asymptomatic for 6 hours, they may be sent home. Since toxic effects (eg, myelosuppression) may be delayed, patients should return to a healthcare provider for any symptoms.
    3) ADMISSION CRITERIA: Symptomatic patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), and daily monitoring of CBC with differential until bone marrow suppression is resolved. Patients with an intrathecal overdose or severe toxicity should be transferred to an intensive care setting.
    4) CONSULT CRITERIA: Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with overdose. In addition, consultation with an infectious diseases physician with expertise in the management of neutropenic patients with infections is strongly recommended.
    5) TRANSFER CRITERIA: Patients with large overdoses may benefit from early transfer to a cancer treatment or bone marrow transplant center.
    O) PITFALLS
    1) Symptoms of overdose are similar to reported side effects of the medication. Early symptoms of overdose may be delayed or not evident (ie, particularly myelosuppression), so reliable follow-up is imperative. Patients taking pemetrexed may have severe comorbidities and may be receiving other drugs that may produce synergistic effects (ie, myelosuppression).
    P) PHARMACOKINETICS
    1) Protein binding: Approximately 81% bound to plasma proteins. Vd: 16.1 L. Metabolism: Not metabolized to any appreciable extent. Excretion: Primarily excreted via the kidney, with 70% to 90% of the dose eliminated unchanged within the first 24 hours of administration. Elimination half-life: 3.5 hours.
    Q) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause myelosuppression.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose of pemetrexed has not been established. Nausea and vomiting, rash, and neutropenia have been reported following intravenous doses of 1200 mg/m(2).
    B) THERAPEUTIC DOSE: ADULT: 500 mg/m(2) administered as an IV infusion over 10 minutes on day 1 of each 21-day cycle. CHILD: Safety and efficacy in the pediatric or adolescent population have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Pemetrexed is used alone or in combination with cisplatin to treat locally advanced or metastatic non-small cell lung cancer in patients. It is also used in combination with cisplatin to treat malignant pleural mesothelioma in patients whose disease is unresectable or who are not candidates for curative surgery.
    B) PHARMACOLOGY: Pemetrexed is an folate analog metabolic inhibitor that exerts its antineoplastic activity by disrupting folate-dependent metabolic processes required for cell replication. In in vitro studies, pemetrexed inhibited 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.
    C) EPIDEMIOLOGY: Inadvertent iatrogenic overdose may occur, but is rare.
    D) WITH THERAPEUTIC USE
    1) Myelosuppression is the dose-limiting toxicity with pemetrexed therapy. Anemia, leukopenia, neutropenia, thrombocytopenia, immune-mediated hemolytic anemia, and febrile neutropenia have been reported. The most common adverse effects are nausea, anorexia, and fatigue. Other adverse effects include chest pain, hypertension, vomiting, constipation, diarrhea, stomatitis, rash/desquamation, alopecia, edema, Stevens-Johnson syndrome, toxic epidermal necrolysis, radiation recall syndrome, pancreatitis, colitis, elevated liver enzymes, hypersensitivity reactions, rhabdomyolysis, myalgia, arthralgia, sensory neuropathy, dyspnea, pneumonitis, fever, and infection.
    E) WITH POISONING/EXPOSURE
    1) Pemetrexed administration, in doses of 600 mg/m(2) or greater, have resulted in neutropenia, anemia, thrombocytopenia, nausea, vomiting, diarrhea, and rash. Other possible overdose effects may include infection (with or without fever) and mucositis.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Fever was reported in 8% of patients treated with pemetrexed (n=265), and in 8% of patients treated with docetaxel (n=276) in a randomized clinical trial comparing pemetrexed (with folic acid and vitamin B12 supplementation) therapy with single agent docetaxel in non-small cell lung cancer (NSCLC). All patients had locally advanced or metastatic NSCLC and had previously been treated with chemotherapy (Prod Info ALIMTA(R) intravenous injection powder, 2013).
    2) During a clinical trial, involving 265 patients with non-small cell lung cancer who received pemetrexed as sole therapy, fever was reported in 26% of the patients, with up to 1% reporting the severity as grade 3/4 (Prod Info ALIMTA(R) injection, 2004).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CHEST PAIN
    1) WITH THERAPEUTIC USE
    a) During a clinical trial, involving 265 patients with non-small cell lung cancer who received pemetrexed as sole therapy, chest pain was reported in 38% of the patients, with 6% and less than 1% reporting the severity as grade 3 and grade 4, respectively (Prod Info ALIMTA(R) injection, 2004).
    B) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) In clinical trials (n=3946; 34% of patients were 65 years or older), Grade 3 or 4 hypertension occurred more often in patients aged 65 and older treated for non-small cell lung cancer with pemetrexed monotherapy or combination therapy than in younger patients. All patients received folic acid and vitamin B12 supplementation (Prod Info ALIMTA(R) intravenous injection powder, 2013).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) During a clinical trial, involving 265 patients with non-small cell lung cancer who received pemetrexed as sole therapy, dyspnea was reported in 72% of the patients, with 14% and 4% reporting the severity as grade 3 and grade 4, respectively (Prod Info ALIMTA(R) injection, 2004).
    B) PNEUMONITIS
    1) WITH THERAPEUTIC USE
    a) During postmarketing surveillance, interstitial pneumonitis has been reported among patients treated with pemetrexed (Prod Info ALIMTA(R) intravenous injection powder, 2013).
    b) CASE REPORT: Pneumonitis was diagnosed in a 72-year-old man who presented with acute dyspnea 3 days after receiving a fifth cycle of pemetrexed (500 mg/m(2) every 3 days) for a new progression of localized non-small cell lung cancer. The patient had also experienced an erythematous rash after the second and third cycles, despite standard premedications (folate, B12 supplementation, and corticosteroids), and was treated with topical corticosteroids. Upon admission for respiratory complications, arterial blood gas analysis showed severe hypoxia (PO2, 68.5 mmHg; PCO2, 22.5 mmHg; nasal cannula O2, 5 L/min) and ambulatory pulse oximetry was less than 80%. Chest x-ray, physical examination, and laboratory analysis revealed bilateral mild interstitial and reticular opacities, tachypnea and fine crackles in the bilateral lower lung fields, decreased hemoglobin level (77 g/L), and elevated WBC (12.9 x 10(9)/L), C-reactive protein (40 mg/L), lactic dehydrogenase (467 international units/L), and haptoglobin (3.8). Broad-spectrum antibiotics and sulfamethoxazole/trimethoprim were initiated and subsequently stopped due a lack of evidence of bacterial, viral, or fungal pathogens from a bronchoalveolar lavage culture (330,000 cells/mL; 50% macrophages, 27% lymphocytes). Pemetrexed therapy was discontinued and IV corticosteroids were administered. The patient's respiratory status returned to normal 4 months after discharge, but he was continued on low-dose corticosteroid therapy (Loriot et al, 2009).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) FATIGUE
    1) WITH THERAPEUTIC USE
    a) During a clinical trial, involving 265 patients with non-small cell lung cancer who received pemetrexed as sole therapy, fatigue was reported in 87% of the patients, with 14% and 2% reporting the severity as grade 3 and grade 4, respectively (Prod Info ALIMTA(R) injection, 2004).
    B) NEUROPATHY
    1) WITH THERAPEUTIC USE
    a) Sensory neuropathy was reported in 1% to 5% of patients treated with pemetrexed (n=265) in a randomized clinical trial comparing pemetrexed (with folic acid and vitamin B12 supplementation) therapy with single agent docetaxel in non-small cell lung cancer (NSCLC). All patients had locally advanced or metastatic NSCLC and had previously been treated with chemotherapy (Prod Info ALIMTA(R) intravenous injection powder, 2013).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting may frequently occur with pemetrexed therapy. In one study, involving 265 patients with non-small cell lung cancer who received pemetrexed as sole therapy, nausea and vomiting were reported in 39% and 25% of the patients, respectively (Prod Info ALIMTA(R) injection, 2004).
    2) WITH POISONING/EXPOSURE
    a) Grade 3 and Grade 4 nausea and vomiting were reported following administration of pemetrexed in doses of 1200 mg/m(2) and 925 mg/m(2), respectively (Niyikiza et al, 2002).
    B) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) Anorexia is frequently reported with pemetrexed therapy. In one study, involving 265 patients with non-small cell lung cancer who received pemetrexed as sole therapy, anorexia was reported in 62% of the patients, with 4% reporting the severity as grade 3 (Prod Info ALIMTA(R) injection, 2004).
    C) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) During a clinical trial, involving 265 patients with non-small lung cancer who received pemetrexed as sole therapy, constipation was reported in 30% of the patients (Prod Info ALIMTA(R) injection, 2004).
    D) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) During a clinical trial, involving 265 patients with non-small lung cancer who received pemetrexed as sole therapy, diarrhea without colostomy was reported in 21% of the patients, with less than 1% reporting the severity as grade 3 (Prod Info ALIMTA(R) injection, 2004).
    2) WITH POISONING/EXPOSURE
    a) Grade 3 diarrhea was reported in one patient who received pemetrexed, 925 mg/m(2), as a single agent during a phase I clinical trial (Niyikiza et al, 2002).
    E) STOMATITIS
    1) WITH THERAPEUTIC USE
    a) Stomatitis/pharyngitis was reported in 15% of patients treated with pemetrexed (n=265) compared with 17% of patients treated with docetaxel (n=276) in a randomized clinical trial comparing pemetrexed (with folic acid and vitamin B12 supplementation) therapy with single agent docetaxel in non-small cell lung cancer (NSCLC). All patients had locally advanced or metastatic NSCLC and had previously been treated with chemotherapy (Prod Info ALIMTA(R) injection, 2004).
    b) During a clinical trial, involving 265 patients with non-small lung cancer who received pemetrexed as sole therapy, stomatitis/pharyngitis was reported in 20% of the patients, with 1% reporting the severity as grade 3 (Prod Info ALIMTA(R) injection, 2004).
    2) WITH POISONING/EXPOSURE
    a) Mucositis may occur with overdose (Prod Info ALIMTA(R) intravenous injection powder, 2013).
    F) PANCREATITIS
    1) WITH THERAPEUTIC USE
    a) Pancreatitis has been reported in postmarketing surveillance with pemetrexed use, both as a single agent and in combination therapies (Prod Info ALIMTA(R) injection, 2004).
    G) COLITIS
    1) WITH THERAPEUTIC USE
    a) During postmarketing surveillance, cases of colitis have been reported among patients treated with pemetrexed (Prod Info ALIMTA(R) injection, 2004).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Grade 3/4 elevated serum hepatic transaminase levels occurred in up to 2% of patients (n=265) with non-small cell lung cancer who received pemetrexed as sole therapy (Prod Info ALIMTA(R) injection, 2004).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) MYELOSUPPRESSION
    1) WITH THERAPEUTIC USE
    a) Myelosuppression is the dose-limiting toxicity with pemetrexed therapy. In one study, involving 265 patients with non-small cell lung cancer who received pemetrexed as sole therapy, all grades of anemia, leukopenia, neutropenia, and thrombocytopenia were reported in 33%, 13%, 11%, and 9% of the patients, respectively (Prod Info ALIMTA(R) injection, 2004).
    b) Immune-mediated hemolytic anemia has been reported during postmarketing surveillance (Prod Info ALIMTA(R) intravenous injection powder, 2013).
    c) Febrile neutropenia has been reported (up to 5% (all grades); 1% to 5% (grade 3 or 4)) following the therapeutic use of pemetrexed (Prod Info ALIMTA(R) intravenous injection powder, 2013)
    2) WITH POISONING/EXPOSURE
    a) Anemia and neutropenia may occur with overdose (Prod Info ALIMTA(R) intravenous injection powder, 2013).
    b) Grade 4 neutropenia was reported in 2 of 6 patients who received 1200 mg/m(2) of pemetrexed during a phase I clinical trial (Niyikiza et al, 2002).
    c) Grade 3/4 thrombocytopenia and grade 3 anemia were reported in patients who received pemetrexed at doses of 600 mg/m(2) or greater (Niyikiza et al, 2002).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Rash/desquamation was reported in 17% of patients (n=265), with non-small cell lung cancer, who received pemetrexed as the sole agent (Prod Info ALIMTA(R) injection, 2004).
    2) WITH POISONING/EXPOSURE
    a) Rash may occur with overdose (Prod Info ALIMTA(R) intravenous injection powder, 2013).
    b) Rash was reported following pemetrexed administration at a dose of 1,200 mg/m(2) (Niyikiza et al, 2002).
    B) VASCULITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 68-year-old man developed an erythematous rash involving both lower extremities, from knees to ankles, two weeks after beginning a second cycle of pemetrexed, 500 mg/m(2). Suspecting cellulitis, the patient was treated with antibiotics; however, despite antibiotic therapy, the skin lesions worsened. A skin biopsy was performed, revealing dermal edema, swollen endothelial cells, and a sparse perivascular infiltrate consisting of lymphocytes, neutrophils, and eosinophils, indicative of urticarial vasculitis. The patient gradually recovered with corticosteroid therapy (Lopes et al, 2006).
    C) RADIATION DERMATITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 75-year-old man presented with an erythematous and pruritic rash approximately 12 days after receiving a second cycle of pemetrexed and cisplatin. The rash occurred in the right axillary region that had been irradiated 4 weeks prior to presentation. Skin lesions also appeared 2 days after presentation of the rash. The erythematous rash and skin lesions persisted with subsequent desquamation following the third course of chemotherapy. Two weeks after the third course of chemotherapy, cicatrization and hyperpigmentation of the irradiated skin developed (Hureaux et al, 2005).
    D) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) During a clinical trial, involving 265 patients with non-small cell lung cancer who received pemetrexed as sole therapy, alopecia was reported in 11% of the patients (Prod Info ALIMTA(R) injection, 2004).
    E) EDEMA
    1) WITH THERAPEUTIC USE
    a) Edema was reported in 1% to 5% of patients treated with pemetrexed (n=438) in a multicenter, randomized, double-blind, placebo-controlled study comparing pemetrexed with placebo in the maintenance treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease had not progressed after 4 cycles of platinum-based first-line chemotherapy. All patients were fully supplemented with folic acid and vitamin B12 (Prod Info ALIMTA(R) intravenous injection powder, 2013).
    b) During a clinical trial, involving 265 patients with non-small cell lung cancer who received pemetrexed as sole therapy, edema was reported in 19% of the patients, with less than 1% reporting the severity as grade 3 (Prod Info ALIMTA(R) injection, 2004).
    F) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) During postmarketing surveillance, Stevens-Johnson syndrome, including some fatal cases, have been reported following pemetrexed administration (Prod Info ALIMTA(R) intravenous injection powder, 2013).
    G) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE
    1) WITH THERAPEUTIC USE
    a) During postmarketing surveillance, toxic epidermal necrolysis, including some fatal cases, have been reported following pemetrexed administration (Prod Info ALIMTA(R) intravenous injection powder, 2013).
    H) RADIATION RECALL SYNDROME
    1) WITH THERAPEUTIC USE
    a) During postmarketing surveillance of pemetrexed, radiation recall has been reported in patients who have previously received radiotherapy (Prod Info ALIMTA(R) intravenous injection powder, 2013).
    b) As of September 2007, 12 cases of radiation recall associated with pemetrexed therapy have been submitted to the Food and Drug Administration. The patients (9 male, 3 female) ranged in age from 49 to 78 years (median 62.5 years). Three patients received pemetrexed therapy for malignant pleural mesothelioma, 7 for non-small cell lung cancer, and 2 for treatment of an unspecified lung cancer. Median time to onset of the radiation recall reaction after first administration of pemetrexed was 6 days (range 1 to 35 days). Time interval between radiation treatment and pemetrexed administration ranged from 15 days to 27 years. All radiation recall events were temporally related to the start of pemetrexed therapy. Of these cases, there were 5 hospitalizations and 1 death. The 1 reported death was due to respiratory insufficiency which may or may not have been related to radiation recall. In some cases, patients had previously received chemotherapeutic agents associated with radiation recall (gemcitabine, docetaxel, paclitaxel, vinorelbine, or etoposide). In 8 cases there was a positive dechallenge and in 6 cases a positive rechallenge. Due to the temporal relationship of the radiation recall reaction with the initiation of pemetrexed and reports of positive dechallenges and positive rechallenges, there appears to be an association between pemetrexed and radiation recall (United States Food and Drug Administration, 2008).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) RHABDOMYOLYSIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 68-year-old man developed severe progressive myalgias, weakness of the arms and legs, and abdominal tenderness 2 days after receiving pemetrexed and carboplatin for treatment of malignant pleural mesothelioma. Laboratory tests, performed 4 days after chemotherapy administration, revealed elevated serum creatine kinase (21,530 units/L) and myoglobin (3000 mcg/L) levels, and elevated hepatic enzyme levels (AST 453 units/L, ALT 159 units/L). With supportive care, the patient's rhabdomyolysis gradually resolved with complete normalization of creatine kinase and transaminase levels one month later (Ceribelli et al, 2006).
    B) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) During a clinical trial, involving 265 patients with non-small cell lung cancer who received pemetrexed as sole therapy, myalgia was reported in 13% of the patients, with 2% reporting the severity as grade 3 (Prod Info ALIMTA(R) injection, 2004).
    C) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) During a clinical trial, involving 265 patients with non-small cell lung cancer who received pemetrexed as sole therapy, arthralgia was reported in 8% of the patients, with less than 1% reporting the severity as grade 3 (Prod Info ALIMTA(R) injection, 2004).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLAXIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 53-year old women with metastatic lung cancer developed an anaphylactic reaction 7 minutes after the start of a pemetrexed 500 mg/m(2) infusion for her 6th cycle of treatment. The reaction was characterized by a sudden onset of nausea, flushing, shortness of breath, wheezing with an increased heart rate (134 beats/minute), increased respiratory rate (32 breaths/minute), decreased oxygen saturation to 88% and an elevated blood pressure (149/90 mm Hg from 111/75 mm Hg at baseline). Baseline vital signs and blood work were all within normal limits and prior pemetrexed infusions were tolerated. The infusion was immediately discontinued and over 60 minutes, symptoms normalized following a normal saline IV bolus, oxygen administration, and IV diphenhydramine (50 mg) followed by IV dexamethasone (20 mg). The patient was discharged home in stable condition (Shah & Hewett, 2013).

Reproductive

    3.20.1) SUMMARY
    A) Pemetrexed is classified as FDA pregnancy category D. Animal studies have shown that administration of pemetrexed to mice resulted in increased embryo-fetal deaths, reduced litter sizes, and fetal malformations.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) MICE - Intraperitoneal administration of pemetrexed to mice at doses of 0.2 mg/kg (approximately 1/833 the recommended intravenous human dose on a mg/m(2) basis) and 5 mg/kg (approximately 1/33 the recommended intravenous human dose on a mg/m(2) basis), given on gestation days 6 through 15, resulted in incomplete ossification of talus and skull bone and cleft palate, respectively. Increased embryo-fetal deaths and reduced litter sizes also occurred at these doses (Prod Info ALIMTA(R) injection, 2004).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer classified pemetrexed as FDA pregnancy category D (Prod Info ALIMTA(R) injection, 2004).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is not known whether pemetrexed or its metabolites are excreted in human milk. Due to potential serious adverse events, breast feeding is not recommended (Prod Info ALIMTA(R) injection, 2004).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) MICE - Intravenous administration of pemetrexed to male mice at doses of 0.1 mg/kg/day or greater (approximately 1/1666 the recommended human dose on a mg/m(2) basis) resulted in decreased fertility, hypospermia, and testicular atrophy (Prod Info ALIMTA(R) injection, 2004).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS137281-23-3 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed

Genotoxicity

    A) Pemetrexed was clastogenic in the mouse bone marrow micronucleus assay, but was not mutagenic in the in vitro Ames assay and the CHO cell assay (Prod Info ALIMTA(R) injection, 2004).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Myelosuppression may occur. Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery. Monitor patient for signs of bleeding.
    D) Monitor for clinical evidence of infection, with particular attention to odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    E) Monitor serum electrolytes, CK, renal function, and hepatic enzymes.

Methods

    A) CHROMATOGRAPHY
    1) Reversed phase high-performance liquid chromatography has been described for the determination of pemetrexed in human plasma and urine. The limit of quantitation in plasma ranged from 5 to 10 ng/mL (Rivory et al, 2001; Hamilton & Kirkwood, 1994).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Symptomatic patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), and daily monitoring of CBC with differential until bone marrow suppression is resolved. Patients with an intrathecal overdose or severe toxicity should be transferred to an intensive care setting.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There is no data to support home management. All exposures should be evaluated in a healthcare facility.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with overdose. In addition, consultation with an infectious diseases physician with expertise in the management of neutropenic patients with infections is strongly recommended.
    6.3.2.4) PATIENT TRANSFER/PARENTERAL
    A) Patients with large overdoses may benefit from early transfer to a cancer treatment or bone marrow transplant center.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) All patients should be sent to a healthcare facility for observation. If patients are asymptomatic for 6 hours, they may be sent home. Since toxic effects (eg, myelosuppression) may be delayed, patients should return to a healthcare provider for any symptoms.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Myelosuppression may occur. Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery. Monitor patient for signs of bleeding.
    D) Monitor for clinical evidence of infection, with particular attention to odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    E) Monitor serum electrolytes, CK, renal function, and hepatic enzymes.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastrointestinal decontamination is not recommended; administered via the parenteral route.
    6.5.3) TREATMENT
    A) SUPPORT
    1) See the PARENTERAL EXPOSURE treatment section for further information.

Enhanced Elimination

    A) HEMODIALYSIS
    1) There is no information regarding the effectiveness of hemodialysis or hemoperfusion for the removal of pemetrexed from plasma; however, due to its high protein binding (81%) and large volume of distribution, it is anticipated that hemodialysis would be ineffective.

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose of pemetrexed has not been established. Nausea and vomiting, rash, and neutropenia have been reported following intravenous doses of 1200 mg/m(2).
    B) THERAPEUTIC DOSE: ADULT: 500 mg/m(2) administered as an IV infusion over 10 minutes on day 1 of each 21-day cycle. CHILD: Safety and efficacy in the pediatric or adolescent population have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) COMBINATION THERAPY: 500 mg/m(2) administered as an IV infusion over 10 minutes on day 1 of each 21-day cycle; 75 mg/m(2) cisplatin is administered as an IV infusion 30 minutes after the pemetrexed infusion (Prod Info ALIMTA(R) intravenous injection powder, 2013).
    B) SINGLE AGENT THERAPY: 500 mg/m(2) administered as an IV infusion over 10 minutes on day 1 of each 21-day cycle (Prod Info ALIMTA(R) intravenous injection powder, 2013).
    7.2.2) PEDIATRIC
    A) Safety and efficacy in the pediatric or adolescent population have not been established (Prod Info ALIMTA(R) intravenous injection powder, 2013).

Maximum Tolerated Exposure

    A) Nausea and vomiting, rash, and grade 3 and 4 neutropenia have been reported following intravenous administration of pemetrexed at a dose of 1200 mg/m(2) (Niyikiza et al, 2002).

Workplace Standards

    A) ACGIH TLV Values for CAS137281-23-3 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS137281-23-3 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS137281-23-3 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS137281-23-3 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Pharmacology Toxicology

Pharmacologic Mechanism

    A) MECHANISM OF ACTION
    1) Pemetrexed is a multitargeted antifolate compound indicated for use as an antitumor agent (Prod Info Alimta(R), 2004; Chen et al, 1999; Mendelsohn et al, 1999; Newell, 1999). It is a pyrrolo-pyrimidine analog of folic acid, chemically similar to lometrexol and methotrexate; it is somewhat similar structurally to raltitrexed.
    2) Pemetrexed gains cell entry via the reduced folate carrier, and is a good substrate for the enzyme folylpolyglutamate synthase (FPGS), which leads to extensive intracellular polyglutamation (Rinaldi et al, 1999; Calvert, 1999; Cassidy, 2000; Moran, 1999); the predominant intracellular form is the pentaglutamate, which is substantially more potent than the pemetrexed itself or its monoglutamate (Cassidy, 2000; Ouellet et al, 2000; Rusthoven et al, 1999). Polarity occurs via polyglutamation, resulting in enhanced cellular retention and a more sustained effect (Rinaldi et al, 1999; Calvert, 1999; Cassidy, 2000).
    3) Pemetrexed and its polyglutamates inhibit at least four enzymes involved in folate metabolism and DNA synthesis: thymidylate synthase (TS), dihydrofolate reductase (DHFR), glycinamide ribonucleotide formyl transferase (GARFT), and aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT) (Prod Info Alimta(R), 2004; Cassidy, 2000; Mendelsohn et al, 1999; Danenberg et al, 1999; Schultz et al, 1999; Chen et al, 1999; Van Triest et al, 2000). Cell death occurs via inhibition of any one these enzymes, particularly during cell division (Chen et al, 1999). The multiple actions of pemetrexed are speculated to reduce development of drug resistance (eg, that acquired by overexpression of one of these enzymes) (Allegra, 1999; Calvert, 1999; Postmus & Green, 1999; Danenberg et al, 1999).
    4) Preclinical studies have indicated a broad spectrum of antitumor activity. In vivo, activity has been observed in lymphoma, lung, colon, pancreatic, and breast cancer (Thodtmann et al, 1999; Rusthoven et al, 1999; Teicher et al, 1999). High activity against CCRF-CEM human leukemia cells in vitro has been reported, with a 50% inhibitory concentration of 7 nanograms/milliliter (ng/mL) (Rusthoven et al, 1999). At least additive in vivo effects were seen when pemetrexed was combined with cisplatin in EMT-6 mammary carcinoma and human H460 non-small cell lung carcinoma; the drug was synergistic with LY329201 (a GARFT inhibitor) in EMT-6 mammary carcinoma, and with irinotecan in human HCT 116 colon carcinoma (Teicher et al, 1999).

Physicochemical

Physical Characteristics

    A) Pemetrexed is a white to light yellow or green-yellow lyophilized powder (Prod Info ALIMTA(R) injection, 2004).

Molecular Weight

    A) 597.49 (Prod Info ALIMTA(R) injection, 2004)

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