`
`1
`
`PV 5200 AMP
`
`ALIMTA®
`pemetrexed
`for injection
`DESCRIPTION
`ALIMTA®, pemetrexed for injection, is an antifolate antineoplastic agent that exerts its action
`by disrupting folate-dependent metabolic processes essential for cell replication. Pemetrexed
`disodium heptahydrate has the chemical name L-Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-
`oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate. It is a white
`to almost-white solid with a molecular formula of C20H19N5Na2O6•7H2O and a molecular weight
`of 597.49. The structural formula is as follows:
`
`- Na+
`CO2
`
`·7H2O
`
`-
`
`CO2
`
`Na+
`
`NH
`
`O
`
`NH
`
`O
`
`HN
`
`H2N
`
`N
`
`ALIMTA is supplied as a sterile lyophilized powder for intravenous infusion available in
`single-dose vials. The product is a white to either light yellow or green-yellow lyophilized solid.
`Each 500-mg vial of ALIMTA contains pemetrexed disodium equivalent to 500 mg pemetrexed
`and 500 mg of mannitol. Hydrochloric acid and/or sodium hydroxide may have been added to
`adjust pH.
`
`CLINICAL PHARMACOLOGY
`
`Pharmacodynamics
`Pemetrexed is an antifolate containing the pyrrolopyrimidine-based nucleus that exerts its
`antineoplastic activity by disrupting 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 MSTO-211H mesothelioma cell line
`showed synergistic effects when pemetrexed was combined concurrently with cisplatin.
`Absolute neutrophil counts (ANC) following single-agent administration of pemetrexed to
`patients not receiving folic acid and vitamin B12 supplementation were characterized using
`population pharmacodynamic analyses. Severity of hematologic toxicity, as measured by the
`depth of the ANC nadir, correlates with the systemic exposure of pemetrexed. It was also
`observed that lower ANC nadirs occurred in patients with elevated baseline cystathionine or
`homocysteine concentrations. The levels of these substances can be reduced by folic acid and
`vitamin B12 supplementation. There is no cumulative effect of pemetrexed exposure on ANC
`nadir over multiple treatment cycles.
`
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`Time to ANC nadir with pemetrexed systemic exposure (AUC), varied between 8 to 9.6 days
`over a range of exposures from 38.3 to 316.8 µg•hr/mL. Return to baseline ANC occurred 4.2 to
`7.5 days after the nadir over the same range of exposures.
`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 is not metabolized to an appreciable extent and 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 (Cmax) increase proportionally with dose.
`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.
`Drug Interactions
`Chemotherapeutic Agents — Cisplatin does not affect the pharmacokinetics of pemetrexed and
`the pharmacokinetics of total platinum are unaltered by pemetrexed.
`Vitamins — Coadministration of oral folic acid or intramuscular vitamin B12 does not affect the
`pharmacokinetics of pemetrexed.
`Drugs Metabolized by Cytochrome P450 Enzymes — Results from in vitro studies with human
`liver microsomes predict that pemetrexed would not cause clinically significant inhibition of
`metabolic clearance of drugs metabolized by CYP3A, CYP2D6, CYP2C9, and CYP1A2. No
`studies were conducted to determine the cytochrome P450 isozyme induction potential of
`pemetrexed, because ALIMTA used as recommended (once every 21 days) would not be
`expected to cause any significant enzyme induction.
`Aspirin — Aspirin, administered in low to moderate doses (325 mg every 6 hours), does not
`affect the pharmacokinetics of pemetrexed. The effect of greater doses of aspirin on pemetrexed
`pharmacokinetics is unknown.
`Ibuprofen — Daily ibuprofen doses of 400 mg qid reduce pemetrexed’s clearance by about
`20% (and increase AUC by 20%) in patients with normal renal function. The effect of greater
`doses of ibuprofen on pemetrexed pharmacokinetics is unknown (see Drug Interactions under
`PRECAUTIONS).
`Special Populations
`The pharmacokinetics of pemetrexed in special populations were examined in about
`400 patients in controlled and single arm studies.
`Geriatric — No effect of age on the pharmacokinetics of pemetrexed was observed over a
`range of 26 to 80 years.
`Pediatric — Pediatric patients were not included in clinical trials.
`Gender — The pharmacokinetics of pemetrexed were not different in male and female
`patients.
`Race — The pharmacokinetics of pemetrexed were similar in Caucasians and patients of
`African descent. Insufficient data are available to compare pharmacokinetics for other ethnic
`groups.
`
`

`

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`Hepatic Insufficiency — 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 (see PRECAUTIONS).
`Renal Insufficiency — 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 (see
`WARNINGS and DOSAGE AND ADMINISTRATION).
`CLINICAL STUDIES
`Malignant Pleural Mesothelioma — The safety and efficacy of ALIMTA have been evaluated
`in chemonaive patients with malignant pleural mesothelioma (MPM) in combination with
`cisplatin.
`Randomized Trial: A multi-center, randomized, single-blind study in 448 chemonaive patients
`with MPM compared survival in patients treated with ALIMTA in combination with cisplatin to
`survival in patients receiving cisplatin alone. ALIMTA was administered intravenously over
`2 and cisplatin was administered intravenously over 2 hours at
`10 minutes at a dose of 500 mg/m
`a dose of 75 mg/m2 beginning approximately 30 minutes after the end of administration of
`ALIMTA. Both drugs were given on Day 1 of each 21-day cycle. After 117 patients were
`treated, white cell and GI toxicity led to a change in protocol whereby all patients were given
`folic acid and vitamin B12 supplementation.
`The primary analysis of this study was performed on the population of all patients randomly
`assigned to treatment who received study drug (randomized and treated). An analysis was also
`performed on patients who received folic acid and vitamin B12 supplementation during the entire
`course of study therapy (fully supplemented), as supplementation is recommended (see
`DOSAGE AND ADMINISTRATION). Results in all patients and those fully supplemented
`were similar. Patient demographics are shown in Table 1.
`
`
`Table 1: Summary of Patient Characteristics in MPM Study
`Randomized and Treated
`Fully Supplemented
`Patients
`Patients
`ALIMTA/cis
`Cisplatin
`ALIMTA/cis
`Cisplatin
`(N=226)
`(N=222)
`(N=168)
`(N=163)
`
`
`
`
`Patient characteristic
`Age (yrs)
` Median (range)
`Gender (%)
` Male
` Female
`Origin (%)
` Caucasian
` Hispanic
` Asian
` African descent
`Stage at Entry (%)
` I
` II
` III
`
`61 (29-85)
`
`60 (19-84)
`
`60 (29-85)
`
`60 (19-82)
`
`184 (81.4)
`42 (18.6)
`
`204 (90.3)
`11 (4.9)
`10 (4.4)
`1 (0.4)
`
`16 (7.1)
`35 (15.6)
`73 (32.4)
`
`181 (81.5)
`41 (18.5)
`
`206 (92.8)
`12 (5.4)
`4 (1.9)
`0
`
`14 (6.3)
`33 (15.0)
`68 (30.6)
`
`136 (81.0)
`32 (19.0)
`
`150 (89.3)
`10 (6.0)
`7 (4.2)
`1 (0.6)
`
`15 (8.9)
`27 (16.2)
`51 (30.5)
`
`134 (82.2)
`29 (17.8)
`
`153 (93.9)
`7 (4.3)
`3 (1.8)
`0
`
`12 (7.4)
`27 (16.8)
`49 (30.4)
`
`

`

`
`
`4
`
`101 (44.9)
`1 (0.4)
`
`154 (68.1)
`37 (16.4)
`18 (8.0)
`17 (7.5)
`
`105 (47.2)
`2 (0.9)
`
`152 (68.5)
`36 (16.2)
`25 (11.3)
`9 (4.1)
`
`74 (44.3)
`1 (0.6)
`
`117 (69.6)
`25 (14.9)
`14 (8.3)
`12 (7.1)
`
`73 (45.3)
`2 (1.2)
`
`113 (69.3)
`25 (15.3)
`17 (10.4)
`8 (4.9)
`
` IV
` Unspecified
`Diagnosis/Histologya (%)
` Epithelial
` Mixed
` Sarcomatoid
` Other
`Baseline KPSb (%)
`69 (42.3)
`83 (49.4)
`97 (43.7)
`109 (48.2)
` 70-80
`94 (57.7)
`85 (50.6)
`125 (56.3)
`117 (51.8)
` 90-100
`a Only 67% of the patients had the histologic diagnosis of malignant mesothelioma confirmed by independent
`review.
`b Karnofsky Performance Scale.
`
`Table 2 summarizes the survival results for all randomized and treated patients regardless of
`vitamin supplementation status and those patients receiving vitamin supplementation from the
`time of enrollment in the trial.
`
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`116
`117
`118
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`120
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`122
`123
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`127
`128
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`132
`
`Table 2: Efficacy of ALIMTA plus Cisplatin vs. Cisplatin in Malignant Pleural
`Mesothelioma
`Randomized and Treated
`Patients
`ALIMTA/cis
`Cisplatin
`(N=226)
`(N=222)
`12.1 mos
`9.3 mos
`(10.0-14.4)
`(7.8-10.7)
`0.77
`0.020
`
`Fully Supplemented
`Patients
`ALIMTA/cis
`Cisplatin
`(N=168)
`(N=163)
`13.3 mos
`10.0 mos
`(11.4-14.9)
`(8.4-11.9)
`0.75
`0.051
`
`
`
`
`Efficacy Parameter
`Median overall survival
`(95% CI)
`Hazard ratio
`Log rank p-value*
`* p-value refers to comparison between arms.
`
`Similar results were seen in the analysis of patients (N=303) with confirmed histologic
`diagnosis of malignant pleural mesothelioma. Exploratory demographic analyses showed no
`apparent differences in patients over or under 65. There were too few non-white patients to
`assess possible ethnic differences. The effect in women (median survival 15.7 months with the
`combination vs. 7.5 months on cisplatin alone), however, was larger than the effect in males
`(median survival 11 vs. 9.4 respectively). As with any exploratory analysis, it is not clear
`whether this difference is real or is a chance finding.
`
`

`

`5
`
`Median Survival = 12.1 mos
`
`Hazard ratio
`Log rank p-value
`Percent censored
`
`Median Survival
`= 9.3 mos
`
` 0.77
`0.020
` 32
`
`0
`
`5
`
`10
`
`15
`Survival Time (Months)
`
`20
`
`25
`
`30
`
`
`
`133
`
`
`
`1.00
`
`0.75
`
`0.50
`
`0.25
`
`0.00
`
`Survival Distribution Function
`
`ALIMTA + Cisplatin (n=226)
`Cisplatin (n=222)
`Figure 1: Kaplan-Meier Estimates of Survival Time for ALIMTA plus Cisplatin and
`Cisplatin Alone in all Randomized and Treated Patients.
`
`
`Objective tumor response for malignant pleural mesothelioma is difficult to measure and
`response criteria are not universally agreed upon. However, based upon prospectively defined
`criteria, the objective tumor response rate for ALIMTA plus cisplatin was greater than the
`objective tumor response rate for cisplatin alone. There was also improvement in lung function
`(forced vital capacity) in the ALIMTA plus cisplatin arm compared to the control arm.
`Patients who received full supplementation with folic acid and vitamin B12 during study
`therapy received a median of 6 and 4 cycles in the ALIMTA/cisplatin (N=168) and
`cisplatin (N=163) arms, respectively. Patients who never received folic acid and vitamin B12
`during study therapy received a median of 2 cycles in both treatment arms (N=32 and N=38 for
`the ALIMTA/cisplatin and cisplatin arm, respectively). Patients receiving ALIMTA in the fully
`supplemented group received a relative dose intensity of 93% of the protocol specified ALIMTA
`dose intensity; patients treated with cisplatin in the same group received 94% of the projected
`dose intensity. Patients treated with cisplatin alone had a dose intensity of 96%.
`Non-Small Cell Lung Cancer (NSCLC) — The safety and efficacy of ALIMTA as a
`single-agent have been evaluated in patients with locally advanced or metastatic (Stage III or IV)
`non-small cell lung cancer after prior chemotherapy.
`Randomized Trial: A multi-center, randomized, open label Phase 3 study was conducted to
`compare the overall survival following treatment with ALIMTA versus docetaxel. ALIMTA was
`2 and docetaxel was
`administered intravenously over 10 minutes at a dose of 500 mg/m
`administered at 75 mg/m2 as a 1-hour intravenous infusion. Both drugs were given on Day 1 of
`each 21-day cycle. All patients treated with ALIMTA received vitamin supplementation with
`folic acid and vitamin B12. The study was intended to show either an overall survival superiority
`or non-inferiority of ALIMTA to docetaxel. Patient demographics of the intent to treat (ITT)
`population are shown in Table 3.
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`

`

`
`
`6
`
`Table 3: Summary of Patient Characteristics in NSCLC Study
`ALIMTA
`Docetaxel
`(N=283)
`(N=288)
`
`59 (22-81)
`
`68.6/31.4
`
`25.1/74.9
`
`154 (54.4)
`78 (27.6)
`4 (1.4)
`51 (18.1)
`
`234 (88.6)
`30 (11.4)
`
`57 (28-87)
`
`75.3/24.7
`
`25.3/74.7
`
`142 (49.3)
`93 (32.3)
`1 (0.3)
`53 (18.5)
`
`240 (87.6)
`34 (12.4)
`
`
`Patient characteristic
`Age (yrs)
` Median (range)
`Gender (%)
` Male/Female
`Stage at Entry (%)
` III/IV
`Diagnosis/Histology (%)
` Adenocarcinoma
` Squamous
` Bronchoalveolar
` Other
`Performance Status (%)
` 0-1
` 2
`
`The primary endpoint in this study was overall survival. The median survival time was
`8.3 months in the ALIMTA treatment arm and 7.9 months in the docetaxel arm, with a hazard
`ratio of 0.99 (see Table 4). The study did not show an overall survival superiority of ALIMTA.
`Non-inferiority of ALIMTA to docetaxel could not be demonstrated, because a reliable and
`consistent survival effect of docetaxel required for a non-inferiority analysis could not be
`estimated from historical trials. In addition, significant treatment crossover at the time of disease
`progression may have confounded the survival interpretation. The demonstrated surrogate
`endpoint, response rate allowed the conclusion that an effect of ALIMTA on survival is
`reasonably likely.
`Exploratory demographic analyses on survival showed no significant differences between
`ALIMTA and docetaxel in patients over or under 65 years of age. There were too few non-white
`patients to assess possible ethnic differences. Regarding gender, females lived longer than males
`in both treatment groups. There was no difference in survival between ALIMTA and docetaxel
`with respect to gender after adjusting for prognostic factors.
`Secondary endpoints evaluated in the trial include objective response rate, progression free
`survival (PFS) and time to progressive disease (TTPD). There was no statistically significant
`difference between ALIMTA and docetaxel with respect to objective response rate, progression
`free survival (PFS) and time to progressive disease (TTPD).
`
`
`Table 4: Efficacy of ALIMTA vs. Docetaxel in Non-Small Cell Lung Cancer – ITT
`Population
`
`
`
`Median overall survival (95% CI)
` Hazard ratio (HR) (95% CI)
` Log rank p-value
` 1-year survival (95% CI)
`Median progression free survival
` Hazard ratio (HR) (95% CI)
`
`Docetaxel
`ALIMTA
`(N=288)
`(N=283)
`7.9 mos (6.3-9.2)
`8.3 mos (7.0-9.4)
`0.99a (0.82-1.20)
`0.93
`29.7% (23.7-35.6)
`29.7% (23.9-35.5)
`2.9 mos
`2.9 mos
`0.97a (0.82-1.16)
`
`160
`161
`162
`163
`164
`165
`166
`167
`168
`169
`170
`171
`172
`173
`174
`175
`176
`177
`178
`179
`180
`181
`
`

`

`
`
`7
`
`Time to Progressive Disease
` Hazard ratio (HR) (95% CI)
`Overall response ratea,b (95% CI)
`a Not statistically significant.
`b Number of qualified patients on the ALIMTA arm (N=264) and docetaxel arm (N=274).
`
`
`3.5 mos
`3.4 mos
`0.97a (0.80-1.17)
`9.1% (5.9-13.2)
`8.8% (5.7-12.8)
`
`INDICATIONS AND USAGE
`Mesothelioma: ALIMTA in combination with cisplatin is indicated for the treatment of
`patients with malignant pleural mesothelioma whose disease is unresectable or who are
`otherwise not candidates for curative surgery.
`Non-Small Cell Lung Cancer: ALIMTA as a single-agent is indicated for the treatment of
`patients with locally advanced or metastatic non-small cell lung cancer after prior chemotherapy.
`The effectiveness of ALIMTA in second-line NSCLC was based on the surrogate endpoint,
`response rate. There are no controlled trials demonstrating a clinical benefit, such as a favorable
`survival effect or improvement of disease-related symptoms.
`CONTRAINDICATIONS
`ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction
`to pemetrexed or to any other ingredient used in the formulation.
`WARNINGS
`
`Decreased Renal Function
`ALIMTA 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,
`ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min (see
`Dose Reduction Recommendations under DOSAGE AND ADMINISTRATION).
`One 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
`ALIMTA alone.
`Bone Marrow Suppression
`ALIMTA can suppress bone marrow function, as manifested by neutropenia,
`thrombocytopenia, and anemia (or pancytopenia) (see ADVERSE REACTIONS);
`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 (see Dose Reduction Recommendations under DOSAGE AND ADMINISTRATION).
`Need for Folate and Vitamin B12 Supplementation
`Patients treated with ALIMTA must be instructed to take folic acid and vitamin B12 as a
`prophylactic measure to reduce treatment-related hematologic and GI toxicity (see DOSAGE
`AND ADMINISTRATION). 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.
`Pregnancy Category D
`ALIMTA may cause fetal harm when administered to a pregnant woman. Pemetrexed was
`fetotoxic and teratogenic in mice at i.p. doses of 0.2 mg/kg (0.6 mg/m2) or 5 mg/kg (15 mg/m2)
`when given on gestation days 6 through 15. Pemetrexed caused fetal malformations (incomplete
`ossification of talus and skull bone) at 0.2 mg/kg (about 1/833 the recommended i.v. human dose
`
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`

`

`
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`8
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`on a mg/m2 basis), and cleft palate at 5 mg/kg (about 1/33 the recommended i.v. human dose on
`
`a mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced
`litter sizes. There are no studies of ALIMTA in pregnant women. Patients should be advised to
`avoid becoming pregnant. If ALIMTA is used during pregnancy, or if the patient becomes
`pregnant while taking ALIMTA, the patient should be apprised of the potential hazard to the
`fetus.
`
`PRECAUTIONS
`
`General
`ALIMTA 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 ALIMTA 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 (see DOSAGE AND ADMINISTRATION).
`The effect of third space fluid, such as pleural effusion and ascites, on ALIMTA is unknown.
`In patients with clinically significant third space fluid, consideration should be given to draining
`the effusion prior to ALIMTA administration.
`Laboratory Tests
`Complete blood cell counts, including platelet counts and periodic chemistry tests, should be
`performed on all patients receiving ALIMTA. 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 ≥1500 cells/mm3,
`the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min.
`Drug Interactions
`ALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration and
`tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed
`clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted
`(e.g., probenecid) could potentially result in delayed clearance of ALIMTA.
`Although ibuprofen (400 mg qid) can be administered with ALIMTA in patients with normal
`renal function (creatinine clearance ≥80 mL/min), caution should be used when administering
`ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency
`(creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insufficiency
`should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the
`day of, and 2 days following administration of ALIMTA.
`In the absence of data regarding potential interaction between ALIMTA and NSAIDs with
`longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days
`before, the day of, and 2 days following ALIMTA administration. If concomitant administration
`of an NSAID is necessary, patients should be monitored closely for toxicity, especially
`myelosuppression, renal, and gastrointestinal toxicity.
`Drug/Laboratory Test Interactions
`None known.
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic
`in the in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple
`in vitro tests (Ames assay, CHO cell assay). Pemetrexed administered at i.v. doses of
`
`225
`226
`227
`228
`229
`230
`231
`232
`233
`234
`235
`236
`237
`238
`239
`240
`241
`242
`243
`244
`245
`246
`247
`248
`249
`250
`251
`252
`253
`254
`255
`256
`257
`258
`259
`260
`261
`262
`263
`264
`265
`266
`267
`268
`269
`270
`
`

`

`271
`272
`273
`274
`275
`276
`277
`278
`279
`280
`281
`282
`283
`284
`285
`286
`287
`288
`289
`290
`291
`292
`293
`294
`295
`296
`297
`298
`299
`300
`301
`302
`303
`304
`305
`306
`307
`308
`309
`310
`311
`
`
`
`9
`
`0.1 mg/kg/day or greater to male mice (about 1/1666 the recommended human dose on a mg/m2
`basis) resulted in reduced fertility, hypospermia, and testicular atrophy.
`Pregnancy
`Pregnancy Category D (see WARNINGS).
`Nursing Mothers
`It is not known whether ALIMTA 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 ALIMTA, it is recommended that nursing be discontinued if the
`mother is treated with ALIMTA.
`Pediatric Use
`The safety and effectiveness of ALIMTA in pediatric patients have not been established.
`Geriatric Use
`Dose adjustments based on age other than those recommended for all patients have not been
`necessary (see Special Populations under CLINICAL PHARMACOLOGY and DOSAGE
`AND ADMINISTRATION).
`Gender
`Dose adjustments based on gender other than those recommended for all patients have not been
`necessary (see Special Populations under CLINICAL PHARMACOLOGY and DOSAGE
`AND ADMINISTRATION).
`Patients with Hepatic Impairment
`Patients with bilirubin >1.5 times the upper limit of normal were excluded from clinical trials
`of ALIMTA. 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
`ALIMTA if they had hepatic metastases.
`Dose adjustments based on hepatic impairment experienced during treatment with ALIMTA
`are provided in Table 9 (see Special Populations under CLINICAL PHARMACOLOGY and
`DOSAGE AND ADMINISTRATION).
`Patients with Renal Impairment
`ALIMTA is known to be primarily excreted by the kidney. Decreased renal function will result
`in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with
`normal renal function. Cisplatin coadministration with ALIMTA has not been studied in patients
`with moderate renal impairment (see Special Populations under CLINICAL
`PHARMACOLOGY).
`
`ADVERSE REACTIONS
`Malignant Pleural Mesothelioma — In Table 5 adverse events occurring in at least 5% of
`patients are shown along with important effects (renal failure, infection) occurring at lower rates.
`Adverse events equally or more common in the cisplatin group are not included. The adverse
`effects more common in the ALIMTA group were primarily hematologic effects, fever and
`infection, stomatitis/pharyngitis, and rash/desquamation.
`
`
`Table 5: Adverse Events* in Fully Supplemented Patients Receiving ALIMTA plus
`Cisplatin in MPM
`CTC Grades (% incidence)
`All Reported Adverse Events Regardless of Causality
`
`
`
`

`

`
`
`Laboratory
` Hematologic
` Neutropenia
` Leukopenia
` Anemia
` Thrombocytopenia
` Renal
` Creatinine elevation
` Renal failure
`Clinical
` Constitutional Symptoms
` Fatigue
` Fever
` Other constitutional
`symptoms
` Cardiovascular General
` Thrombosis/embolism
` Gastrointestinal
` Nausea
` Vomiting
` Constipation
` Anorexia
` Stomatitis/pharyngitis
` Diarrhea without
`colostomy
` Dehydration
` Dysphagia/esophagitis/
`odynophagia
` Pulmonary
` Dyspnea
` Pain
` Chest pain
` Neurology
` Neuropathy/sensory
` Mood
`alteration/depression
` Infection/Febrile
`Neutropenia
` Infection without
`neutropenia
` Infection with Grade 3 or
`Grade 4 neutropenia
`
`All
`Grades
`
`
`58
`55
`33
`27
`
`16
`2
`
`
`80
`17
`11
`
`
`7
`
`84
`58
`44
`35
`28
`26
`
`7
`6
`
`
`66
`
`40
`
`17
`14
`
`
`
`11
`
`6
`
`ALIMTA/cis
`(N=168)
`Grade 3
`
`Grade 4
`
`
`
`19
`14
`5
`4
`
`1
`0
`
`
`17
`0
`2
`
`
`4
`
`11
`10
`2
`2
`2
`4
`
`3
`1
`
`
`10
`
`8
`
`0
`1
`
`
`
`1
`
`1
`
`
`
`5
`2
`1
`1
`
`0
`1
`
`
`0
`0
`1
`
`
`2
`
`1
`1
`1
`0
`1
`0
`
`1
`0
`
`
`1
`
`1
`
`0
`0
`
`
`
`1
`
`0
`
`10
`
`Cisplatin
`(N=163)
`Grade 3 Grade 4
`
`
`
`3
`1
`0
`0
`
`1
`0
`
`
`12
`0
`1
`
`
`3
`
`6
`4
`1
`1
`0
`1
`
`1
`0
`
`
`5
`
`5
`
`1
`1
`
`
`
`0
`
`0
`
`
`
`1
`0
`0
`0
`
`0
`0
`
`
`1
`0
`1
`
`
`1
`
`0
`1
`0
`0
`0
`0
`
`0
`0
`
`
`2
`
`1
`
`0
`0
`
`
`
`0
`
`0
`
`All
`Grades
`
`
`16
`20
`14
`10
`
`12
`1
`
`
`74
`9
`8
`
`
`4
`
`79
`52
`39
`25
`9
`16
`
`1
`6
`
`
`62
`
`30
`
`15
`9
`
`
`
`4
`
`4
`
`

`

`
`
`11
`
`3
`
`1
`
`2
`
`
`22
`
`1
`
`1
`
`0
`
`
`1
`
`0
`
`0
`
`0
`
`
`0
`
`2
`
`1
`
`1
`
`
`9
`
`0
`
`0
`
`0
`
`
`0
`
`0
`
`0
`
`0
`
`
`0
`
` Infection/febrile
`neutropenia-other
` Febrile neutropenia
` Immune
` Allergic reaction/
`hypersensitivity
` Dermatology/Skin
` Rash/desquamation
`* Refer to NCI CTC Version 2.0.
`
`Table 6 compares the incidence (percentage of patients) of CTC Grade 3/4 toxicities in patients
`who received vitamin supplementation with daily folic acid and vitamin B12 from the time of
`enrollment in the study (fully supplemented) with the incidence in patients who never received
`vitamin supplementation (never supplemented) during the study in the ALIMTA plus
`cisplatin arm.
`
`Table 6: Selected Grade 3/4 Adverse Events Comparing Fully Supplemented versus Never
`Supplemented Patients in the ALIMTA plus Cisplatin arm in MPM (% incidence)
`Fully Supplemented
`Never Supplemented
`
`Patients
`Patients
`Adverse Event Regardless of
`Causalitya (%)
`(N=168)
`(N=32)
`24
`38
`Neutropenia
`5
`9
`Thrombocytopenia
`12
`31
`Nausea
`11
`34
`Vomiting
`2
`9
`Anorexia
`4
`9
`Diarrhea without colostomy
`4
`9
`Dehydration
`0
`6
`Fever
`1
`9
`Febrile neutropenia
`1
`6
`Infection with Grade 3/4 neutropenia
`17
`25
`Fatigue
`a Refer to NCI CTC criteria for lab and non-laboratory values for each grade of toxicity (Version 2.0).
`
`The following adverse events were greater in the fully supplemented group compared to the
`never supplemented group: hypertension (11%, 3%), chest pain (8%, 6%), and
`thrombosis/embolism (6%, 3%).
`For fully supplemented patients treated with ALIMTA plus cisplatin, the incidence of CTC
`Grade 3/4 fatigue, leukopenia, neutropenia, and thrombocytopenia were greater in patients
`65 years or older as compared to patients younger than 65. No relevant effect for ALIMTA
`safety due to gender or race was identified, except an increased incidence of rash in men (24%)
`compared to women (16%).
`Non-Small Cell Lung Cancer (NSCLC) — Table 7 provides the clinically relevant undesirable
`effects that have been reported in 265 patients randomly assigned to receive single-agent
`ALIMTA with folic acid and vitamin B12 supplementation and 276 patients randomly assigned to
`receive single-agent docetaxel. All patients were diagnosed with locally advanced or metastatic
`NSCLC and had received prior chemotherapy.
`
`312
`313
`314
`315
`316
`317
`318
`319
`
`320
`321
`322
`323
`324
`325
`326
`327
`328
`329
`330
`331
`332
`333
`334
`
`

`

`Table 7: Adverse Events* in Patients Receiving ALIMTA vs. Docetaxel in NSCLC
`CTC Grades (% incidence)
`All Reported Adverse Events Regardless of Causality
`ALIMTA
`Docetaxel
`(N=265)
`(N=276)
`Grade 3 Grade 4
`Grade 3 Grade 4
`
`335
`
`
`
`
`
`
`
`Laboratory
` Hematologic
` Anemia
` Leukopenia
` Neutropenia
` Thrombocytopenia
` Hepatic/Renal
` ALT elevation
` AST elevation
` Decreased creatinine
`clearance
` Creatinine elevation
` Renal failure
`Clinical
` Constitutional Symptoms
` Fatigue
` Fever
` Edema
` Myalgia
` Alopecia
` Arthralgia
` Other constitutional
`symptoms
` Cardiovascular General
` Thrombosis/embolism
` Cardiac ischemia
` Gastrointestinal
` Anorexia
` Nausea
` Constipation
` Vomiting
` Diarrhea without
`colostomy
` Stomatitis/pharyngitis
` Dysphagia/esophagitis/
`odynophagia
` Dehydration
`
`All
`Grades
`
`
`33
`13
`11
`9
`
`10
`8
`5
`
`3
`<1
`
`
`87
`26
`19
`13
`11
`8
`8
`
`
`4
`3
`
`62
`39
`30
`25
`21
`
`20
`5
`
`3
`
`12
`
`
`
`6
`17
`8
`1
`
`<1
`<1
`0
`
`0
`0
`
`
`16
`<1
`<1
`3
`NA
`3
`1
`
`
`2
`<1
`
`7
`3
`1
`1
`4
`
`1
`1
`
`1
`
`
`
`<1
`11
`32
`0
`
`0
`0
`0
`
`0
`0
`
`
`1
`0
`0
`0
`NA
`0
`<1
`
`
`1
`0
`
`<1
`0
`0
`0
`0
`
`0
`0
`
`0
`
`
`
`6
`4
`3
`2
`
`2
`<1
`1
`
`0
`0
`
`
`14
`1
`<1
`2
`NA
`<1
`1
`
`
`2
`2
`
`4
`4
`0
`2
`<1
`
`1
`1
`
`1
`
`
`
`2
`<1
`2
`0
`
`1
`1
`0
`
`0
`0
`
`
`2
`<1
`0
`0
`NA
`0
`1
`
`
`1
`1
`
`1
`0
`0
`0
`0
`
`0
`<