Drug Safety-related Labeling Changes (SrLC)

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ALIMTA (NDA-021462)

(PEMETREXED DISODIUM)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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08/31/2022 (SUPPL-55)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7 Embryo-Fetal Toxicity

‘last’ replaces ‘final’ throughout subsection.

8 Use in Specific Populations

8.3 Females and Males of Reproductive Potential

Additions and/or revisions underlined:

Based on animal data ALIMTA can cause malformations and developmental delays when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify pregnancy status of females of reproductive potential prior to initiating Pemetrexed Injection [see Use in Specific Populations (8.1)].

Contraception

Females

Because of the potential for genotoxicity, advise females of reproductive potential to use effective contraception during treatment with ALIMTA and for 6 months after the last dose.

Males

Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with ALIMTA and for 3 months after the last dose [see Nonclinical Toxicology (13.1)].

Infertility

Males

ALIMTA may impair fertility in males of reproductive potential. It is not known whether these effects on fertility are reversible [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of ALIMTA in pediatric patients have not been established.

The safety and pharmacokinetics of ALIMTA were evaluated in two clinical studies conducted in pediatric patients with recurrent solid tumors (NCT00070473 N=32 and NCT00520936 N=72). Patients in both studies received concomitant vitamin B12 and folic acid supplementation and dexamethasone.

No tumor responses were observed. Adverse reactions observed in pediatric patients were similar to those observed in adults.

Single-dose pharmacokinetics of ALIMTA were evaluated in 22 patients age 4 to 18 years enrolled in NCT00070473 were within range of values in adults.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

Additions and/or revisions underlined:

What is ALIMTA?

ALIMTA is a prescription medicine used to treat:

• a kind of lung cancer called non-squamous non-small cell lung cancer (NSCLC). ALIMTA is used: …

  • alone when your lung cancer has returned or spread after prior chemotherapy.

    ALIMTA is not for use for the treatment of people with squamous cell non-small cell lung cancer.

01/30/2019 (SUPPL-53)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive information added related to newly approved indication in combination with pembrolizumab and platinum chemotherapy, for the initial treatment of patients with metastatic, non-squamous, non-small cell lung cancer (NSCLC) with no EGFR or ALK genomic tumor aberrations.

06/04/2018 (SUPPL-51)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trial Experience

Table 5: Adverse Reactions Occurring in greater than or equal to 5% of Fully Supplemented Patients Receiving ALIMTA in Study JMEI

The following additional adverse reactions were observed in patients assigned to receive ALIMTA.

Incidence less than 1%

Cardiovascular — supraventricular arrhythmias

Renal — renal failure

Newly added information:

First-line Treatment of Non-squamous NSCLC, with Carboplatin and Pembrolizumab

The safety of ALIMTA administered with carboplatin and pembrolizumab was investigated in a randomized (1:1) open- label cohort in Study KEYNOTE-021. Patients with previously untreated, metastatic non-squamous NSCLC received ALIMTA with carboplatin and pembrolizumab (n=59) or ALIMTA with carboplatin alone (n=62). Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression;

or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.

The median number of cycles of ALIMTA was 11 (range, 1-24). The study population characteristics were: median age of 64 years (range: 37 to 80), 48% age 65 years or older, 39% Male, 87% White and 8% Asian, 97% with metastatic disease, and 12% with brain metastases.

ALIMTA was discontinued for adverse reactions in 9% of patients. The most common adverse reaction resulting in discontinuation of ALIMTA (greater than or equal to 2%) was acute kidney injury (3.4%). Adverse reactions leading to interruption of ALIMTA occurred in 36% of patients; the most common (greater than or equal to 2%) were fatigue (9%), neutrophil count decreased (9%), anemia (7%), dyspnea (3.4%), and pneumonitis (3.4%).

Table 6 summarizes the adverse reactions that occurred in at least 20% of patients in KEYNOTE-021. KEYNOTE-021 was not designed to demonstrate a statistically significant difference in adverse reactions between study arms for any specified reaction listed in Table 6.

Table 6: Adverse Reactions Occurring in greater than or equal to 20% of Patients in KEYNOTE-021

Table 7: Laboratory Abnormalities Worsened from Baseline in greater than or equal to 20% of Patients in KEYNOTE-021

Table 8: Adverse Reactions Occurring in greater than or equal to 5% of Fully Supplemented Subgroup of Patients Receiving ALIMTA/Cisplatin in Study JMCHa

Table 9: Exploratory Subgroup Analysis of Selected Grade 3/4 Adverse Reactions Occurring in Patients Receiving ALIMTA in Combination with Cisplatin with or without Full Vitamin Supplementation in Study JMCHa

Please refer to the label to view the complete data for the four tables listed above.

10/11/2017 (SUPPL-50)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Increased Risk of Myelosuppression without Vitamin Supplementation

(subsection revised, additions underlined)

ALIMTA can cause severe myelosuppression resulting in a requirement for transfusions and which may lead to neutropenic infection. The risk of myelosuppression is increased in patients who do not receive vitamin supplementation. In Study JMCH, incidences of Grade 3-4 neutropenia (38% versus 23%), thrombocytopenia (9% versus 5%), febrile neutropenia (9% versus 0.6%), and neutropenic infection (6% versus 0) were higher in patients who received ALIMTA plus cisplatin without vitamin supplementation as compared to patients who were fully supplemented with folic acid and vitamin B12 prior to and throughout ALIMTA plus cisplatin treatment.

Initiate supplementation with oral folic acid and intramuscular vitamin B12 prior to the first dose of ALIMTA; continue vitamin supplementation during treatment and for 21 days after the last dose of ALIMTA to reduce the severity of hematologic   and gastrointestinal toxicity of ALIMTA. Obtain a complete blood count at the beginning of each cycle. Do not administer ALIMTA until the ANC is at least 1500 cells/mm3 and platelet count is at least 100,000 cells/mm3. Permanently reduce ALIMTA in patients with an ANC of less than 500 cells/mm3 or platelet count of less than 50,000 cells/mm3 in previous cycles.

In Studies JMDB and JMCH, among patients who received vitamin supplementation, incidence of Grade 3-4 neutropenia was 15% and 23%, the incidence of Grade 3-4 anemia was 6% and 4%, and incidence of Grade 3-4 thrombocytopenia was 4% and 5%, respectively. In Study JMCH, 18% of patients in the ALIMTA arm required red blood cell transfusions compared to 7% of patients in the cisplatin arm. In Studies JMEN, PARAMOUNT, and JMEI, where all patients received vitamin supplementation, incidence of Grade 3-4 neutropenia ranged from 3% to 5%, and incidence of Grade 3-4 anemia ranged from 3% to 5%.

5.2 Renal Failure

(subsection revised, additions underlined)

ALIMTA can cause severe, and sometimes fatal, renal toxicity. The incidences of renal failure in clinical studies in which patients received ALIMTA with cisplatin were: 2.1% in Study JMDB and 2.2% in Study JMCH. The incidence of renal failure in clinical studies in which patients received ALIMTA as a single agent ranged from 0.4% to 0.6% (Studies JMEN, PARAMOUNT, and JMEI. Determine creatinine clearance before each dose and periodically monitor renal function during treatment with ALIMTA. Withhold ALIMTA in patients with a creatinine clearance of less than 45 mL/minute.

5.3 Bullous and Exfoliative Skin Toxicity

(new subsection added)

Serious and sometimes fatal, bullous, blistering and exfoliative skin toxicity, including cases suggestive of Stevens- Johnson Syndrome/Toxic epidermal necrolysis can occur with ALIMTA. Permanently discontinue ALIMTA for severe and life-threatening bullous, blistering or exfoliating skin toxicity.

5.4 Interstitial Pneumonitis

(new subsection added)

Serious interstitial pneumonitis, including fatal cases, can occur with ALIMTA treatment. Withhold ALIMTA for acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, or fever pending diagnostic evaluation. If pneumonitis is confirmed, permanently discontinue ALIMTA.

5.5 Radiation Recall

(new subsection added)

Radiation recall can occur with ALIMTA in patients who have received radiation weeks to years previously. Monitor patients for inflammation or blistering in areas of previous radiation treatment. Permanently discontinue ALIMTA for signs of radiation recall.

5.6 Increased Risk of Toxicity with Ibuprofen in Patients with Renal Impairment

(subsection revised, additions underlined)

Exposure to ALIMTA is increased in patients with mild to moderate renal impairment who take concomitant ibuprofen, increasing the risks of adverse reactions of ALIMTA. In patients with creatinine clearances between 45 mL/min and 79 mL/min, avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of ALIMTA. If concomitant ibuprofen use cannot be avoided, monitor patients more frequently for ALIMTA adverse reactions, including myelosuppression, renal, and gastrointestinal toxicity.

5.7 Embryo-Fetal Toxicity

(subsection revised, additions underlined)

Based on findings from animal studies and its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman.In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and increased malformations at doses lower than the recommended human dose of 500 mg/m2. Advise pregnant women of the potential risk to the fetus. Advise

females of reproductive potential to use effective contraception during treatment with ALIMTA and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ALIMTA and for 3 months after the final dose.

6 Adverse Reactions

(additions underlined)

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Myelosuppression

• Renal failure

• Bullous and exfoliative skin toxicity

• Interstitial pneumonitis

• Radiation recall

6.1 Clinical Trials Experience

(extensive additions and revisions, please refer to label)

6.2 Postmarketing Experience

(additions underlined)

The following adverse reactions have been identified during post-approval use of ALIMTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System — immune-mediated hemolytic anemia

Gastrointestinal — colitis, pancreatitis

General Disorders and Administration Site Conditions — edema Injury, poisoning, and procedural complications — radiation recall

Respiratory — interstitial pneumonitis

Skin — Serious and fatal bullous skin conditions, Stevens-Johnson syndrome, and toxic epidermal necrolysis

7 Drug Interactions

(section revised, additions underlined)

Effects of Ibuprofen on Pemetrexed

Ibuprofen increases exposure (AUC) of pemetrexed in patients with creatinine clearance between 45 mL/min and 79 mL/min.

• Avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of ALIMTA.

• Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided.

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion, additions underlined)

Risk Summary

Based on findings from animal studies and its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman.There are no available data on ALIMTA use in pregnant women. In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and malformations at doses lower than the

recommended human dose of 500 mg/m2 [see Data]. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

Pemetrexed was teratogenic in mice. Daily dosing of pemetrexed by intravenous injection to pregnant mice during the period of organogenesis increased the incidence of fetal malformations (cleft palate; protruding tongue; enlarged or misshaped kidney; and fused lumbar vertebra) at doses (based on BSA) 0.03 times the human dose of 500 mg/m2. At doses, based on BSA, greater than or equal to 0.0012 times the 500 mg/m2 human dose, pemetrexed administration resulted in dose-dependent increases in developmental delays (incomplete ossification of talus and skull bone; and decreased fetal weight).

8.2 Lactation

(PLLR conversion, additions underlined)

Risk Summary

There is no information regarding the presence of pemetrexed or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed infants from ALIMTA, advise women not to breastfeed during treatment with ALIMTA and for one week after last dose.

8.3 Females and Males of Reproductive Potential

(PLLR conversion)

Contraception

Females

ALIMTA can cause fetal harm when administered to a pregnant woman. Because of the potential for genotoxicity, advise females of reproductive potential to use effective contraception during treatment with ALIMTA for at least 6 months after the final dose of ALIMTA.

Males

Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with ALIMTA and for 3 months after the final dose.

Infertility

Males

ALIMTA may impair fertility in males of reproductive potential. It is not known whether these effects on fertility are reversible

8.4 Pediatric Use

(additions underlined)

The safety and effectiveness of ALIMTA in pediatric patients have not been established. The safety and pharmacokinetics of ALIMTA were evaluated in two clinical studies conducted in pediatric patients with recurrent solid tumors. ALIMTA was administered at doses ranging from 400 to 2480 mg/m2 intravenously over 10 minutes on Day 1 of a 21-day cycle to 32 recurrent solid tumors in a dose-finding study. The maximum tolerated dose (MTD) was determined to be 1910 mg/m2 (60 mg/kg for patients <12 months old). ALIMTA was administered at the MTD every 21 days in an activity-estimating study enrolling 72 patients with relapsed or refractory osteosarcoma, Ewing sarcoma/peripheral primitive neural ectodermal tumor (PNET), rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/supratentorial PNET, or non-brainstem high grade glioma. Patients in both studies received concomitant vitamin B12 and folic acid supplementation and dexamethasone.

No  tumor responses were observed. Adverse reactions observed in pediatric patients were similar to those observed in adults.

Single-dose pharmacokinetics of ALIMTA administered at doses ranging from 400 to 2480 mg/m2 were evaluated in  the 22 patients (13 males and 9 females) age 4 to 18 years (average age 12 years). Pemetrexed exposure (AUC and Cmax) appeared to increase proportionally with dose. Average clearance (2.30 L/h/m2) and half-life (2.3 hours) were similar in pediatric patients compared to adults.

8.5 Geriatric Use

(additions underlined)

Of the 3,946 patients enrolled in clinical studies of ALIMTA, 34% were 65 and over and 4% were 75 and over. No overall differences in effectiveness were observed between these patients and younger patients. The incidences of Grade 3-4 anemia, fatigue, thrombocytopenia, hypertension, and neutropenia were higher in patients 65 years of age and older as compared to younger patients: in at least one of five randomized clinical trials.

8.6 Patients with Renal Impairment

(additions underlined)

ALIMTA is primarily excreted by the kidneys. Decreased renal function results in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function. No dose is recommended for patients with creatinine clearance less than 45 mL/min

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(additions underlined)

Advise the patient to read the FDA-approved patient labeling (Patient Information).

 Premedication  and Concomitant Medication: Instruct patients to Instructtake folic acid as directed and to keep appointments for vitamin B12 injections to reduce the risk of treatment-related toxicity. Instruct patients of the requirement to take corticosteroids to reduce the risks of treatment-related toxicity.

 

Myelosuppression: Inform patients of the risk of low blood cell counts and instruct them to immediately contact their physician for signs of infection, fever, bleeding, or symptoms of anemia.

Renal Failure: Inform patients of the risks of renal failure, which may be exacerbated in patients with dehydration arising from severe vomiting or diarrhea. Instruct patients to immediately contact their healthcare provider for a decrease in urine output.

Bullous and Exfoliative Skin Disorders: Inform patients of the risks of severe and exfoliative skin disorders. Instruct patients to immediately contact their healthcare provider for development of bullous lesions or exfoliation in the skin or mucous membranes.

Interstitial Pneumonitis: Inform patients of the risks of pneumonitis. Instruct patients to immediately contact their healthcare provider for development of dyspnea or persistent cough.

Radiation Recall: Inform patients who have received prior radiation of the risks of radiation recall. Instruct patients to immediately contact their healthcare provider for development of inflammation or blisters in an area that was previously irradiated.

Increased Risk of Toxicity with Ibuprofen in Patients with Renal Impairment: Advise patients with mild to moderate renal impairment of the risks associated with concomitant ibuprofen use and instruct them to avoid use of all ibuprofen containing products for 2 days before, the day of, and 2 days following administration of ALIMTA.

Embryo-Fetal Toxicity: Advise females of reproductive potential and males with female partners of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ALIMTA and for 6 months after the final dose. Advise females to inform their prescriber of a known or suspected pregnancy. Advise males with female partners of reproductive potential to use effective contraception during treatment with ALIMTA and for 3 months after the final dose.

Lactation : Advise women not to breastfeed during treatment with ALIMTA and for 1 week after the final dose

PATIENT INFORMATION

(additions and revisions, please refer to label)