PEMETREXED Drug Interactions: What You Need to Know

INTERACTIONS OAT3 Inhibitors: Modify the ibuprofen dosage as recommended. Avoid other OAT3 inhibitors. ( 2.5 , 5.6 , 7 )

7.1 Effects of Other Drugs on Pemetrexed Injection OAT3 Inhibitors Avoid concomitant administration of ibuprofen for 2 days before, the day of, and 2 days following administration of Pemetrexed Injection <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5 )]</span> . Avoid concomitant administration of other OAT3 inhibitors before and after administration of Pemetrexed Injection, when possible. If concomitant administration cannot be avoided, monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity. Pemetrexed is an OAT3 substrate <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . Concomitant use with an OAT3 inhibitor increases pemetrexed systemic exposure (AUC) <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> , which may increase the risk of Pemetrexed Injection adverse reactions.

Pemetrexed for Injection is contraindicated in patients with a history of severe hypersensitivity reaction to pemetrexed [see Adverse Reactions ( 6.1 )] . History of severe hypersensitivity reaction to pemetrexed. ( 4 )

AND PRECAUTIONS

• Myelosuppression: Can cause severe bone marrow suppression resulting in cytopenia and an increased risk of infection. Do not administer pemetrexed for injection when the absolute neutrophil count is less than 1500 cells/mm 3 and platelets are less than 100,000 cells/mm 3 .Initiate supplementation with oral folic acid and intramuscular vitamin B 12 to reduce the severity of hematologic and gastrointestinal toxicity of pemetrexed for injection ( 2.4 , 5.1 )
• Renal Failure:Can cause severe, and sometimes fatal, renal failure. Do not administer when creatinine clearance is less than 45 mL/min. ( 2.3 , 5.2 )
• Bullous and Exfoliative Skin Toxicity: Permanently discontinue for severe and life-threatening bullous, blistering or exfoliating skin toxicity. ( 5.3 )
• Interstitial Pneumonitis: Withhold for acute onset of new or progressive unexplained pulmonary symptoms. Permanently discontinue if pneumonitis is confirmed. ( 5.4 )
• Radiation Recall: Can occur in patients who received radiation weeks to years previously; permanently discontinue for signs of radiation recall. ( 5.5 )
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.7 , 8.1 , 8.3 )

5.1 Myelosuppression and Increased Risk of Myelosuppression without Vitamin Supplementation Pemetrexed forinjection 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 to 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 pemetrexed plus cisplatin without vitamin supplementation as compared to patients who were fully supplemented with folic acid and vitamin B 12 prior to and throughout pemetrexed plus cisplatin treatment. Initiate supplementation with oral folic acid and intramuscular vitamin B 12 prior to the first dose of pemetrexed; continue vitamin supplementation during treatment and for 21 days after the last dose of pemetrexed to reduce the severity of hematologic and gastrointestinal toxicity of pemetrexed for injection [see Dosage and Administration ( 2.4 ) ]. Obtain a complete blood count at the beginning of each cycle. Do not administer pemetrexed for injection until the ANC is at least 1500 cells/mm 3 and platelet count is at least 100,000 cells/mm 3 . Permanently reduce pemetrexed for injection in patients with an ANC of less than 500 cells/mm 3 or platelet count of less than 50,000 cells/mm 3 in previous cycles [see Dosage and Administration ( 2.6 ) ].

In

Studies JMDB and JMCH, among patients who received vitamin supplementation, incidence of Grade 3 to 4 neutropenia was 15% and 23%, the incidence of Grade 3 to 4 anemia was 6% and 4%, and incidence of Grade 3 to 4 thrombocytopenia was 4% and 5%, respectively.

In

Study JMCH, 18% of patients in the pemetrexed for injection arm required red blood cell transfusions compared to 7% of patients in the cisplatin arm [see Adverse Reactions ( 6.1 ) ].

In

Studies JMEN, PARAMOUNT, and JMEI, where all patients received vitamin supplementation, incidence of Grade 3 to 4 neutropenia ranged from 3% to 5%, and incidence of Grade 3 to 4 anemia ranged from 3% to 5%.

5.2 Renal Failure Pemetrexed for injection can cause severe, and sometimes fatal, renal toxicity. The incidences of renal failure in clinical studies in which patients received pemetrexed 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 pemetrexed for injection as a single agent ranged from 0.4% to 0.6% (Studies JMEN, PARAMOUNT, and JMEI <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 ) ]</span>. Determine creatinine clearance before each dose and periodically monitor renal function during treatment with pemetrexed for injection. Withhold pemetrexed for injection in patients with a creatinine clearance of less than 45 mL/minute <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 ) ]</span>.

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

5.4 Interstitial Pneumonitis Serious interstitial pneumonitis, including fatal cases, can occur with pemetrexed for injection treatment. Withhold pemetrexed 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 pemetrexed.

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

5.6 Increased Risk of Toxicity with Ibuprofen in Patients with Renal Impairment Exposure to pemetrexed is increased in patients with mild to moderate renal impairment who take concomitant ibuprofen, increasing the risks of adverse reactions of pemetrexed. 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 pemetrexed. If concomitant ibuprofen use cannot be avoided, monitor patients more frequently for pemetrexed adverse reactions, including myelosuppression, renal, and gastrointestinal toxicity <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5 ), Drug Interactions ( 7 ), and Clinical Pharmacology ( 12.3 ) ]</span>.

5.7 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, pemetrexed 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/m 2 . Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with pemetrexed and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with pemetrexed and for 3 months after the last dose <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.3 ) and Clinical Pharmacology ( 12.1 ) ]</span>.

5.7 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, pemetrexed 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/m 2 . Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with pemetrexed and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with pemetrexed and for 3 months after the last dose <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.3 ) and Clinical Pharmacology ( 12.1 ) ]</span>.