(pemetrexed for injection)

Prescribing Information
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12 CLINICAL PHARMACOLOGY

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Pemetrexed Injection is a folate analog metabolic inhibitor that disrupts folate-dependent metabolic processes essential for cell replication. In vitro studies show that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase (GARFT), which are folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is taken into cells by membrane carriers such as 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.

12.2 Pharmacodynamics

Pemetrexed inhibited the in vitro growth of mesothelioma cell lines (MSTO-211H, NCI-H2052) and showed synergistic effects when combined with cisplatin.

Based on population pharmacodynamic analyses, the depth of the absolute neutrophil counts (ANC) nadir correlates with the systemic exposure to pemetrexed and supplementation with folic acid and vitamin B12. There is no cumulative effect of pemetrexed exposure on ANC nadir over multiple treatment cycles.

12.3 Pharmacokinetics

Absorption

The pharmacokinetics of pemetrexed when pemetrexed was 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 total systemic exposure (AUC) and maximum plasma concentration (Cmax) increased proportionally with increase of dose. The pharmacokinetics of pemetrexed did not change over multiple treatment cycles.

Distribution

Pemetrexed has a steady-state volume of distribution of 16.1 liters. In vitro studies indicated that pemetrexed is 81% bound to plasma proteins.

Elimination

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). As renal function decreases, the clearance of pemetrexed decreases and exposure (AUC) of pemetrexed increases.

Metabolism

Pemetrexed is not metabolized to an appreciable extent.

Excretion

Pemetrexed is primarily eliminated in the urine, with 70% to 90% of the dose recovered unchanged within the first 24 hours following administration. In vitro studies indicated that pemetrexed is a substrate of OAT3 (organic anion transporter 3), a transporter that is involved in the active secretion of pemetrexed.

Specific Populations

Age (26 to 80 years) and sex had no clinically meaningful effect on the systemic exposure of pemetrexed based on population pharmacokinetic analyses.

Racial Groups

The pharmacokinetics of pemetrexed were similar in Whites and Blacks or African Americans. Insufficient data are available for other ethnic groups.

Patients with Hepatic Impairment

Pemetrexed has not been formally studied in patients with hepatic impairment. No effect of elevated AST, ALT, or total bilirubin on the PK of pemetrexed was observed in clinical studies.

Patients with Renal Impairment

Pharmacokinetic analyses of pemetrexed included 127 patients with impaired 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 systemic exposure (AUC) compared to patients with creatinine clearance of 100 mL/min [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)].

Third-Space Fluid

The pemetrexed plasma concentrations in patients with various solid tumors with stable, mild to moderate third-space fluid were comparable to those observed in patients without third-space fluid collections. The effect of severe third-space fluid on pharmacokinetics is not known.

Drug Interaction Studies

Drugs Inhibiting OAT3 Transporter

Ibuprofen, an OAT3 inhibitor, administered at 400 mg four times a day decreased the clearance of pemetrexed and increased its exposure (AUC) by approximately 20% in patients with normal renal function (creatinine clearance >80 mL/min).

In Vitro Studies

Pemetrexed is a substrate for OAT3. Ibuprofen, an OAT3 inhibitor inhibited the uptake of pemetrexed in OAT3-expressing cell cultures with an average [Iu]/IC50 ratio of 0.38. In vitro data predict that at clinically relevant concentrations, other NSAIDs (naproxen, diclofenac, celecoxib) would not inhibit the uptake of pemetrexed by OAT3 and would not increase the AUC of pemetrexed to a clinically significant extent [see Drug Interactions (7)].

Pemetrexed is a substrate for OAT4. In vitro, ibuprofen and other NSAIDs (naproxen, diclofenac, celecoxib) are not inhibitors of OAT4 at clinically relevant concentrations.

Aspirin

Aspirin, administered in low to moderate doses (325 mg every 6 hours), does not affect the pharmacokinetics of pemetrexed.

Cisplatin

Cisplatin does not affect the pharmacokinetics of pemetrexed and the pharmacokinetics of total platinum are unaltered by pemetrexed.

Vitamins

Neither folic acid nor vitamin B12 affect the pharmacokinetics of pemetrexed.

Drugs Metabolized by Cytochrome P450 Enzymes

In vitro studies suggest that pemetrexed does not inhibit the clearance of drugs metabolized by CYP3A, CYP2D6, CYP2C9, and CYP1A2.

Medication Guide

MEDICATION GUIDE

PATIENT INFORMATION
Pemetrexed (peh-meh-TREX-ed) Injection
for intravenous use
This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: 6/2022

What is Pemetrexed Injection?

Pemetrexed Injection is a prescription medicine used to treat:

•
a kind of lung cancer called non-squamous non-small cell lung cancer (NSCLC). Pemetrexed Injection is used:
o
as the first treatment in combination with cisplatin when your lung cancer has spread (advanced NSCLC).
o
alone as maintenance treatment after you have received 4 cycles of chemotherapy that contains platinum for first treatment of your advanced NSCLC and your cancer has not progressed.
o
alone when your lung cancer has returned or spread after prior chemotherapy.
 
Pemetrexed Injection is not for use for the treatment of people with squamous cell, non-small cell lung cancer.
•
a kind of cancer called malignant pleural mesothelioma. This cancer affects the lining of the lungs and chest wall. Pemetrexed Injection is used in combination with cisplatin as the first treatment for malignant pleural mesothelioma that cannot be removed by surgery or you are not able to have surgery.

Pemetrexed Injection has not been shown to be safe and effective in children.

Do not take Pemetrexed Injection if you have had a severe allergic reaction to any medicine that contains pemetrexed.

Before taking Pemetrexed Injection, tell your healthcare provider about all of your medical conditions, including if you:

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have kidney problems.
•
have had radiation therapy.
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are pregnant or plan to become pregnant. Pemetrexed Injection can harm your unborn baby.
Females who are able to become pregnant:
Your healthcare provider will check to see if you are pregnant before you start treatment with Pemetrexed Injection.
You should use effective birth control (contraception) during treatment with Pemetrexed Injection and for 6 months after the last dose. Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with Pemetrexed Injection.
Males with female partners who are able to become pregnant should use effective birth control (contraception) during treatment with Pemetrexed Injection and for 3 months after the last dose.
•
are breastfeeding or plan to breastfeed. It is not known if Pemetrexed Injection passes into breast milk. Do not breastfeed during treatment with Pemetrexed Injection and for 1 week after the last dose.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
Tell your healthcare provider if you have kidney problems and take a medicine that contains ibuprofen. You should avoid taking ibuprofen for 2 days before, the day of, and 2 days after receiving treatment with Pemetrexed Injection.

How is Pemetrexed Injection given?

•
It is very important to take folic acid and vitamin B12 during your treatment with Pemetrexed Injection to lower your risk of harmful side effects.
o
Take folic acid exactly as prescribed by your healthcare provider 1 time a day, beginning 7 days (1 week) before your first dose of Pemetrexed Injection and continue taking folic acid until 21 days (3 weeks) after your last dose of Pemetrexed Injection.
o
Your healthcare provider will give you vitamin B12 injections during treatment with Pemetrexed Injection. You will get your first vitamin B12 injection 7 days (1 week) before your first dose of Pemetrexed Injection, and then every 3 cycles.
•
Your healthcare provider will prescribe a medicine called corticosteroid for you to take 2 times a day for 3 days, beginning the day before each treatment with Pemetrexed Injection.
•
Pemetrexed Injection is given to you by intravenous (IV) infusion into your vein. The infusion is given over 10 minutes.
•
Pemetrexed Injection is usually given once every 21 days (3 weeks).

What are the possible side effects of Pemetrexed Injection?

Pemetrexed Injection can cause serious side effects, including:

•
Low blood cell counts. Low blood cell counts can be severe, including low white blood cell counts (neutropenia), low platelet counts (thrombocytopenia), and low red blood cell counts (anemia). Your healthcare provider will do blood tests to check your blood cell counts regularly during your treatment with Pemetrexed Injection. Tell your healthcare provider right away if you have any signs of infection, fever, bleeding, or severe tiredness during your treatment with Pemetrexed Injection.
•
Kidney problems, including kidney failure. Pemetrexed Injection can cause severe kidney problems that can lead to death. Severe vomiting or diarrhea can lead to loss of fluids (dehydration) which may cause kidney problems to become worse. Tell your healthcare provider right away if you have a decrease in the amount of urine you make.
•
Severe skin reactions. Severe skin reactions that may lead to death can happen with Pemetrexed Injection. Tell your healthcare provider right away if you develop blisters, skin sores, skin peeling, or painful sores, or ulcers in your mouth, nose, throat or genital area.
•
Lung problems (pneumonitis). Pemetrexed Injection can cause serious lung problems that can lead to death. Tell your healthcare provider right away if you get any new or worsening symptoms of shortness of breath, cough, or fever.
•
Radiation recall. Radiation recall is a skin reaction that can happen in people who have received radiation treatment in the past and are treated with Pemetrexed Injection. Tell your healthcare provider if you get swelling, blistering, or a rash that looks like a sunburn in an area that was previously treated with radiation.

The most common side effects of Pemetrexed Injection when given alone are:

•
tiredness
•
nausea
•
loss of appetite

The most common side effects of Pemetrexed Injection when given with cisplatin are:

•
vomiting
•
swelling or sores in your mouth or sore throat
•
constipation
•
low white blood cell counts (neutropenia)
•
low platelet counts (thrombocytopenia)
•
low red blood cell counts (anemia)

Pemetrexed Injection may cause fertility problems in males. This may affect your ability to father a child. It is not known if these effects are reversible. Talk to your healthcare provider if this is a concern for you.
Your healthcare provider will do blood tests to check for side effects during treatment with Pemetrexed Injection. Your healthcare provider may change your dose of Pemetrexed Injection, delay treatment, or stop treatment if you have certain side effects.
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
These are not all of the possible side effects of Pemetrexed Injection. For more information, ask your healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of Pemetrexed Injection.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet.
You can ask your pharmacist or healthcare provider for information about Pemetrexed Injection that is written for health professionals.

What are the ingredients in Pemetrexed Injection?
Active ingredient: pemetrexed
Inactive ingredient: monothioglycerol, water for injection and may contain sodium hydroxide for pH adjustment.

Manufactured by: Zydus Hospira Oncology Private Ltd.
Ahmedabad 382-213, Gujarat, India.

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Distributed by: Hospira, Inc., Lake Forest, IL 60045 USA
LAB-1432-1.0
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