What Is Pemetrexed (Alimta)? FDA Approval, Authorization in Türkiye, and Reimbursement

• FDA Approved: Yes (Initial approval: 4 February 2004)
• Brand Name: Alimta
• Active Ingredient: Pemetrexed
• Administration: Intravenous (IV)
• Class: Antimetabolite (antifolate antineoplastic agent)
• Category: Chemotherapy drug
• Manufacturer: Eli Lilly and Company
• Approved Cancers: Malignant pleural mesothelioma and metastatic nonsquamous non-small cell lung cancer

What Is Alimta? How Does It Work?

Alimta, containing pemetrexed, is used to treat advanced malignant pleural mesothelioma and metastatic non-small cell lung cancer (NSCLC). It is an intravenously administered antimetabolite chemotherapy drug. It specifically targets folate metabolism, suppressing DNA and RNA synthesis and thereby stopping cancer cells from dividing and multiplying.

What Is an Antimetabolite?

Antimetabolites disrupt DNA and RNA synthesis by mimicking the essential building blocks cells use in these processes. Pemetrexed specifically substitutes for folic acid derivatives, inhibiting intracellular folate-dependent enzymes such as thymidylate synthase (TS), dihydrofolate reductase (DHFR), and GAR transformylase (GART). This disrupts DNA synthesis and leads to cancer cell death.

What Is Its Mechanism of Action?

• Pemetrexed is an antineoplastic agent resembling folate in structure.
• It enters cells via the reduced folate carrier (RFC) and folate receptors (FRP).
• Within cells, folylpolyglutamate synthetase (FPGS) converts it to active polyglutamate forms, increasing the drug's retention and activity.
• It inhibits enzymes involved in DNA synthesis, primarily thymidylate synthase (TS), along with DHFR and GART.
• These inhibitory effects halt DNA repair and cell division, triggering cancer cell death.
• These effects are particularly pronounced in rapidly dividing tumor cells and improve treatment success.

FDA (US Food and Drug Administration) Approval History

• 4 February 2004: Initial approval in combination with cisplatin for malignant pleural mesothelioma
• 29 September 2008: FDA approval as first-line treatment for locally advanced or metastatic nonsquamous non-small cell lung cancer.
• 7 July 2009: FDA approval expanded to “maintenance” treatment after chemotherapy in nonsquamous NSCLC.
• 19 September 2024: The FDA approved amivantamab-vmjw + Carboplatin + pemetrexed for advanced NSCLC with an EGFR mutation.

Authorization in Türkiye

The authorized uses / therapeutic indications for Pemetrexed in Türkiye are specified as follows:

Therapeutic indications;

• Malignant pleural mesothelioma: Pemetrexed is indicated in combination with platinum for patients with unresectable malignant pleural mesothelioma who have not previously received chemotherapy.
• Nonsquamous non-small cell lung cancer (NSCLC): Pemetrexed is indicated with cisplatin as initial treatment for locally advanced or metastatic non-small cell lung cancer, restricted to nonsquamous histological subgroups.
• Pemetrexed is indicated as single-agent maintenance treatment for relapsed or metastatic non-small cell lung cancer restricted to nonsquamous histological subtypes, when disease has not progressed after first-line platinum-based chemotherapy.
• Pemetrexed is indicated as second-line treatment for relapsed or metastatic nonsquamous non-small cell lung cancer in patients who have not previously received a pemetrexed-based treatment.

Is It Reimbursed by SGK?

The Social Security Institution (SGK) reimburses Pemetrexed in the following treatment settings:

• SGK covers Pemetrexed for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) of a nonsquamous histological subtype (adenocarcinoma or large-cell carcinoma) whose disease progresses after first-line chemotherapy.
• For patients with malignant pleural mesothelioma who have not previously received chemotherapy and whose disease cannot be surgically removed (unresectable), SGK covers Pemetrexed combined with platinum-based chemotherapy.

What Is Pemetrexed's Status on the List of Off-Label Drugs That Can Be Used Without Additional TİTCK Approval?

• Advanced Urothelial Cancer: Suitable for 4th-line use after gemcitabine, platinum, taxanes, and vinorelbine/vinflunine.
• Advanced Epithelial Ovarian, Fallopian Tube, and Primary Peritoneal Cancer: Suitable for 4th-line and later use.

Price: Alimta 500 mg tb 19,920.19 TL.

Resistance Mechanisms 

As an antimetabolite chemotherapy agent, pemetrexed inhibits various folate-dependent enzymes, primarily thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT). However, some tumor cells develop acquired or intrinsic resistance, reducing treatment response. The following mechanisms may explain this resistance:

• Reduced Drug Uptake: Pemetrexed enters cells primarily through the reduced folate carrier (RFC) and proton-coupled folate transporter (PCFT). Reduced expression of these transporters limits cellular entry of pemetrexed, lowering its efficacy.
• Impaired Polyglutamation: Once inside the cell, pemetrexed is converted to polyglutamate forms by folylpolyglutamate synthetase (FPGS), retaining it within the cell and enhancing its inhibitory effect. Reduced FPGS activity or increased γ-glutamyl hydrolase (GGH) prevents formation of these active forms and facilitates their elimination from the cell.
• Target Enzyme Expression or Mutation: Overexpression or structural changes (mutations) in pemetrexed's target enzymes, TS, DHFR, and GARFT, reduce drug binding. TS gene amplification in particular is frequently associated with pemetrexed resistance.
• Increased Efflux Mechanisms:Overexpression of ATP-dependent transporters in the cell membrane, such as multidrug resistance proteins (e.g., MRP5 / ABCC5), increases the export of pemetrexed from cells. This mechanism reduces intracellular drug concentrations.
• Metabolic Reprogramming: Tumor cells can activate alternative metabolic pathways that bypass folate pathways. Alternative routes such as salvage purine/pyrimidine synthesis reduce dependence on the key enzymes blocked by pemetrexed.
• Increased DNA Repair Capacity: DNA damage arising in the pathways targeted by pemetrexed can become tolerable through repair mechanisms. Increased DNA repair proteins such as ERCC1 may particularly protect against the drug's cytotoxic effect.

Absorption

• Administered intravenously (IV).
• No oral formulation exists; the absorption stage is therefore bypassed.
• Bioavailability after IV administration is considered 100%.

Distribution

• Volume of distribution (Vd): Approximately 16.1 L/m² (by body surface area).
• Plasma protein binding: ~81%, particularly to albumin.
• Limited penetration into the central nervous system; efficacy against brain metastases may be low.

Metabolism

• Pemetrexed is not extensively metabolized.
• It does not undergo significant biotransformation by hepatic cytochrome P450 enzymes.
• It is excreted unchanged, generally making dose adjustment unnecessary in hepatic impairment.

Excretion

• The main route is through the kidneys (renal elimination).
• Approximately 70-90% of the administered dose is excreted unchanged in urine (within the first 24 hours).
• Elimination half-life (t1/2): A mean of 3.5 hours (may range from 2–5 hours).
• Use caution in patients with creatinine clearance < 45 mL/min; kidney function is critical for dose adjustment.

Dose Range 

• As a single agent (monotherapy): 500 mg/m² IV every 21 days (every 3 weeks)
• In combination with cisplatin: 500 mg/m² IV followed by cisplatin, every 21 days
• As maintenance treatment: 500 mg/m² IV every 21 days. 

Doses are calculated by body surface area. Dose adjustment may be needed in patients with impaired kidney function.

Certain supportive medications are given before pemetrexed to improve treatment safety and reduce side effects. 

Before starting treatment, oral folic acid should begin at least 5–7 days beforehand. It should be taken at 350–1000 micrograms (mcg) daily and continued throughout pemetrexed treatment.

In addition, 1000 mcg of vitamin B12 (cyanocobalamin) should be given intramuscularly one week before treatment starts. This injection should be repeated every 9 weeks (approximately every 3 months).

Drug Interactions 

• Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): NSAIDs can affect kidney function, reducing pemetrexed excretion. This may increase pemetrexed toxicity (mucositis, bone marrow suppression, etc.), particularly in patients with mild-to-moderate renal impairment. If possible, NSAIDs should be stopped for 2 days before and after treatment. Examples: Ibuprofen, diclofenac, naproxen
• Other Renally Excreted Drugs: Concurrent use may cause competition for renal excretion, increasing pemetrexed plasma levels and toxicity risk. Examples: Aminoglycosides (gentamicin), probenecid, loop diuretics
• Proton Pump Inhibitors (PPIs): PPIs may affect renal tubular secretion of pemetrexed. Its toxic effects may increase, particularly with high doses and prolonged use (neutropenia, mucositis). Examples: Omeprazole, pantoprazole, lansoprazole
• Folate-Free Multivitamins or Antifolates: These drugs also affect folate metabolism. Given with pemetrexed, they may increase efficacy but also substantially increase toxicity. Combinations such as trimethoprim–sulfamethoxazole (Bactrim) in particular should be closely monitored. Examples: Trimethoprim, methotrexate
• Live Vaccines: Pemetrexed can suppress the immune system. Live vaccines (such as live influenza vaccine, BCG, or yellow fever vaccine) should therefore not be given during pemetrexed treatment.

Situations Requiring Caution

Assessment of Kidney Function

• Pemetrexed is eliminated by the kidneys, so creatinine clearance (CrCl) must be measured before treatment.
• Pemetrexed is not recommended in patients with CrCl < 45 mL/min.
• Regular monitoring of kidney function is required during treatment.

Premedications (Essential)

• Folic acid, vitamin B12, and corticosteroids (dexamethasone) must be given regularly and on time.
• These supportive treatments prevent serious hematologic and gastrointestinal toxicities.

Blood Count Monitoring

• Pemetrexed can suppress bone marrow, causing neutropenia, anemia, and thrombocytopenia.
• A complete blood count must therefore be performed before treatment and before every cycle.
• Dose reduction or treatment delay should be planned if needed.

Infection Risk

• Patients who develop leukopenia and neutropenia have a high infection risk.
• Fever or fatigue may require emergency intervention for neutropenic fever.

Skin Reactions

• Skin rashes (maculopapular, itchy) are common, particularly during initial cycles.
• This risk increases further without corticosteroid premedication.

Drug Interactions

• NSAIDs and PPIs (omeprazole, etc.) can increase pemetrexed levels through their effects on kidney function, causing toxicity.
• These drugs should be used cautiously and temporarily stopped if necessary.

Pregnancy and Breastfeeding

• Pemetrexed is contraindicated during pregnancy because of fetal toxicity risk.
• It should also not be used during breastfeeding because it may enter breast milk and harm the baby.

Vaccines

• Do not give live vaccines during treatment (such as BCG or live influenza vaccine).
• Immunosuppression may make the vaccine ineffective or create a risk of serious infection.

Liver Function

• Pemetrexed is not metabolized in the liver, so dose adjustment is generally unnecessary in mild-to-moderate hepatic impairment.
• However, elevated ALT/AST should be monitored.

Side Effects 

• Neutropenia (low neutrophil count): 56–67%
• Anemia (low red blood cells): 33–33.7%
• Thrombocytopenia (low platelets): 14–25%
• Leukopenia (low white blood cells): 27–31%
• Fatigue: 34–40%
• Nausea: 30–40%
• Vomiting: 16–25%
• Loss of appetite (anorexia): 20–31%
• Mucositis (mouth sores): 18–23%
• Diarrhea: 14–19%
• Constipation: 12–16%
• Skin rash: 14–26%
• Abdominal pain: 12–18%
• Infections (particularly associated with neutropenia): 7–15%
• Kidney dysfunction (increased creatinine): 2–8%
• Fever: 6–10%
• Headache: 7–9%
• Elevated transaminases (AST/ALT): 5–8%
• Peripheral neuropathy (uncommon): <5%