Pemetrexed is a medication used in chemotherapy to treat certain types of cancer. It is sold under the brand name Alimta. Pemetrexed belongs to a class of drugs known as antifolate antineoplastic agents.

Pemetrexed is primarily used in the treatment of non-small cell lung cancer (NSCLC), which is the most common type of lung cancer. It is also used in combination with cisplatin for the treatment of malignant pleural mesothelioma, a cancer that affects the lining of the lungs and other organs.

Indications of Pemetrexed (Alimta):

• Mesothelioma:
  • It is given as first-line treatment of malignant pleural mesothelioma (in combination with cisplatin) that is unresectable or in patients who are inoperable.
• Non-small cell lung cancer (NSCLC), nonsquamous:
  • It is indicated for initial treatment of locally advanced or metastatic nonsquamous NSCLC (in combination with cisplatin)
  • Initial treatment of metastatic, nonsquamous NSCLC (in combination with platinum chemotherapy and pembrolizumab) in patients with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations.
  • It is also given as maintenance treatment (single-agent) of locally advanced or metastatic nonsquamous NSCLC if no progression after 4 cycles of platinum-based first-line therapy
  • It is used as monotherapy (after prior chemotherapy) of recurrent/metastatic nonsquamous NSCLC.
  • Limitation of use: Not indicated for the treatment of squamous cell cancer.
• Off Label Use of Pemetrexed in Adults:
  • Metastatic Bladder cancer;
  • Persistent or recurrent cervical cancer;
  • Malignant pleural mesothelioma (single agent and off-label combination);
  • Platinum-resistant Ovarian cancer;
  • Metastatic Thymic malignancies.

Pemetrexed dose in adults:

Note:

Before starting pemetrexed treatment, it is recommended to take certain vitamin supplements to help manage its side effects.

• Folic acid: Take 400 to 1,000 micrograms of folic acid by mouth once a day. Start taking it seven days before your first pemetrexed dose and continue daily throughout your treatment. Keep taking it for 21 days after your last pemetrexed dose.
• Vitamin B: Take 1,000 micrograms of vitamin B intramuscularly (injected into the muscle) seven days before your first pemetrexed dose. After that, take it every three treatment cycles.

To minimize skin reactions, you should also take dexamethasone. Take 4 milligrams of dexamethasone by mouth twice a day for three days, starting the day before your treatment.

It's important to note that you should not begin new treatment cycles unless the following conditions are met: your absolute neutrophil count (ANC) is equal to or greater than 1,500 cells per millimeter, your platelet count is equal to or greater than 100,000 cells per millimeter, your creatinine clearance (a measure of kidney function) is equal to or greater than 45 milliliters per minute, and any non-blood-related side effects have improved to grade 2 or lower.

Pemetrexed Treatment dose of Malignant pleural mesothelioma:

• In the treatment of malignant pleural mesothelioma, pemetrexed is typically given intravenously (IV) at a dose of 500 milligrams per square meter (mg/m²) on day 1 of each 21-day treatment cycle.
• This is done in combination with cisplatin, another chemotherapy drug.
• The treatment is continued until there is disease progression, unacceptable toxicity, or as an off-label use, it can be combined with carboplatin instead of cisplatin (as supported by studies like Castagneto 2008 and Ceresoli 2006).
• Pemetrexed can also be used as a single-agent therapy for malignant pleural mesothelioma in certain cases, even though it is considered an off-label use.

Pemetrexed Treatment dose of non-small cell lung cancer, nonsquamous:

In the treatment of non-small cell lung cancer (NSCLC), specifically the nonsquamous type, pemetrexed is administered intravenously (IV) at different dosages and treatment durations depending on the stage and specific treatment plan.

• Initial treatment for locally advanced or metastatic NSCLC (in combination with cisplatin):
  • IV administration of 500 milligrams per square meter (mg/m²) on day 1 of each 21-day cycle.
  • This treatment is given for up to 6 cycles or until there is disease progression or unacceptable toxicity.
• Initial treatment for metastatic NSCLC (in combination with pembrolizumab and either carboplatin or cisplatin):
  • IV administration of 500 mg/m² on day 1 of each 21-day cycle.
  • This treatment is given for 4 cycles in combination with pembrolizumab and either carboplatin or cisplatin.
  • Following the platinum-based therapy, pemetrexed can be continued as maintenance therapy, either alone or in combination with pembrolizumab, until there is disease progression or unacceptable toxicity.
• Maintenance treatment for locally advanced or metastatic NSCLC (after 4 cycles of initial platinum-based therapy):
  • IV administration of 500 mg/m² on day 1 of each 21-day cycle.
  • This is given as a single-agent (without other chemotherapy drugs).
  • The maintenance treatment is continued until there is disease progression or unacceptable toxicity.
• Second-line treatment for recurrent/metastatic NSCLC (after prior chemotherapy):
  • IV administration of 500 mg/m² on day 1 of each 21-day cycle.
  • This is given as a single-agent.
  • The treatment is continued until there is disease progression or unacceptable toxicity.

Pemetrexed Treatment dose of metastatic bladder cancer (off-label):

• In the off-label treatment of metastatic bladder cancer, pemetrexed is administered intravenously (IV) at a dosage of 500 milligrams per square meter (mg/m²) on day 1 of each 21-day cycle.
• The treatment is continued until there is disease progression or unacceptable toxicity.
• It's important to note that off-label use refers to the use of a medication for a purpose that is not specifically approved by regulatory authorities.
• In this case, while pemetrexed is not officially approved for the treatment of metastatic bladder cancer, its off-label use may be considered based on clinical judgment and individual patient circumstances.

Pemetrexed Treatment dose of Cervical cancer, persistent or recurrent (off-label):

In the off-label treatment of persistent or recurrent cervical cancer, pemetrexed can be administered intravenously (IV) at different dosages based on different studies.

• IV administration of 500 milligrams per square meter (mg/m²) on day 1 of each 21-day cycle until disease progression or unacceptable toxicity occurs.
• IV administration of 900 mg/m² on day 1 of each 21-day cycle.

Pemetrexed Treatment dose of platinum-resistant ovarian cancer (off-label):

• In the off-label treatment of platinum-resistant ovarian cancer, pemetrexed can be administered intravenously (IV) at a dosage of 500 milligrams per square meter (mg/m²) on day 1 of each 21-day cycle.

Pemetrexed Treatment dose of metastatic thymic malignancies (off-label):

• In the off-label treatment of metastatic thymic malignancies, pemetrexed can be administered intravenously (IV) at a dosage of 500 milligrams per square meter (mg/m²) on day 1 of each 21-day cycle.
• This treatment is typically given for 6 cycles or until there is disease progression or unacceptable toxicity.

Pemetrexed Dose in Children:

Not indicated

Pregnancy Risk Category: D

• Pemetrexed can be harmful to unborn babies if given to pregnant women, based on studies in animals and how the medication works.
• Women who can become pregnant should use reliable birth control methods while receiving pemetrexed and for at least 6 months after the last dose.
• Men who have female partners capable of becoming pregnant should also use effective contraception during treatment and for 3 months after the last dose of pemetrexed.
• Pemetrexed may also affect male fertility.

Use of pemetrexed during lactation

• The presence of pemetrexed in breast milk is currently unknown.
• As there is a possibility of serious adverse reactions in breastfed infants, it is not recommended to breastfeed during treatment with pemetrexed and for one week after the final dose.

Pemetrexed Dose adjustment in renal disease:

The estimation of renal function in patients receiving pemetrexed can be done using the Cockcroft-Gault formula.

• If the calculated creatinine clearance (CrCl) is 45 mL/minute or higher, no dosage adjustment is necessary.
• If the CrCl is below 45 mL/minute, the use of pemetrexed is not recommended by the manufacturer due to limited data on dosage recommendations for such patients.
• In cases where renal toxicity occurs during treatment, pemetrexed should be withheld until the CrCl reaches 45 mL/minute or higher.

A phase I study in advanced cancer patients with renal impairment found that pemetrexed doses up to 500 mg/m², along with vitamin supplementation, were well tolerated in patients with glomerular filtration rates (GFR) ranging from 40 to 79 mL/minute. However, accrual was stopped for patients with GFR below 29 mL/minute due to toxicity, and no accrual occurred for patients with GFR ranging from 30 to 39 mL/minute. Patients with GFR equal to or higher than 80 mL/minute tolerated doses of 600 mg/m².

Regarding concomitant use of ibuprofen in patients with renal dysfunction:

• If the CrCl is 80 mL/minute or higher, no dosage adjustment is necessary.
• If the CrCl is between 45 and 79 mL/minute, ibuprofen should be avoided for 2 days before, the day of, and for 2 days following a dose of pemetrexed. If avoiding concomitant ibuprofen is not possible, closer monitoring for myelosuppression, renal, and gastrointestinal toxicities is recommended.

Pemetrexed Dose adjustment in liver disease:

There are no dosage adjustments provided in the manufacturer's labeling. Pemetrexed pharmacokinetics is not affected by transaminitis or raised bilirubin.

Common Side Effects of Pemetrexed (Alimta):

• Central Nervous System:
  • Fatigue
• Dermatologic:
  • Desquamation
  • Skin Rash
• Gastrointestinal:
  • Nausea
  • Anorexia
  • Vomiting
  • Stomatitis
  • Diarrhea
• Hematologic & Oncologic:
  • Anemia
  • Neutropenia
• Respiratory:
  • Pharyngitis

Rare Side Effects Of Pemetrexed (Alimta):

• Cardiovascular:
  • Edema
• Central Nervous System:
  • Neuropathy
• Dermatologic:
  • Pruritus
  • Alopecia
  • Erythema Multiforme
• Gastrointestinal:
  • Constipation
  • Abdominal Pain
• Hematologic & Oncologic:
  • Thrombocytopenia
  • Febrile Neutropenia
• Hepatic:
  • Increased Serum Alanine Aminotransferase
  • Increased Serum Aspartate Aminotransferase
• Hypersensitivity:
  • Hypersensitivity Reaction
• Infection:
  • Infection
  • Sepsis
• Ophthalmic:
  • Conjunctivitis
  • Increased Lacrimation
• Miscellaneous:
  • Fever

Contraindication to Pemetrexed (Alimta):

• In addition to severe hypersensitivity to pemetrexed or any component of the formulation, there are additional contraindications mentioned in the Canadian labeling that are not present in the US labeling. One of these additional contraindications is the concomitant use of the yellow fever vaccine. This means that individuals who are receiving pemetrexed treatment should not receive the yellow fever vaccine at the same time.

Warnings and precautions

Suppression of bone marrow

• Pemetrexed can lead to severe myelosuppression, which includes low red blood cell count (anemia), low white blood cell count (neutropenia), low platelet count (thrombocytopenia), or a decrease in all blood cell types (pancytopenia).
• Regular monitoring of blood counts is necessary, and dose adjustments may be required due to myelosuppression.
• Blood transfusion may be needed in severe cases.
• Taking prophylactic folic acid and vitamin B supplements before and during treatment can help reduce hematologic toxicity.

Cutaneous reactions

• Serious skin reactions can occur with pemetrexed treatment, including potentially life-threatening conditions like Stevens-Johnson syndrome and toxic epidermal necrolysis.
• To minimize the incidence and severity of these reactions, pretreatment with dexamethasone is necessary.
• Severe or life-threatening skin reactions may require permanent discontinuation of pemetrexed.

Gastrointestinal toxicities:

• Gastrointestinal side effects can occur with pemetrexed treatment.
• Prophylactic folic acid and vitamin B supplementation is needed to reduce gastrointestinal toxicity.
• These supplements should be initiated before treatment and continued for a certain period of time after the last dose.

Hypersensitivity

• Some individuals may experience hypersensitivity or allergic reactions to pemetrexed.
• It is important to be aware of any signs of allergic reactions and seek immediate medical attention if they occur.

Nephrotoxicity

• Pemetrexed can cause severe and potentially fatal kidney toxicity.
• Monitoring of kidney function, measured by creatinine clearance, is essential before each dose and throughout the treatment.
• Pemetrexed may need to be withheld if creatinine clearance falls below a certain level.

Toxicity in the lungs:

• There have been reports of interstitial pneumonitis, a lung inflammation, associated with pemetrexed use.
• Acute onset of new or progressive pulmonary symptoms such as difficulty breathing, cough, or fever should be evaluated promptly.
• If interstitial pneumonitis is confirmed, pemetrexed should be permanently discontinued.

Radiation recall

• Patients who previously received radiation therapy and are later treated with pemetrexed may experience a phenomenon called radiation recall, where radiation-related inflammation or blistering reoccurs.
• Monitoring for such symptoms is important, and if confirmed, pemetrexed should be discontinued.

Renal impairment

• Pemetrexed is primarily eliminated through the kidneys, so decreased kidney function can increase the risk of toxicity.
• The manufacturer does not recommend its use if creatinine clearance is below 45 mL/minute.
• Caution should be exercised when using pemetrexed concurrently with other drugs that may affect kidney function.

Fluid for third space:

• The effect of third space fluid accumulation (e.g., ascites or pleural effusions) on pemetrexed pharmacokinetics is not fully understood.
• However, studies have shown that pemetrexed concentrations in patients with mild-to-moderate ascites/pleural effusions are similar to those in patients without fluid accumulation.

Pemetrexed: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

Complete Blood Count (CBC) with differential and platelets:

• Before each treatment cycle
• On days 8 and 15 of each cycle
• As needed to monitor for low blood cell counts (nadir) and recovery

Renal Function Tests:

• Serum creatinine, creatinine clearance, blood urea nitrogen (BUN)
• Prior to each treatment cycle
• As needed to assess kidney function

Liver Function Tests:

• Total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST)
• Periodic monitoring to assess liver function
• Watch for signs/symptoms of:

Mucositis (inflammation of the mouth and throat) and diarrhea

• Pulmonary toxicity (new or worsening breathing difficulties, cough, or fever)
• Dermatologic toxicity (severe skin reactions, blisters, or peeling)
• Radiation recall (inflammation or blistering in areas previously treated with radiation)

Regular monitoring of these parameters and vigilance for any associated symptoms will help ensure the safe and effective use of pemetrexed during treatment.

How to administer Pemetrexed (Alimta)?

Intravenous (IV) Administration:

• Infuse the medication over a duration of 10 minutes.

Combination with Platinum-Based Therapy:

• When using pemetrexed in combination with platinum-based therapy (cisplatin or carboplatin), administer pemetrexed before the platinum medication.

Combination with Pembrolizumab:

• If pemetrexed and pembrolizumab are both scheduled to be administered on the same day, administer pembrolizumab first followed by pemetrexed.

Following these administration guidelines helps ensure the proper sequencing and timing of pemetrexed in combination with other medications, optimizing its effectiveness in your treatment.

Mechanism of action of Pemetrexed (Alimta):

• Pemetrexed is classified as an antifolate medication because it interferes with important cellular processes that rely on folate.
• It specifically targets enzymes like thymidylate synthase (TS), dihydrofolate reductase (DHFR), glycinamide ribonucleotide formyltransferase (GARFT), and aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT).
• These enzymes play key roles in folate metabolism and DNA synthesis, which are crucial for cell replication.
• By inhibiting these enzymes, pemetrexed disrupts the synthesis of purine and thymidine nucleotides, as well as protein production.
• This disruption ultimately impairs the ability of cancer cells to replicate and grow.

Distribution:

• Volume of distribution (V): Approximately 16.1 liters. This indicates the extent of pemetrexed's distribution throughout the body.

Protein Binding:

• Pemetrexed is highly bound to proteins in the bloodstream, with approximately 81% of the drug binding to plasma proteins. Protein binding affects the distribution and availability of the medication in the body.

Metabolism:

• Pemetrexed undergoes minimal metabolism in the body. This means that it is primarily eliminated from the body without significant metabolic transformation.

Elimination Half-life:

• In individuals with normal renal (kidney) function, the elimination half-life of pemetrexed is approximately 3.5 hours. This refers to the time it takes for half of the drug concentration in the bloodstream to decrease.

Excretion:

• Pemetrexed is primarily excreted through the urine. Around 70% to 90% of the drug is eliminated from the body unchanged, indicating that the unchanged drug is the main form excreted through urine.

International Brands of Pemetrexed:

• Alimta
• TARO-PEMEtrexed
• Armisarte
• Ciambra
• Emetex
• Empet
• Enzastar
• Jie Baili
• Mytrex
• Pemecine
• Pemeker
• Pemeted
• Pemetrex
• Pemex
• Pemirex
• Pexate
• Pleutrex
• Reladdin
• Tevatrexed
• Virplazit

Pemetrexed Brand Names in Pakistan: