Pemetrexed; Uses, Dosage, Side Effects, Interaction, Pregnanc

Pemetrexed is a synthetic pyrimidine-based antifolate. Pemetrexed binds to and inhibits the enzyme thymidylate synthase (TS), which catalyzes the methylation of 2′-deoxyuridine-5′-monophosphate (dUMP) to 2′-deoxythymidine-5′-monophosphate (dTMP), an essential precursor in DNA synthesis.

Pemetrexed is a Folate Analog Metabolic Inhibitor. The mechanism of action of pemetrexed is as a Folic Acid Metabolism Inhibitor.

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Pemetrexed is a chemotherapy drug manufactured and marketed by Eli Lilly and Company. Its indications are the treatment of pleural mesothelioma as well as non-small cell lung cancer.It is a novel pyrrolo[2,3-d]pyrimidine-based antifolate ]. It gains entry to the cell via the reduced folate carrier. Once inside the cell, the antifolate is polyglutamated by folylpolyglutamate synthase, an enzyme for which it shows high affinity. Pemetrexed and its tri- and pentaglutamate derivatives demonstrate.

Mechanism of Action of Pemetrexed

Pemetrexed is an antifolate containing the pyrrolopyrimidine-based nucleus that exerts its antineoplastic activity by disrupting folate-dependent metabolic processes essential for cell replication. In vitro studies have shown that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), all folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is transported into cells by both 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. Polyglutamation is a time- and concentration-dependent process that occurs in tumor cells and, to a lesser extent, in normal tissues. Polyglutamated metabolites have an increased intracellular half-life resulting in prolonged drug action in malignant cells.

Indications of Pemetrexed

• Malignant pleural mesothelioma in patients who cannot be treated with surgery.
• Non-small cell lung cancer (certain types) in patients whose disease is locally advanced or has metastasized (spread to other parts of the body).
• Treatment of pleural mesothelioma and non-small cell lung cancer.
• Malignant Pleural Mesothelioma
• Non-Small Cell Lung Cancer
• Cancer of the Ovary
• Mesothelioma
• Pleural Mesotheliomas
• Urothelial carcinoma ureter metastatic
• Locally advanced nonsquamous non-small cell lung cancer
• Metastatic nonsquamous non-small cell lung cancer
• Recurrent, IV-B Cervical cancer
• Unresectable Thymoma
• Treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery in combination with cisplatin.

Contra-Indications of Pemetrexed

• Diabetes
• Overweight
• Anemia
• Decreased blood platelets
• Decreased neutrophils a type of white blood cell
• Fluid accumulation in the brain
• High blood pressure
• Coronary artery disease
• Fluid in the covering of the heart or pericardium
• Heart valve disease
• Chronic heart failure
• Failure of the left ventricle of the heart
• Inflammation of the middle tissue heart muscle
• Bleeding
• Escape of fluid into the lungs
• Fluid in the lungs
• Liver problems
• Severe liver disease
• Bleeding of the stomach or intestines
• Kidney disease with reduction in kidney function
• Heart disease present at birth
• Visible water retention
• Blood circulation failure due to the Serious heart condition

Dosage of Pemetrexed

• Strengths: 100 mg ; 500 mg;

Malignant Pleural Mesothelioma

• 500 mg/m2 IV over 10 minutes on day 1 of each 21 day cycle along with cisplatin
• Cisplatin 75 mg/m2 infused over 2 hours beginning approximately 30 minutes after the end of the pemetrexed administration. Patients should receive hydration consistent with local practice prior to and/or after receiving cisplatin.

PREMEDICATION REGIMEN AND CONCURRENT MEDICATIONS

Vitamin Supplementation

• Patients should initiate folic acid 400 to 1000 mcg orally once daily beginning 7 days before the first dose of chemotherapy. Folic acid should be continued during the full course of therapy and for 21 days after the last dose.
• Vitamin B12 1 mg should be administered IM 1 week prior to the first dose of chemotherapy and every 3 cycles thereafter.
• Subsequent vitamin B12 injections may be given the same day as treatment.

Corticosteroids

• Dexamethasone 4 mg orally 2 times a day the day before, the day of, and the day after chemotherapy administration.

Non-Small Cell Lung Cancer

COMBINATION USE WITH CISPLATIN FOR NONSQUAMOUS NON-SMALL CELL LUNG CANCER

• 500 mg/m2 IV over 10 minutes on day 1 of each 21 day cycle along with cisplatin
• Cisplatin 75 mg/m2 infused over 2 hours beginning approximately 30 minutes after the end of the pemetrexed administration. Patients should receive hydration consistent with local practice prior to and/or after receiving cisplatin.

AS A SINGLE AGENT FOR NONSQUAMOUS NON-SMALL CELL LUNG CANCER MAINTENANCE AND NONSQUAMOUS NON-SMALL LUNG CANCER AFTER PRIOR CHEMOTHERAPY

• 500 mg/m2 IV over 10 minutes on day 1 of each 21 day cycle

PREMEDICATION REGIMEN AND CONCURRENT MEDICATIONS

Vitamin Supplementation

• Patients should initiate folic acid 400 to 1000 mcg orally once daily beginning 7 days before the first dose of chemotherapy. Folic acid should be continued during the full course of therapy and for 21 days after the last dose.
• Vitamin B12 1 mg should be administered IM 1 week prior to the first dose of chemotherapy and every 3 cycles thereafter.
• Subsequent vitamin B12 injections may be given the same day as treatment.

Corticosteroids

• Dexamethasone 4 mg orally 2 times a day the day before, the day of, and the day after chemotherapy administration.

Side Effects of Pemetrexed

The most common

• certainly hair loss
• chest pain
• headache
• joint painPain
• dizziness
• nausea and vomiting
• Severe stomach ache
• epigastric pain,
• diarrheaa,
• anorexia,
• flatulence,
• headache,
• dizziness,
•  fainting, fast or pounding heartbeats.

More common

• Fast or irregular heartbeat
• appetite loss
• changes in nails
• constipation
• fatigue
• fever
• Back pain
• dizziness
• headache
• increased cough
• Acid or sour stomach
• decreased appetite
• Agitation
• chest congestion
• chest pain
• cold sweats
• confusion
• decreased sexual ability or desire
• stomach or abdominal cramps, gas, or pain
• trouble sleeping

Less common

• bleeding gums
• blood in the urine or stools
• chest pain
• diarrhea
• Burning, crawling, itching, numbness, prickling, “pins and needles“, or tingling feelings
• difficulty in moving
• muscle stiffness
• redness of the face, neck, arms and occasionally, upper chest
• lack or loss of strength
• muscle spasm
• difficult or labored breathing
• dry mouth
• headache
• irritability
• lack or loss of strength
• loose stools
• loss of interest or pleasure
• muscle stiffness
• night sweats
• passing gas
• stomach discomfort, upset, or pain
• swollen joints
• trouble concentrating
• increased blood pressure

Drug Interactions of Pemetrexed

Imatinib may interact with the following drugs, suppliments & may decrease the efficacy of the drug.

• alpha blockers (e.g., alfuzosin, doxazosin, silodosin, tamsulosin)
• anticancer medications (e.g., cabazitaxel, docetaxel, doxorubicin, etoposide, ifosfamide, irinotecan, vincristine)
• “azole” antifungal medications (e.g.,  fluconazole, itraconazole, ketoconazole)
• beta-blockers (e.g., atenolol, propranolol, metoprolol)
• barbiturates (e.g., butalbital, pentobarbital, phenobarbital)
• benzodiazepines (e.g., chlordiazepoxide, clonazepam, diazepam, lorazepam)
• calcium channel blockers (e.g., nifedipine, diltiazem, verapamil, amlodipine, felodipine)
• bupropion
• estrogen and estrogen-containing birth control (women)
• medications that promote loss of bone density (e.g., prednisone)
• testosterone and androgens (men)
• corticosteroids (e.g., dexamethasone, prednisone, methylprednisolone)
• cyclosporine
• “gliptin” diabetes medications (e.g., linagliptin, saxagliptin, sitagliptin)
• losartan
• macrolide antibiotics (e.g., azithromycin, clarithromycin, erythromycin)
• metronidazole
• montelukast
• norfloxacin
• ondansetron
• carbamazepine
• phenytoin
• proton pump inhibitors (PPIs; e.g., esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole)
• selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, duloxetine, fluoxetine,paroxetine, sertraline)
• sildenafil
• “statin” anticholesterol medications (e.g., atorvastatin, lovastatin, simvastatin)
• tadalafil
• tamoxifen
• tetracycline
• theophylline
• tocilizumab
• tolterodine
• tramadol
• other selective serotonin reuptake inhibitors (SSRIs;e.g., citalopram, fluoxetine, sertraline)
• 5-HT3 antagonists (e.g., granisetron, ondansetron)
• tamsulosin
• tapentadol
• thiazide diuretics (e.g., hydrochlorothiazide, indapamide)
• tramadol
• tricyclic antidepressants (e.g., nortriptyline, amitriptyline, imipramine, 
• trimethoprim
• other tyrosine kinase inhibitors (e.g., dasatinib, imatinib, nilotinib, sunitinib)
• tetracycline
• tocilizumab
• warfarin

The avobe list is complete or probable drugs interactions list. Before using this drug always consult your oncologist.

Pregnancy & Lactation of Pemetrexed

 FDA Pregnancy Category D

Pregnancy

This medication may harm a fetus or baby. Women who could become pregnant should have a negative blood pregnancy test before starting this medication and should use effective contraception to prevent pregnancy during treatment. If you become pregnant while receiving this medication, contact your doctor immediately.

Lactation

It is not known if pemetrexed passes into breast milk. Women should not breast-feed while receiving this medication.The safety and effectiveness of using this medication have not been established for children.

Self-Care Tips

• Folic acid supplementation should be started before you first dose of pemetrexed, continued during your course of therapy, and should continue until 21 days after your last dose of pemetrexed. Vitamin B12 is to be given 1 week before your first dose of pemetrexed, with doses of vitamin B12 every 9 week thereafter. Folic acid and vitamin B12 are used to minimize some of the side effects of pemetrexed.
• Drink at least two to three quarts of fluid every 24 hours, unless you are instructed otherwise.
• You may be at risk of infection so try to avoid crowds or people with colds and those not feeling well, and report fever or any other signs of infection immediately to your health care provider.
• Wash your hands often.
• Use an electric razor and a soft toothbrush to minimize bleeding.
• Avoid contact sports or activities that could cause injury.
• To reduce nausea, take anti-nausea medications as prescribed by your doctor, and eat small, frequent meals.
• Avoid sun exposure. Wear SPF 15 (or higher) sunblock and protective clothing.
• In general, drinking alcoholic beverages should be kept to a minimum or avoided completely. You should discuss this with your doctor.
• Get plenty of rest.
• Maintain good nutrition.
• Keep your bowels moving. Your health care provider may prescribe a stool softener to help prevent constipation that may be caused by this medicine.
• For flu-like symptoms, keep warm with blankets and drink plenty of liquids. There are medications that can help reduce the discomfort caused by chills.
• Acetaminophen may help relieve discomfort from fever, headache and/or generalized aches and pains. However, be sure to talk with your doctor before taking it.
• If you experience symptoms or side effects, be sure to discuss them with your health care team. They can prescribe medications and/or offer other suggestions that are effective in managing such problems.

References

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