Anti folates in use for cancer chemotherapy

ANTI FOLATES

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Dietary Sources
Purine Synthesis
N10-Formyl THF
MTHFC
N5, N10- methenyl THF
DHF, SAM
FADH2 5-methyl THF NADP+
Folate
HPDAN
*
NADP+ dTMP
MTX
NADPH Dihydrofolate
(DHF)
NADP+ DHFR
5-FU -
Thymidylate Synthase
Serine
Pyr. Phosph. Vit. B6
Methionine
Activated Mehtyl
Ceycl
Vit. B12 Homocysteine
S-Adenosyl- Methionine (SAM)
SHMT FADH2
dUMP
NS, N10- methylene THF
HPDAN
NADHP
MTHED
FAD
MTHFR 4,0
NADP+ 1
MS
Tetrahydrofolate (THF)
Methionine Adenosyltransferase

PTERIDINE
P ETOANZENOBAMI
GLUTAMATE
Folic acid
Dihydrofolate
Tetrahydrofolate
5-methyltetrahydrofolate

Leucovorin

Folyl polyglutamate synthetase (FPGS)

Proton-coupled folate transporter (PCFT)
• Small intestine
• Liver
• Choroid plexus
• PCT nephron
• Solid Tumors
Reduced folate carrier (RFC)
Malignant & Normal Tissues
Multidrug resistance associated proteins MRP & Breast cancer-resistance protein (BCRP)
• ATP dependant exporters
• polyglutamates are not substrates of exporters
• Over-expression assosciated with increased resistance

Methotrexate

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Methotrexate is a folate antimetabolite that inhibits DNA synthesis, repair, and cellular replication.
Methotrexate irreversibly binds to and inhibits dihydrofolate reductase, inhibiting the formation of reduced folates, thymidylate synthetase, resulting in inhibition of purine and thymidylic acid synthesis, interfering with DNA synthesis, repair, and cellular replication.
It also inhibits enzyme Aminoimidazole-4-carboxamide ribonucleotide transformoylase (AICART) &Glycinamide ribonucleotide forml transferase (GARFT)
Methotrexate is cell cycle specific for the S phase of the cycle.
Actively proliferative tissues are more susceptible to the effects of methotrexate.
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Oncology indications:
• Acutelymphoblasticleukemia(ALL)
• Gestationaltrophoblasticdiseases
• Breastcancer
• Head and neck cancer
• Cutaneous T-Cell lymphoma
• Non-Hodgkinlymphomas(NHL)
• Osteosarcoma
• Psoriasis(severe,recalcitrant, disabling) that is unresponsive to other therapies;
Nononcology uses:
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Severe, active Rheumatoid arthritis (RA) that is unresponsive to or intolerant of first-line therapy including full dose nonsteroidal anti- inflammatory agents (NSAIDs)
Active polyarticular-course juvenile idiopathic arthritis (pJIA) that is unresponsive to or intolerant of first- line therapy including full dose NSAIDs.
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SPECIAL PRECAUTIONS
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Third space accumulation: Methotrexate exits slowly from third space compartments resulting in prolonged half-life and unexpected toxicity.
In patients with significant third space accumulation, the fluid should be removed prior to treatment and methotrexate levels should be monitored.
If the fluid cannot be drained prior to therapy, a dose reduction is appropriate.
Elderly population: Elderly patients may be at increased risk for toxicity due to decreased hepatic and renal function, as well as decreased folate stores.

Fertility: Methotrexate can induce a spontaneous abortion in pregnant wome

1. ANTI FOLATES

2. Leucovorin

3. Folyl polyglutamate synthetase (FPGS )

4. Proton-coupled folate transporter (PCFT) Small intestine Liver Choroid plexus PCT nephron Solid Tumors R educed folate carrier (RFC) Malignant & Normal Tissues Multidrug resistance associated proteins MRP & Breast cancer-resistance protein (BCRP) ATP dependant exporters polyglutamates are not substrates of exporters Over-expression assosciated with increased resistance

5. Methotrexate

6. Methotrexate is a folate antimetabolite that inhibits DNA synthesis, repair, and cellular replication. Methotrexate irreversibly binds to and inhibits dihydrofolate reductase, inhibiting the formation of reduced folates, thymidylate synthetase, resulting in inhibition of purine and thymidylic acid synthesis, interfering with DNA synthesis, repair, and cellular replication. It also inhibits enzyme Aminoimidazole-4-carboxamide ribonucleotide transformoylase (AICART) &Glycinamide ribonucleotide forml transferase (GARFT) Methotrexate is cell cycle specific for the S phase of the cycle. Actively proliferative tissues are more susceptible to the effects of methotrexate.

7. Oncology indications : Acute lymphoblastic leukemia (ALL) Gestational trophoblastic diseases B reast cancer H ead and neck cancer C utaneous T-Cell lymphoma N on-Hodgkin lymphomas (NHL) O steosarcoma Nononcology uses: P soriasis (severe, recalcitrant, disabling) that is unresponsive to other therapies; S evere, active R heumatoid arthritis (RA) that is unresponsive to or intolerant of first-line therapy including full dose nonsteroidal anti-inflammatory agents (NSAIDs) A ctive polyarticular-course juvenile idiopathic arthritis (pJIA) that is unresponsive to or intolerant of first-line therapy including full dose NSAIDs.

8. SPECIAL PRECAUTIONS Third space accumulation : Methotrexate exits slowly from third space compartments resulting in prolonged half-life and unexpected toxicity. In patients with significant third space accumulation, the fluid should be removed prior to treatment and methotrexate levels should be monitored. If the fluid cannot be drained prior to therapy, a dose reduction is appropriate. Elderly population: Elderly patients may be at increased risk for toxicity due to decreased hepatic and renal function, as well as decreased folate stores.

9. Fertility: Methotrexate can induce a spontaneous abortion in pregnant women especially if given in the first trimester. Methotrexate therapy may result in impairment of fertility, oligospermia, and menstrual dysfunction in humans, during and for a short period after cessation of therapy. Pregnancy should be avoided if either partner is receiving methotrexate. Males: during and for a minimum of three months after therapy. Females: during and for at least one ovulatory cycle after therapy.

10. Pregnancy: ( FDA Pregnancy Category D ) There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective) Breastfeeding is contraindicated as methotrexate is detected in human breast milk .

11. Dosage Forms Solution, Injection: 500mg/10ml 250 mg/10 mL (10 mL); 50 mg/2 mL (2 mL) Oral: Tablet 2.5mg,5mg,7.5mg,10mg,15mg Routes of administration: IV IM SC IT Intra-arterial Oral

12. E metogenic potential: Hi gh for >1000 mg/m2 M oderate for 250-1000 mg/m2 L ow for 50-250 mg/m2 R are for <50 mg/m2

13. Dosage : Intra-venous : Dose-dense MVAC regimen: 30 mg/m2 on day 1 every 14 days (in combination with vinblastine, doxorubicin, cisplatin, and growth factor support) MVAC regimen: 30 mg/m2 on days 1, 15, and 22 every 28 days (in combination with vinblastine, doxorubicin, and cisplatin) CMF regimen: 40 mg/m2 days 1 and 8 every 4 weeks (in combination with cyclophosphamide and fluorouracil)

14. EMA-CO regimen: 100 mg/m2 IV push followed by 200 mg/m2 over 12 hours on day 1 (with leucovorin 24 hours after the start of methotrexate; in combination with dactinomycin, etoposide, vincristine, and cyclophosphamide) every 14 days Gestational trophoblastic diseases, choriocarcinoma, chorioadenoma: 15 to 30 mg IM daily for a 5-day course . EMA-EP regimen: Patients without brain metastases: 100 mg/m2 IV push followed by 200 mg/m2 over 12 hours on day 1 every 2 weeks (in combination with etoposide, leucovorin, dactinomycin, and cisplatin) Patients with brain metastases: 100 mg/m2 IV push followed by 1,000 mg/m2 over 12 hours on day 1 every 2 weeks (in combination with etoposide, leucovorin, dactinomycin, and cisplatin)

15. CODOX-M/IVAC regimen : Adults ≤65 years of age: IV: 300 mg/m2 over 1 hour (on day 10) followed by 2,700 mg/m2 over 23 hours (with leucovorin rescue). Adults >65 years of age: IV: 100 mg/m2 over 1 hour (on day 10) followed by 900 mg/m2 over 23 hours (with leucovorin rescue). Hyper-CVAD alternating with high-dose methotrexate/cytarabine regimen : IV: 1,000 mg/m2 over 24 hours on day 1 . MAP regimen: 12 g/m2 (maximum: 20 g/dose) over 4 hours (followed by leucovorin rescue) MT-R regimen: 8 g/m2 once every 2 weeks in combination with leucovorin, temozolomide, and rituximab

16. Intrathecal Dosage: 6 mg (age <1 yr) 8 mg (age 1-2 yr) 10 mg (age 2-3 yr) 12 mg (age > 3 yr) Oral: 1 week : 15-25 mg/m2 PO for one dose on day 1 and then day 3 or 4 (total dose per cycle 30-50 mg/m2 ) 4 weeks : 2.5 mg PO once or twice a day for 2 consecutive days starting on day 1 and 2 of each week* (total dose per cycle 20-40 mg)

17. DOSE MODIFICATION: RENAL DOSE MODIFICATION: HEPATIC DOSE ADJUSTMENT:

18. Adverse effects: Myelosuppression: Anemia ,Neutropenia,thrombocytopenia WBC 1st nadir 4-7 days with recovery in 7-13 days; 2nd nadir 12-21 days with recovery in 15-20 days. Platelet nadir 5-12 days with recovery in 15-27 days.

19. Hepatotoxicity: Increased serum aminotransferases (14%) and less commonly hyperbilirubinemia is seen more often in high-dose methotrexate. The liver enzymes can increase with each cycle, and usually return to pretreatment levels once methotrexate has been discontinued for 1 month. Cirrhosis and fibrosis are more often seen with chronic low-dose methotrexate.

20. Renal toxicity: High-dose methotrexate-induced renal failure is a medical emergency because methotrexate is mainly eliminated by the kidneys. Renal damage is due to precipitation of methotrexate in the tubules and to tubule injury. Drug precipitation can often be prevented by hydration and alkalization of the urine. Hydration produces a high urine output and lowers the concentration of methotrexate in the tubular fluid; alkalization of the urine increases the solubility of methotrexate. During the recovery period sustained methotrexate levels may result in substantial bone marrow and gastrointestinal toxicity. Management should include continued monitoring of methotrexate levels, administration of leucovorin (see leucovorin rescue) and alkalinized intravenous fluids until plasma levels fall below 0.05 micromol/L.

21. Pulmonary toxicity: Methotrexate-induced pulmonary toxicity can be seen with both high and low-dose methotrexate, and can be life-threatening. Pulmonary toxicity can be either symptomatic or asymptomatic and can be caused by inflammation, infection or neoplasia. Methotrexate-induced pulmonary toxicity can be acute, subacute, or chronic. Patients who experience pulmonary toxicity will often develop this within the first year of methotrexate therapy, but it can occur much earlier or much later. Subacute toxicity is the most common and includes dyspnea, non-productive cough, fever, crackles, cyanosis, pulmonary fibrosis, pleural effusions. Treatment includes discontinuing methotrexate and initiating corticosteroid therapy. Improvement can occur within days of stopping methotrexate; rechallenging with the drug is not recommended.

22. Neurologic complications: Methotrexate-induced neurotoxicities can be seen with intrathecal injection of methotrexate and with high-dose methotrexate. The neurotoxicities may be due to the accumulation of adenosine resulting from the inhibition of purine synthesis. For Intrathecal (IT) administration : Aseptic meningitis: This is the most common toxicity seen with IT administration (10%); includes headache, neck rigidity, back pain, nausea, vomiting, fever, and lethargy. Aseptic meningitis can begin 2-4 hours after the drug is injected, and can last 12-72 hours. There is usually no treatment required; the risk of developing this can be decreased by the administration of IT hydrocortisone, or oral corticosteroids. Patients may be rechallenged.

23. Transverse myelopathy: This is much less common; includes isolated spinal cord dysfunction over hours or days. Transverse myelopathy can begin between 30 minutes and 48 hours after treatment. This is more common with concurrent radiotherapy or frequent IT injections of methotrexate. Recovery from this condition is variable. Patients are not rechallenged.

24. Leukoencephalopathy: This can be a delayed complication and is more common in patients receiving whole brain radiotherapy or previous IV methotrexate. Symptoms include confusion, irritability, somnolence, ataxia, dementia, and occasionally seizures and coma. Encephalopathy, seizures, neurologic deficits, lumbosacral radiculopathy, neurogenic pulmonary edema, and sudden death can rarely occur. Can be rechallenged but recurs in 10 - 50 % cases.

25. For high-dose methotrexate (> 1000 mg/m2) : Acute neurotoxicity: includes somnolence, confusion, and seizures within 24 hours of treatment. These usually resolve spontaneously; rechallenge is possible. Subacute neurotoxicity: seen with weekly or every two week administration. “Stroke-like” syndrome, including transient neurologic deficits, confusion, and seizures. Occurring about 6 days after drug administration, lasting from 15 minutes to 72 hours and then resolving. Rechallenge is possible.

26. Other adverse effects: Mucositis Dermatologic: acne,alopecia, dermatitis,erythema multiforme (Stevens-Johnson syndrome), exfoliative dermatitis,photosensitivity,pigmentary changes ,pruritus,rash telangiectasia ,urticaria. Gastrointestinal: Diarrhea (≤11%), nausea and vomiting (≤11%), stomatitis (2% to 10%), abdominal distress, anorexia, aphthous stomatitis, enteritis, gastrointestinal hemorrhage, gingivitis, hematemesis, intestinal perforation, melena, pancreatitis. Endocrine & metabolic: Decreased libido, diabetes mellitus, gynecomastia, menstrual disorders. Ophthalmic: Blurred vision, conjunctivitis, eye pain, visual disturbance

27. CLASSIFICATION OF METHOTREXATE DOSE : HIGH DOSE MTX -- >500 mg/ M2 INTERMEDIATE DOSE MTX -- 50 - 500 mg / m2 LOW DOSE MTX -- < 50 mg/ m2 Leucovorin rescue is rarely needed when dose < 250 mg/m2.

28. H igh-dose MTX (HDMTX) is defined as doses ≥500 mg/m2, which are commonly used for central nervous system (CNS) prophylaxis in patients with leukemia , high-risk lymphoma, treatment of leptomeningeal metastases, primary CNS lymphoma, and osteosarcoma. These regimens deliver an otherwise lethal dose of MTX in a 4 to 36 hour infusion, and require a two to three day period of multiple leucovorin doses to terminate the toxic effect of MTX (termed leucovorin "rescue"). Successful rescue by leucovorin depends on rapid elimination of MTX by the kidneys, which requires aggressive pretreatment as well as posttreatment hydration and urinary alkalinization. The main toxicities of HDMTX are elevated serum transaminase levels and renal insufficiency, which can delay drug clearance .

29. Rationale of High dose methotrexate: The rationale for high-dose MTX is that high blood and extracellular drug levels facilitate diffusion of drug into the core of solid tumors and passive diffusion across the tumor cell membrane, where carrier mediated transport might be compromised. Protection of normal tissues is achieved by the subsequent administration of low doses of Leucovorin (5-formylTHF; leucovorin) following treatment with MTX. Presumably, leucovorin has access to bone marrow and intestinal cells via an intact vascular supply to these normal tissues, and intact membrane transport, while delivery to tumor cells is limited by the low blood levels of the rescue agent, the compromised vascular supply, and impaired transport across the tumor cell membrane. Additionally, as the MTX blood level falls, leucovorin concentrations in the blood are sufficiently high to competitively inhibit MTX transport into normal cells via RFC, (a transport mechanism that MTX and leucovorin share), allowing the MRP exporters to pump the drug, unopposed, out of these cells.

30. When significant intracellular levels are present, MTX is polyglutamated by enzyme Folyl polyglutamate synthetase (FPGS) . C onversion to polyglutamated MTX (PGMTX) does not occur until cells have been exposed to the drug for at least six hours at concentrations of at least 2 micromoles/liter (2 microM, 2 X 10 [-6] M). These concentrations are easily achievable in plasma with high-dose MTX (HDMTX) but not with intermediate or low-dose regimens. Polyglutamation:

31. The accumulation of PGMTX metabolites serves to further amplify and prolong the antiproliferative effects of MTX: ●Intracellular accumulation and decreased efflux of PGMTX enhances and prolongs inhibition of DHFR, since PGMTX is less readily dissociable from the enzyme than is free MTX . ●Polyglutamated forms of MTX also bind to other enzymes involved in DNA synthesis such as TS, AICARFT, and GARFT; this further depletes intracellular thymidine and inhibits purine synthesis Inhibition of TS also leads to accumulation of dUMP, which cannot be incorporated into DNA, further disrupting DNA synthesis and repair

32. Administration: Pretreatment assessment of renal function is needed prior to each dose; if feasible, third-space fluid collections (pleural effusions, ascites) should be drained prior to treatment, as they provide a drug reservoir that prolongs MTX excretion. Several drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), phenytoin, ciprofloxacin, probenecid, amiodarone, proton pump inhibitors, and levetiracetam, may delay elimination, and their use should be avoided, if possible, during HDMTX treatment. Maintaining adequate hydration and urine output is essential for rapid clearance of HDMTX. Aggressive hydration (2.5 to 3.5 liters of intravenous [IV] fluid/m2 per day) should start 4 to 12 hours before the MTX infusion is begun and should continue until plasma MTX levels are ≤0.1 microM.

33. Urinary alkalinization, usually with sodium bicarbonate added to each liter of IV fluid hydration, should be used to maintain the urine pH ≥7.0 until plasma MTX levels are below 0.1 microM. Hydration recommended is 2.5-3.5 L/m2. A typical choice is IV D5W or NS with 100 to 150 mEq of sodium bicarbonate per liter, administered by continuous infusion at 125 to 150 mL/hour. Alternatively, sodium bicarbonate dosing can be accomplished intermittently either by the IV or oral route .

34. Serum creatinine and electrolytes as well as plasma MTX levels should be followed daily. A rise in the serum creatinine above normal values indicates renal dysfunction and the potential for delayed MTX elimination. Early studies conducted in the 1970s revealed that the following drug levels after MTX infusion indicated a high risk for bone marrow and gastrointestinal mucosal toxicity : ●Levels above 5 to 10 microM at 24 hours ●Levels above 0.9 to 1 microM at 48 hours ●Levels above 0.1 microM at 72 hours MONITORING PARAMETERS:

35. Leucovorin administration — Leucovorin rescue should be started within 24 to 36 hours of the start of the MTX infusion. Most patients receive a racemic mixture of d,l-leucovorin (leucovorin or leucovorin calcium). However, the l-isomer is the biologically active moiety (ie, has the capacity to rescue cells from MTX toxicity ), and an IV preparation of l-leucovorin is now commercially available in the United States (LEVOleucovorin, Fusilev, Khapzory). It is dosed at one-half that of d,l leucovorin.

36. A variety of dosing schedules have been published for leucovorin, but most administer 10 mg/m2 IV or 15 mg/m2 of leucovorin calcium orally , every six hours until plasma MTX levels are less than 0.05 to 0.1 microM . In contrast, higher concentrations of leucovorin are needed if rapid elimination of MTX is compromised by renal insufficiency.

37. Oral versus intravenous : Orally administered leucovorin can successfully reverse MTX toxicity. The inactive d-isomer has a longer plasma half-life than the active l-isomer and repeated parenteral administration of the d,l racemic mixture may result in selective accumulation of the inactive d-isomer, which could, at least in theory, compete with the active isomer for cellular uptake, compromising efficacy. Since the active l-isomer is preferentially absorbed from the intestinal tract, oral rather than IV administration of leucovorin calcium may be preferred in this setting as long as the dose is 25 mg or less (oral bioavailability is reduced at doses 40 mg and above ). LEVOleucovorin is not available as an oral preparation. For doses higher than 25 mg, oral bioavailability of the active l-isomer is significantly decreased, and IV administration of either the d,l racemic mixture or levoleucovorin is preferred.

38. Leucovorin calcium dosing: Normal methotrexate elimination (serum methotrexate level ~10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and <0. 1 micromolar at 72 hours): Leucovorin calcium 15 mg (oral, IM, or IV) every 6 hours for 60 hours (10 doses) beginning 24 -36 hours after the start of methotrexate infusion Delayed late methotrexate elimination (serum methotrexate level remaining >0.2 micromolar at 72 hours and >0.05 micromolar at 96 hours after administration) : Continue leucovorin calcium 15 mg (oral, IM or IV) every 6 hours until methotrexate level is <0.05 micromolar . Delayed early methotrexate elimination and/or acute renal injury (serum methotrexate level ≥50 micromolar at 24 hours, or ≥5 micromolar at 48 hours, or a doubling of serum creatinine level at 24 hours after methotrexate administration): Leucovorin calcium 150 mg IV every 3 hours until methotrexate level is <1 micromolar, then 15 mg IV every 3 hours until methotrexate level <0.05 micromolar .

39. Abnormal Methotrexate levels: At 24 hours: For methotrexate levels of ≥100 micromolar at ~24 hours, leucovorin is initially dosed at 1,000 mg/m2 IV every 6 hours For methotrexate levels of ≥10 to <100 micromolar at 24 hours, leucovorin is initially dosed at 100 mg/m2 IV every 3 or 6 hours For methotrexate levels of ~1 to 10 micromolar at 24 hours, leucovorin is initially dosed at 10 mg/m2 IV or orally every 3 or 6 hours .

40. At 48 hours: For methotrexate levels of ≥100 micromolar at 48 hours, leucovorin is dosed at 1,000 mg/m2 IV every 6 hours For methotrexate levels of ≥10 to <100 micromolar at 48 hours, leucovorin is dosed at 100 mg/m2 IV every 3 hours For methotrexate levels of ~1 to 10 micromolar at 48 hours, leucovorin is dosed at 100 mg/m2 IV every 6 hours or 10 mg/m2 IV or orally to 100 mg/m2 IV every 3 hours

41. At 72 hours: For methotrexate levels of ≥10 micromolar at 72 hours, leucovorin is dosed at 100 to 1,000 mg/m2 IV every 3 to 6 hours For methotrexate levels of ~1 to 10 micromolar at 72 hours, leucovorin is dosed at 10 mg/m2 IV or orally to 100 mg/m2 IV every 3 hours For methotrexate levels of ~0.1 to 1 micromolar at 72 hours, leucovorin is dosed at 10 mg/m2 IV or orally every 3 to 6 hours If serum creatinine is increased more than 50% above baseline, increase the standard leucovorin dose to 100 mg/m2 IV every 3 hours, then adjust according to methotrexate levels above. Follow methotrexate levels daily, leucovorin may be discontinued when methotrexate level is <0.1 micromolar .

42. GLUCARPIDASE : Glucarpidase (carboxypeptidase-G2, CPDG2, VORAXAZE®) is a recombinant bacterial enzyme that inactivates extracellular methotrexate to 2,4-diamino-N10–methylpteroic acid [DAMPA]. Glucarpidase can rapidly lower serum methotrexate levels by >95% within 15 minutes of administration. Glucarpidase can be used to treat patients at risk for methotrexate toxicity secondary to delayed elimination .

43. Dose: 50 units/kg IV over 5 minutes For methotrexate level > 100 micromol/L, may give second dose of glucarpidase 48 hours after administration of first dose. High-dose leucovorin ( 1000 mg/m2 IV every 6 hours) should be given prior to the receipt and administration of glucarpidase. Leucovorin should be given at least 2-4 hours before or after administration of glucarpidase. After administration of glucarpidase, leucovorin should be continued at a high dose of 250 mg/m2 IV every 6 hours for a total of 48 hours; after that time, leucovorin rescue should be modified based on methotrexate levels and clinical signs of toxicity.

44. Pemetrexed Pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), glycinamide ribonucleotide formyltransferase (GARFT), and aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT), the enzymes involved in folate metabolism and DNA synthesis, resulting in inhibition of purine and thymidine nucleotide and protein synthesis. Mechanism of action :

45. Pharmacokinetics

46. Dosage Forms : Solution Reconstituted, Intravenous: Alimta: 500 mg (1 ea) Solution Reconstituted, Intravenous [preservative free]: Alimta: 100 mg (1 ea) Administration: Reconstitute with NS (preservative free); add 4.2 mL to the 100 mg vial and 20 mL to the 500 mg vial, resulting in a 25 mg/mL concentration. Gently swirl until powder is completely dissolved. Solution may be colorless to green-yellow. Further dilute in 100 mL NS prior to infusion (the manufacturer recommends a total volume of 100 mL) It is administred IV over 10mins.

47. Special considerations: Start vitamin supplements 1 week before initial pemetrexed dose: Folic acid 400 to 1,000 mcg orally once daily (begin 7 days prior to treatment initiation; continue daily during treatment and for 21 days after last pemetrexed dose) and vitamin B12 1,000 mcg IM 7 days prior to treatment initiation and then every 3 cycles. Give dexamethasone 4 mg orally twice daily for 3 days, beginning the day before treatment to minimize cutaneous reactions. New treatment cycles should not begin unless ANC ≥1,500/mm3, platelets ≥100,000/mm3, CrCl ≥45 mL/minute, and recovery of nonhematologic toxicity to ≤ grade 2.

48. Effects on Fertility & pregnancy: Females of reproductive potential should use effective contraception during treatment and for at least 6 months after the last pemetrexed dose. Males with female partners of reproductive potential should use effective contraception during treatment and for 3 months after the last pemetrexed dose. Pemetrexed may impair fertility in males. There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk Breastfeeding is not recommended due to the potential secretion into breast milk.

49. Indications: Mesothelioma Non small cell lung cancer(non squamous ) OFF label indications : Bladder cancer, metastatic Cervical cancer, persistent or recurrent Malignant pleural mesothelioma (single agent and off-label combination) Ovarian cancer, platinum-resistant Thymic malignancies, metastatic Dose: 500 mg/m2 on day 1 of each 21-day cycle.

50. Dose adjustment: Haematologic: ANC <500/mm3 and platelets ≥50,000/mm3: Reduce pemetrexed dose to 75% of previous dose Platelets <50,000/mm3 without bleeding: Reduce pemetrexed dose to 75% of previous dose Platelets <50,000/mm3 with bleeding: Reduce pemetrexed dose to 50% of previous dose Recurrent grade 3 or 4 myelosuppression after 2 dose reductions: Discontinue

51. Non Haematologic: Grade 3 or 4 diarrhea or any diarrhea requiring hospitalization: Reduce pemetrexed dose to 75% of previous dose Grade 3 or 4 mucositis: Reduce pemetrexed dose to 50% of previous dose Grade 3 or 4 neurotoxicity: Permanently discontinue Interstitial pneumonitis: Permanently discontinue Radiation recall signs/symptoms: Permanently discontinue Severe or life-threatening dermatologic toxicity: Permanently discontinue Recurrent grade 3 or 4 nonhematologic toxicity after 2 dose reductions: Permanently discontinue

52. Side effects: Fatigue . Desquamation , skin rash . Nausea , anorexia , vomiting, stomatitis , diarrhea . Anemia , neutropenia . Pharyngitis

53. PRALATREXATE: Mechanism of Action : Pralatrexate is an antifolate analog; inhibits DNA, RNA, and protein synthesis by selectively entering cells expressing reduced folate carrier (RFC-1), is polyglutamylated by folylpolyglutamate synthetase (FPGS) and then competes for the DHFR-folate binding site to inhibit dihydrofolate reductase (DHFR) . Pharmackinetics: Distribution: S-diastereomer: 105 L; R-diastereomer: 37 L Protein binding: ~67% Metabolism: Not significantly metabolized by phase I hepatic isoenzymes or phase II glucuronidases Half-life elimination: 12 to 18 hours Excretion: Urine (~34% as unchanged drug; parent drug [racemic pralatrexate]: ~39%); Feces (34%); Respiratory (10% [exhaled])

54. Availability: Solution, Intravenous [preservative free]: Folotyn: 20 mg/mL (1 mL); 40 mg/2 mL (2 mL) Dose & Administration: Peripheral T-cell lymphoma (PTCL), relapsed or refractory: IV: 30 mg/m2 once weekly for 6 weeks of a 7-week treatment cycle; continue until disease progression or unacceptable toxicity Cutaneous T-cell lymphoma, relapsed or refractory (off-label use): IV: 15 mg/m2 once weekly for 3 weeks of a 4-week treatment cycle

55. Administration: Initiate vitamin supplements before initial pralatrexate dose: Folic acid 1 to 1.25 mg/day orally beginning 10 days prior to initial pralatrexate dose; continue during treatment and for 30 days after last pralatrexate dose; vitamin B12 1,000 mcg IM within 10 weeks prior to initial pralatrexate dose and every 8 to 10 weeks thereafter. Prior to administering any dose, mucositis should be ≤ grade 1 and absolute neutrophil count (ANC) should be ≥1,000/mm3; platelets should be ≥100,000/mm3 for the first dose and ≥50,000/mm3 for subsequent doses. Low emetogenic potential. Administer IV push (undiluted) over 3 to 5 minutes into the line of a free-flowing normal saline IV .

56. Renal Impairment: Peripheral T-cell lymphoma, relapsed or refractory: eGFR ≥30 mL/minute/1.73 m2: No dosage adjustment necessary. eGFR 15 to <30 mL/minute/1.73 m2: Initial: Reduce dose to 15 mg/m2; monitor renal function and further reduce dose if necessary based on toxicity. End-stage renal disease, including dialysis: Avoid use; if the potential benefit outweighs risks, monitor renal function and reduce dose based on toxicity. Toxicities: Grade 3: Omit dose; when recovered to ≤ grade 2, resume pralatrexate at a reduced dose . Grade 4: Discontinue treatment.

57. Hematologic toxicity: Platelets: <50,000/mm3 (for 1-week duration): Omit dose; continue at previous dose if platelets recover within 1 week. <50,000/mm3 (for 2-week duration): Omit dose; decrease to 20 mg/m2 (10 mg/m2 in patients with eGFR 15 to <30 mL/minute/1.73 m2) if platelets recover within 2 weeks. <50,000/mm3 (for 3-week duration): Discontinue treatment.

58. ANC: 500 to 1,000/mm3 without fever (for 1-week duration): Omit dose; continue at previous dose if ANC recovers within 1 week. 500 to 1,000/mm3 with fever or ANC <500/mm3 (for 1-week duration): Omit dose, give growth factor support; continue at previous dose (with growth factor support) if ANC recovers within 1 week. 500 to 1,000/mm3 with fever or ANC <500/mm3 (recurrent or for 2-week duration): Omit dose and give growth factor support; decrease to 20 mg/m2 with growth factor support if ANC recovers within 2 weeks. 500 to 1,000/mm3 with fever or ANC <500/mm3 (second recurrence or for 3 week duration): Discontinue treatment.

59. Nonhematologic toxicity: Mucositis (on day of treatment): Grade 2: Omit dose; continue at previous dose when recovers to ≤ grade 1. Grade 3 or recurrent grade 2: Omit dose and decrease to 20 mg/m2 when recovers to ≤ grade 1. Grade 4: Discontinue treatment. Nonhematologic toxicity (other than mucositis): Grade 3: Omit dose; decrease to 20 mg/m2 when recovers to ≤ grade 2. Grade 4: Discontinue treatment.

60. Side effects: Fatigue Skin rash, pruritus. Mucositis , nausea , constipation , vomiting , diarrhea, anorexia , abdominal pain . Thrombocytopenia , anemia , neutropenia , leukopenia Increased serum transaminases Miscellaneous: Fever (32%)

61. RALTITREXED: Mechanism of Action : Raltitrexed is a folate analogue that selectively inhibits thymidylate synthase, blocking purine synthesis. This results in an overall inhibition of DNA synthesis. Pharmacokinetics: Protein binding: 93% Excretion: Urine (~50% as unchanged drug); feces (~15%) Half-life elimination: 198 hours

62. Used in treatment of advanced stage colon cancer and malignant mesothelioma , used in canada & European countries but not approved by US FDA. Availabile as Solution Reconstituted, Intravenous (Tomudex) 2 mg . Administered as an infusion over 15 minutes. Dose :3 mg/m2 once every 3 weeks. Treatment should be administered only if ANC >2,000/mm3, and platelets >100,000/mm3

63. Adjustment for Toxicity: Grade 4 gastrointestinal toxicity or grade 3 gastrointestinal toxicity in combination with grade 4 hematologic toxicity: Discontinue therapy and manage with supportive measures (consider administering leucovorin). Grade 3 hematologic toxicity or grade 2 gastrointestinal toxicity : Reduce dose by 25%. Grade 4 hematologic toxicity or grade 3 gastrointestinal toxicity : Reduce dose by 50%.

64. Renal Impairment: CrCl >65 mL/minute - No dosage adjustment necessary. CrCl 55 to 65 mL/minute: Reduce dose to 75% of usual dose once every 4 weeks. CrCl 25 to 54 mL/minute: Reduce dose to percentage of dose equivalent to CrCl once every 4 weeks (eg, reduce dose to 25% of usual dose for CrCl of 25 mL/minute) CrCl <25 mL/minute: Do not administer (use is contraindicated in severe renal impairment) Hepatic Impairment: Preexisting impairment: Use is not recommended in clinical jaundice or decompensated liver disease. Mild to moderate impairment: No dosage adjustment necessary; use with caution. Severe impairment: Use is contraindicated. Hepatotoxicity during treatment: Interrupt therapy until toxicity returns to grade 2 or lower.

65. Dermatologic: Skin rash Gastrointestinal: Nausea , diarrhea , vomiting , anorexia , abdominal pain mucositis Hematologic & oncologic: Leukopenia nadir within 7 to 14 days, recovery by 21 days), anemia . Hepatic: Increased serum AST , increased serum ALT Neuromuscular & skeletal: Weakness Miscellaneous: Fever Side effects:

66. THANK YOU