Systemic Therapy Program

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Document Type

Drug Monographs
Treatment Regimens

Scientific Name:
PEMETREXED
Brand Name(s):
Alimta®

Drug Monograph

Pharmacology

Mechanism of Action

Pemetrexed is an antifolate agent that inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), thus blocking purine synthesis. Pemetrexed is transported into cells by the membrane folate binding protein transport systems and the reduced folate carrier.  In the cell, pemetrexed is polygutamated by folyl polyglutamate syntase.  It is the polyglutamate forms which are potent inhibitors of TS and GARFT.  Polyglutamation is time- and concentration-dependant in tumour cells and, to a lesser extent, normal cells.  Polyglutamated metabolites have an increased intracellular half-life and a prolonged drug action in malignant cells.

Pharmacokinetics

Oral Absorption:
no information
Distribution:
AUC does not change over multiple cycles, but increases if renal function impaired
cross blood brain barrier? No information
Vd: 16.1L 
PPB: 81%
Metabolism:
minimal metabolism
metabolite(s): no information
Excretion:
primarily renal excretion- 70-90% total dose as unchanged drug in urine in first 24 hours
Elimination  t½ = 3.5 hours (normal renal function)
Cl: 91.8 mL/min; increased in patients with renal dysfunction

Side Effects

Side effects (especially myelosuppression and nausea & vomiting) are increased when patients do not receive supplementation with folic acid and vitamin B12
IMMEDIATE ONSET (hours to days)
    nausea (39-84%), vomiting (25-58%)
EARLY ONSET  (days to weeks)
* myelosuppression: anemia (33%-10% severe), leukopenia (13-55%- 4-16% severe), neutropenia (11-58%; 3-24% severe), thrombocytopenia (9-27%- 2-5% severe)
* thrombosis/embolism 4-7%
* cardiac ischemia 3%- severe
* fever (26%), infection (25-30%)
   fatigue (80-87% -16% severe)
   anorexia (35-62%), constipation (30-44%), stomatitis/pharyngitis (26-28%), diarrhea (21%)
   skin rash/desquamation (17-22%)
   hepatotoxicity- Increased liver enzymes (↑ALT 10%, ↑AST 8%)
   nephrotoxicity- decreased creatinine clearance (5%), renal failure (<1%)
   edema 19%
   myalgia 13%, arthralgia 8%
   alopecia 11%
   dyspnea 26-66%
* chest pain 38-40%
   neuropathy/sensory 17-29%
  mood alteration/depression 11-14%
  allergic reaction/ hypersensitivity 8%
Side effects which are slightly increased when pemetrexed added to cisplatin
IMMEDIATE ONSET (hours to days)
   nausea (84%), vomiting (58%)
EARLY ONSET  (days to weeks)
* myelosuppression (58% neutropenia, 33% anemia, 27% thrombocytopenia)
   diarrhea (26%)
* fever (17%), infection (11%)
   stomatitis/pharyngitis (28%)
   skin rash/desquamation (22%)
   fatigue (80%), constipation (44%), anorexia (35%)

Therapeutics

Approved Indications

• In combination with cisplatin for the treatment of patients with malignant pleural mesothelioma which is unresectable or not a surgical candidate
• As a single-agent for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after prior chemotherapy.

Routes

Intravenous infusion over 10 minutes.

Administration

• Mix in 100 mL minibag (Normal Saline); Infuse over 10 minutes
• Pretreatment with dexamethasone 4 mg PO BID for 3 days (on the day before, the day of and the day after treatment)
• Pretreatment with folic acid 400 mcg daily for at least 5 of 7 days preceding pemetrexed treatment (may use a multivitamin preparation wihich includes 5 mg folic acid), and vitamin B12 1000 mcg IM injection one week before first dose of pemetrexed and every 3 cycles thereafter.

IV Compatibility

Sodium chloride 0.9% (preservative-free)
NOT compatible with calcium-containing diluents.

Dosing

Intravenous:
3 week:
• 500 mg/m² IV for one dose on day 1, followed 30 minutes later by cisplatin 75 mg/m² IV

Pediatric:
• Safety & effectiveness not established

Dose Adjustment Criteria

Renal Failure:  (Suggested action)
• If Cr Cl < 45mL/min, OMIT pemetrexed dose
Hematologic Toxicities: (Suggested action)
• If ANC <  0.5 x 109/L and platelets > 50 x 109/L, reduce to 75% dose
• If platelets > 50 x 109/L, reduce to 50% dose
Non-Hematologic Toxicities: (Suggested action)
• If Grade 3 or 4 toxicity, reduce to 75% dose
• If diarrhea which requires hospitalization, reduce to 75% dose
• If Grade 3 or 4 stomatitis, reduce to 50% dose

Antiemetic Risk

LOW RISK (Less than 10% of patients)
• No routine antiemetic pre-chemotherapy or post-chemotherapy
In Combination with Cisplatin
• See Cisplatin monograph for antiemetic therapy

Contraindications

Hypersensitivity to pemetrexed or any other ingredients in product.

Monitoring

Clinical Monitoring

RECOMMENDED CRITERIA (in addition to clinical monitoring for Cisplatin)
• Clinical assessment of stomatitis; oral examination upon patient complaint of a sore mouth
 
STOMATITIS (Pharyngitis)
0. None
1. Painless ulcers, erythema, or mild soreness in the absence of lesions
2.Painful erythema, edema, or ulcers, but can eat or swallow
3. Painful erythema, edema, or ulcers requiring IV hydration
4.Severe ulceration or requires parenteral or enteral nutritional support or prophylactic intubation
Rated at each visit

Extravasation Hazard

Not a vesicant.

Significant Interactions

NSAIDs reduce pemetrexed clearance. Oral folic acid and IM vitamin B12 do not affect pharmacokinetics of pemetrexed.

Product Information

Commercial Product Description

Alimta® Other Name: LY231514

Pharmaceutical Considerations

Injection:
500 mg vial of lyophilized powder for reconstitution. Contains 500 mg mannitol and pH buffers. Store at room temperature.

Reconstituted solution for injection:
Reconstitute with 20 mL of 0.9% sodium chloride solution (preservative-free) to a concentration of 25 mg/mL. Solution should be clear to light yellow/green and particulate-free.  Further dilution is required.
Chemically and physically stable for up to 24 hours at room temperature or refrigeration, when exposed to ambient light; however, it is recommended that pemetrexed be refrigerated to avoid bacterial contamination.

Diluted solution for infusion:
Dilute in 100 mL NS. Chemically stable for 24 hours at room temperature exposed to ambient light. If not used promptly, it is recommended that pemetrexed be refrigerated to avoid bacterial contamination.

Compatibility:
It is not recommended that pemetrexed may be mixed with other drugs.

Handling Risk Level

Pregnancy DKNOWN HAZARDOUS DRUG
FDA Pregnancy Risk Factor D

  • This drug must be handled using precuations outlined in CCNS Policies for Occupational Safety and Administering Cancer Chemotherapy

Note

HANDLING RISK LEVEL:
HAZARD RISK LEVEL 2
FDA Pregnancy Risk Factor D
• This drug must be handled using precautions outlined in CCNS Policies for Preparing Cancer Chemotherapy and Administering Cancer Chemotherapy
• Go to "Additional Information" tab (above) for links to CCNS Policies

GUIDELINES:

NCDF Coverage Criteria: Non-Small Cell Lung Cancer
1. In combination with cisplatin as a first line treatment option in patients with advanced or metastatic NSCLC with non-squamous histology who have an ECOG performance status of 0-2.
2. As a single agent second line treatment option in patients with advanced or metastatic NSCLC with non-squamous histology who have an ECOG performance status of 0-2 after failure of only one prior line of therapy.
3. As a single agent maintenance treatment option in patients with advanced or metastatic NSCLC with non-squamous histology immediately following a non-pemetrexed containing first line platinum doublet who have an ECOG performance status of 0-2 and have achieved clinical benefit (tumor response or stable disease) from first line therapy.

As a single agent in patients with documented evidence of advanced or metastatic NSCLC, as a second line alternate option to docetaxel, have an ECOG performance status of 0-2, exhibit peripheral neuropathy after first line platinum, taxane or vinorelbine based therapy, for whom this monotherapy would recommended and choose to receive systemic chemotherapy. Pemetrexed would be a reasonable treatment option in those patients who are at high risk of developing peripheral neuropathy (i.e. diabetes, underlying neurologic problems, neurologic paraneoplastic syndromes) and due to administrative issues unable to receive docetaxel in another district. In any one patient, only one of these options may be used (i.e. docetaxel or pemetrexed).

Mesothelioma
NCDF Coverage Criteria:
Pemetrexed / Cisplatin: As combination first line treatment in patients with histologically proven MPM not candidates for curative surgery who have an ECOG performance status of 0-1 and choose to receive systemic therapy.

NCDF Coverage Criteria: Advanced Non-Squamous Non Small Cell Lung Cancer
pCODR Recommendations: Pemetrexed as a maintenance treatment following first-line treatment following pemetrexed plus cisplatin in patients with advanced or metastatic non-squamous non-small cell lung cancer (NS-NSCLC) in patients who have achieved stable disease or better with 4 cycles of induction pemetrexed plus  cisplatin and with an ECOG performance status of 0 or 1 after induction therapy.  November 19, 2013

Visit the Pan-Canadian Oncology Drug Review website (www.pcodr.ca) for the guidelines on pemetrexed for advanced non-squamous non small cell lung cancer.
• Go to "Additional Information" tab (above) for links to pCODR Reviews

Availability & Funding

Administrative Information (Nova Scotia)

• CCNS Provincial Formulary Status- Intermediate Level; indication restrictions • Provincial New Cancer Drug Fund- Funding for use in advanced Non-small cell lung cancer. • Go to "Additional Information" tab (above) for links to Provincial Formulary of Cancer Drugs • Pharmacare Formulary Status- Non-Formulary • NOTE: It is recommended to limit ordering of this medication to standard preprinted order forms, for patient safety.

New Cancer Drug Fund Status (Nova Scotia)

New Cancer Drug Fund (NCDF) funding approved for: Treatment of Non-Small Cell Lung Cancer- • First Line and Continued Maintenance A) In combination with platinum as a first line treatment option in patients with advanced or metastatic NSCLC with non-squamous histology who have an ECOG PS of 0-2. B) In those patients who achieved stable disease or better post 4 cycles of first line pemetrexed/platinum based induction therapy and have ECOG PS of 0-1 an option to continue maintenance pemetrexed as a single agent is available (continued maintenance therapy). • Switch Maintenance As a single agent maintenance treatment option (switch maintenance) in patients with advanced or metastatic NSCLC with non-squamous histology immediately following a non-pemetrexed containing first line platinum doublet who have an ECOG PS of 0-2 and have achieved clinical benefit (tumor response or stable disease) from first line therapy. • Second Line As a single agent second line treatment option in patients with advanced or metastatic NSCLC with non-squamous histology who have an ECOG PS of 0-2 after failure of only one prior line of therapy Treatment of Malignant Pleural Mesothelioma - Pemetrexed / Cisplatin: As combination first line treatment in patients with histologically proven MPM not candidates for curative surgery who have an ECOG performance status of 0-1 and choose to receive systemic therapy. Advanced Non-Squamous Non Small Cell Lung Cancer- Pemetrexed as a maintenance treatment following first-line treatment following pemetrexed plus cisplatin in patients with advanced or metastatic non-squamous non-small cell lung cancer (NS-NSCLC) in patients who have achieved stable disease or better with 4 cycles of induction pemetrexed plus cisplatin and with an ECOG performance status of 0 or 1 after induction therapy.



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