Pemetrexed shilpa
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PEMETREXED SHILPA
Composition:
Active substance: pemetrexed;
1 vial contains 100 mg or 500 mg of pemetrexed as pemetrexed disodium hemipentahydrate;
Excipients: mannitol, sodium hydroxide, hydrochloric acid.
Pharmaceutical form. Lyophilisate for solution for infusion.
Main physico-chemical properties: lyophilisate of white to pale yellow or greenish-yellow color.
Pharmacotherapeutic group. Antimetabolites. Structural analogues of folic acid.
ATC code L01B A04.
Pharmacological Properties.
Pharmacodynamics.
Pemetrexed Shilpa (pemetrexed) is an antifolate antitumor agent with multi-targeted activity, disrupting key folate-dependent metabolic processes essential for cell replication.
In vitro studies have demonstrated that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), which are key folate-dependent enzymes required for de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed enters cells via both the reduced folate carrier and membrane folate-binding protein transport systems. Once inside the cell, pemetrexed is rapidly converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms accumulate within cells and are more potent inhibitors of TS and GARFT. Polyglutamation is a time- and concentration-dependent process that occurs predominantly in tumor cells and to a lesser extent in healthy tissues. Polyglutamate metabolites have a prolonged intracellular half-life, resulting in prolonged drug action within malignant cells.
Studies using the mesothelioma cell line MSTO-211H demonstrated synergistic effects when pemetrexed was combined with cisplatin.
Pharmacokinetics.
The pharmacokinetic properties of pemetrexed were studied in 426 oncology patients with various solid tumors following administration as monotherapy via 10-minute infusion at doses ranging from 0.2 to 838 mg/m². Pemetrexed has a consistent volume of distribution of 9 L/m². In vitro studies showed that approximately 81% of pemetrexed is protein-bound in plasma. The degree of renal impairment does not affect protein binding. Pemetrexed undergoes limited hepatic metabolism; 70–90% of the administered dose is excreted unchanged in the urine within 24 hours after administration. In vitro studies indicate that pemetrexed is actively secreted by OAT3 (organic anion transporter 3).
The total plasma clearance of pemetrexed is 91.8 mL/min, and the plasma half-life is 3.5 hours in patients with normal renal function (creatinine clearance of 90 mL/min).
Inter-patient variability in clearance is moderate, at 19.3%. The overall systemic exposure to pemetrexed (AUC) and the maximum plasma concentration increase proportionally with dose escalation. The pharmacokinetics of pemetrexed remain consistent over multiple treatment cycles.
Concomitant administration of cisplatin does not affect the pharmacokinetic properties of pemetrexed. Oral supplementation with folic acid and intramuscular administration of vitamin B₁₂ do not influence the pharmacokinetics of pemetrexed.
Clinical characteristics.
Indications.
Malignant pleural mesothelioma.
Pemetrexed Shilpa in combination with cisplatin is indicated for the treatment of patients with malignant unresectable pleural mesothelioma.
Non-small cell lung cancer.
Pemetrexed Shilpa in combination with cisplatin is indicated for the treatment of patients with locally advanced or metastatic non-small cell non-squamous lung cancer in the first-line chemotherapy.
Pemetrexed Shilpa as monotherapy is indicated for maintenance treatment of patients with locally advanced or metastatic non-small cell non-squamous lung cancer who have not experienced disease progression following platinum-based chemotherapy.
Pemetrexed Shilpa as monotherapy is indicated for the treatment of patients with locally advanced or metastatic non-small cell non-squamous lung cancer in the second-line chemotherapy.
Contraindications.
Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
Breastfeeding period.
Concomitant use of yellow fever vaccine.
Safety precautions.
As with handling other potentially toxic antineoplastic agents, careful attention should be paid to safety measures during the preparation and administration of pemetrexed infusion solution. Gloves are recommended. If pemetrexed solution comes into contact with the skin, the skin should be immediately washed with soap and water. If pemetrexed solution contacts mucous membranes, they should be flushed thoroughly with water. Pemetrexed is not a vesicant. There is no specific antidote to reverse hemorrhage resulting from pemetrexed administration. Several cases of hemorrhage attributed to pemetrexed have been reported, which were not considered serious by investigators. Hemorrhage should be managed according to local standards.
Interaction with other medicinal products and other forms of interaction.
Pemetrexed is predominantly excreted unchanged by the kidneys via tubular secretion, and less frequently via glomerular filtration. Concomitant use of nephrotoxic agents (e.g., aminoglycosides, loop diuretics, platinum compounds, cyclosporine) may lead to reduced pemetrexed clearance. Such combinations should be used with caution. When necessary, creatinine clearance should be closely monitored.
Concomitant use of substances that are also excreted via tubular secretion (e.g., probenecid, penicillin) may potentially reduce pemetrexed clearance. These medicinal products should be used cautiously in combination with pemetrexed. When necessary, creatinine clearance should be closely monitored.
In patients with normal renal function (creatinine clearance ≥ 80 mL/min), high doses of nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen (>1600 mg/day), and acetylsalicylic acid (≥ 1.3 g/day) may reduce pemetrexed elimination and thereby increase the frequency of adverse reactions. Therefore, high doses of NSAIDs or acetylsalicylic acid should be prescribed with caution together with pemetrexed in patients with normal renal function (creatinine clearance ≥ 80 mL/min).
In patients with mild to moderate renal impairment (creatinine clearance 45–79 mL/min), concomitant use of pemetrexed with NSAIDs (e.g., ibuprofen) or high-dose acetylsalicylic acid should be avoided for 2 days before, on the day of, and for 2 days after pemetrexed administration.
In the absence of data on potential interactions with NSAIDs having a long half-life, such as piroxicam or rofecoxib, concomitant use of these agents in patients with mild to moderate renal impairment should be discontinued 5 days before, on the day of, and for 2 days after pemetrexed administration. If concomitant use of NSAIDs is necessary, patients should be closely monitored for signs of toxicity, particularly myelosuppression and gastrointestinal toxicity.
Pemetrexed undergoes minimal hepatic metabolism. In vitro studies with human liver microsomes suggest that pemetrexed does not clinically significantly inhibit the clearance of drugs metabolized by CYP3A, CYP2D6, CYP2C9, or CYP1A2.
Interactions common to all cytotoxic agents.
Due to the increased risk of thrombosis, oncology patients are often treated with anticoagulant therapy. High individual variability in coagulation status during the disease course and the potential for interaction between oral anticoagulants and antineoplastic chemotherapy agents necessitate increased frequency of INR (International Normalized Ratio) monitoring if oral anticoagulants are administered to such patients.
Concomitant use is contraindicated: yellow fever vaccine – due to the risk of developing fatal generalized vaccine disease.
Concomitant use is not recommended: live attenuated vaccines (except yellow fever vaccine, for which concomitant use is contraindicated) – due to the risk of systemic, possibly fatal, disease. The risk is increased if the patient already has immunosuppression due to the underlying disease. In such cases, inactivated vaccines should be used if available (e.g., poliomyelitis).
Special precautions for use.
Pemetrexed can suppress bone marrow function, manifested as neutropenia, thrombocytopenia, anemia (or pancytopenia); myelosuppression is usually the dose-limiting toxicity. Myelosuppression should be monitored throughout treatment. Pemetrexed must not be administered to patients until the absolute neutrophil count (ANC) has recovered to ≥1.5×10⁹/L and platelet count has recovered to ≥100×10⁹/L. Dose reduction in subsequent cycles is based on the following parameters obtained from the previous treatment: the lowest ANC value, platelet count, and the most severe non-hematological toxicity.
Lower overall toxicity and reduced incidence of hematological and non-hematological toxicities of grade 3–4, such as neutropenia, febrile neutropenia, and infection with neutropenia of grade 3–4, have been observed when folic acid and vitamin B₁₂ were administered prophylactically. Therefore, patients receiving pemetrexed therapy should receive folic acid and vitamin B₁₂ prophylactically to reduce treatment-related toxicity.
Skin reactions have been observed in patients who did not receive corticosteroids. Premedication with dexamethasone (or equivalent) may reduce the frequency and severity of skin reactions.
Clinical experience with pemetrexed in patients with creatinine clearance <45 mL/min is limited; therefore, pemetrexed should not be administered to such patients.
Patients with mild to moderate renal impairment should avoid taking NSAIDs, such as ibuprofen and acetylsalicylic acid (>1.3 g/day), for 2 days before, on the day of, and for 2 days after pemetrexed administration.
Patients with mild to moderate renal impairment who are receiving pemetrexed therapy should discontinue NSAIDs with a long elimination half-life 5 days before treatment, on the day of administration, and for 2 days after pemetrexed administration.
Severe renal disorders, including acute renal failure, have been observed both with pemetrexed monotherapy and in combination with other chemotherapeutic agents. Most patients who developed such disorders had risk factors for renal impairment, including dehydration, arterial hypertension, or diabetes.
The impact of cavity fluids such as pleural effusion and ascites on pemetrexed pharmacokinetics has not been fully established. In a phase 2 study involving 31 patients with solid tumors and stable levels of fluid in serous cavities, no difference was observed in dose-normalized plasma concentration or pemetrexed clearance compared to patients without fluid in serous cavities. Therefore, drainage should be considered before administering pemetrexed to patients with significant volumes of cavity fluid.
Severe dehydration associated with gastrointestinal toxicity of pemetrexed in combination with cisplatin has been observed. Therefore, patients should receive adequate antiemetic therapy and appropriate hydration before and/or after treatment.
Serious cardiovascular events, including myocardial infarction, and cerebrovascular events have been infrequently observed in clinical trials of pemetrexed, usually when pemetrexed was used in combination with other cytotoxic agents. Most patients in whom such events occurred had pre-existing cardiovascular risk factors.
Most cancer patients are immunocompromised; therefore, concomitant use of live vaccines is not recommended.
Pemetrexed may cause genetic damage. Sexually active men are advised not to father a child during pemetrexed treatment and for 6 months after therapy. Contraception should be used or sexual intercourse avoided. Due to the potential of pemetrexed to cause irreversible infertility, men are advised to consider sperm preservation before starting treatment.
Women of childbearing potential must use effective contraception during pemetrexed therapy.
Cases of "radiation recall" have been reported in patients who received treatment in previous weeks or years.
The medicinal product contains approximately 54 mg of sodium per vial, which should be taken into account for patients on a controlled sodium diet.
Use during pregnancy or breastfeeding.
Contraception.
Women of childbearing potential must use effective contraception during pemetrexed therapy. Pemetrexed may cause genetic damage.
Pregnancy.
There are no data on the use of pemetrexed in pregnant women, but like other antimetabolites, pemetrexed may cause severe congenital defects when administered during pregnancy. Animal studies have shown reproductive toxicity. Pemetrexed should not be used during pregnancy except in cases of clear necessity and only after careful assessment of benefit to the pregnant woman and risk to the fetus.
Breastfeeding.
It is unknown whether pemetrexed is excreted in human milk. Adverse reactions in breastfed infants cannot be excluded. Therefore, breastfeeding must be discontinued during pemetrexed therapy.
Effect on ability to drive and use machines.
No studies on the effect of the drug on the ability to drive or operate machinery have been conducted. However, fatigue has been reported with pemetrexed; therefore, patients should exercise caution when driving or operating machinery.
Administration and Dosage
The medicinal product should be administered under the supervision of a qualified physician experienced in the use of antineoplastic agents.
Combination with cisplatin
The recommended dose of Pemetrexed Shilpa is 500 mg/m² body surface area administered as an intravenous infusion over 10 minutes on day 1 of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m² body surface area administered as an infusion over 2 hours, approximately 30 minutes after completion of pemetrexed infusion, on day 1 of each 21-day cycle. Patients should receive appropriate antiemetic therapy. Adequate patient hydration should be provided before and/or after cisplatin administration.
Monotherapy use
For the treatment of non-small cell lung cancer (NSCLC) after prior chemotherapy, the recommended dose of Pemetrexed Shilpa is 500 mg/m² body surface area administered as an intravenous infusion over 10 minutes on day 1 of each 21-day cycle.
Premedication regimen
To reduce the frequency and severity of skin reactions, corticosteroids should be administered one day before, on the day of, and the day after pemetrexed administration. The corticosteroid dose should be equivalent to 4 mg of dexamethasone orally twice daily.
To reduce toxicity, patients receiving pemetrexed therapy must be given folic acid supplements or multivitamins containing folic acid (350–1000 mcg) daily. At least 5 daily doses of folic acid should be taken during the 7-day period before the first dose of pemetrexed. Folic acid supplementation should continue throughout the course of therapy and for 21 days after the last dose of pemetrexed. Patients should also receive vitamin B12 intramuscularly once weekly starting 1 week before the first dose of pemetrexed and once every 3 cycles thereafter. Subsequent vitamin B12 injections may be administered on the same day as pemetrexed infusion.
Monitoring
In patients receiving pemetrexed, complete blood counts, including differential white cell count (WCC) and platelets, should be assessed before each administration. Before each chemotherapy cycle, biochemical blood tests should be performed to evaluate liver and kidney function. ANC should be ≥ 1.5 × 10⁹/L and platelet count ≥ 100 × 10⁹/L prior to initiating any chemotherapy cycle.
Creatinine clearance should be ≥ 45 mL/min.
Total bilirubin levels should not exceed 1.5 times the upper limit of normal. Alkaline phosphatase (AP), ALT, and AST levels should not exceed normal limits by more than 3 times. Elevations in AP, ALT, and AST up to 5 times the upper limit of normal are acceptable if liver metastases are present.
Dose modification
Dose modification prior to the next cycle should be based on the lowest hematological values or the maximum non-hematological toxicity observed after the previous treatment cycle. Treatment may be delayed to allow sufficient time for recovery. After recovery, patients should resume therapy according to the recommendations in Tables 1–3, corresponding to pemetrexed use as monotherapy or in combination with cisplatin.
Table 1
Dose modification of Pemetrexed Shilpa (combination therapy or monotherapy) and cisplatin.
Hematological toxicity
| Parameters |
Dose |
| Minimum ANC value < 0.5x10⁹/L and minimum platelet value ≥ 50x10⁹/L |
75% of previous dose (for both drugs) |
| Minimum platelet value < 50x10⁹/L regardless of minimum ANC value |
75% of previous dose (for both drugs) |
| Minimum platelet value < 50x10⁹/L in the presence of bleeding, regardless of minimum ANC value |
50% of previous dose (for both drugs) |
and Criteria according to the National Cancer Institute Common Toxicity Criteria version (CTC v2.0; NCI 1998) correspond to the definition of bleeding ≥ CTC grade 2.
If a patient develops signs of non-hematological toxicity (except neurotoxicity) ≥ grade 3, administration of pemetrexed should be discontinued until lower values are reached or values corresponding to the patient's baseline prior to initiation of therapy. Therapy should be resumed according to the recommendations outlined in Table 2.
Table 2
Dosage modification of Pemetrexed Shilpa (combination therapy or monotherapy) and cisplatin.
Non-hematological toxicity a,b
| Pemetrexed Shilpa Dose (mg/m2) |
Cisplatin Dose (mg/m2) |
|
| Any grade 3 or 4 toxicity except mucositis |
75% of previous dose |
75% of previous dose |
| Any diarrhea requiring hospitalization (regardless of grade), or grade 3 or 4 diarrhea |
75% of previous dose |
75% of previous dose |
| Grade 3 or 4 mucositis |
50% of previous dose |
100% of previous dose |
a According to the National Cancer Institute, USA, Common Toxicity Criteria (CTC v2.0; NCI 1998).
b Except for neurotoxicity.
Recommended dose modification of Pemetrexed Shilpa and cisplatin in the case of neurotoxicity is presented in Table 3. In cases of grade 3 or 4 neurotoxicity, treatment should be discontinued.
Table 3
Dose modification of Pemetrexed Shilpa (combination therapy or monotherapy) and cisplatin.
Neurotoxicity
| CTCa grade |
Pemetrexed Shilpa dose (mg/m2) |
Cisplatin dose (mg/m2) |
| 0-1 |
100 % of previous dose |
100 % of previous dose |
| 2 |
100 % of previous dose |
50 % of previous dose |
a Criteria according to the National Cancer Institute Common Toxicity Criteria (CTC v2.0; NCI 1998).
Pemetrexed therapy should be discontinued if any hematological or non-hematological toxicity of grade 3 or 4 occurs after two dose reductions, or immediately discontinued if neurotoxicity of grade 3 or 4 occurs.
Elderly patients. Clinical studies provided no evidence that patients aged 65 years or older have a higher risk of adverse effects compared to patients under 65 years of age. Therefore, there is no need for dose reduction in elderly patients.
Patients with renal impairment (using the standard Cockcroft-Gault formula or glomerular filtration rate (GFR) determined by plasma clearance of Tc99m-DPTA). Pemetrexed is predominantly excreted unchanged by the kidneys. In clinical studies, dose adjustments were not required for patients with creatinine clearance ≥ 45 ml/min, apart from those recommended for all patients. The number of patients with creatinine clearance below 45 ml/min was insufficient to provide dosing recommendations specifically for this patient group. Therefore, the use of pemetrexed in patients with creatinine clearance < 45 ml/min is not recommended.
Patients with hepatic impairment. No correlation has been established between levels of AST, ALT, total bilirubin, and the pharmacokinetics of pemetrexed. However, the effect of the drug in patients with hepatic dysfunction, such as bilirubin levels > 1.5 times the upper limit of normal (ULN), or aminotransferase levels > 3 times ULN (in absence of liver metastases), or > 5 times ULN (in presence of liver metastases), has not been specifically studied.
Method of administration.
Warnings regarding preparation and administration of Pemetrexed Shilpa are provided in the section "Special precautions". The drug should be administered as an intravenous infusion over 10 minutes on day 1 of each 21-day cycle. Recommendations for reconstitution and dilution of Pemetrexed Shilpa are provided below.
Recommendations for administration
- Appropriate aseptic technique should be used during reconstitution and subsequent dilution of pemetrexed for intravenous infusion.
- Calculate the required dose and number of Pemetrexed Shilpa vials. Each vial contains an excess of pemetrexed to ensure the labeled dose can be withdrawn.
- Reconstitute the contents of the 500 mg vial with 20 ml of 0.9% sodium chloride injection (without preservatives) to obtain a solution containing 25 mg/ml of pemetrexed. Gently swirl each vial until the lyophilisate is completely dissolved. The resulting solution should be clear, colorless to yellow or greenish-yellow, and free from particulate matter. The pH of the reconstituted solution is 6.6–7.8. FURTHER DILUTION IS REQUIRED.
- The required volume of the reconstituted pemetrexed solution should be further diluted to 100 ml with 0.9% sodium chloride solution (without preservatives) and administered as an intravenous infusion over 10 minutes.
- The pemetrexed infusion solution prepared as described above is compatible with infusion bags and administration sets made of polyvinyl chloride and polyolefin.
- Parenteral preparations should be inspected visually for particulate matter and discoloration prior to administration. If particulate matter is present, the solution must not be used.
- The pemetrexed solution is intended for single-patient use. Any unused medicinal product or waste material should be disposed of in accordance with applicable regulations.
Children.
There are no relevant data on the use of pemetrexed in pediatric practice for the treatment of malignant pleural mesothelioma and non-small cell lung cancer.
Overdose.
Symptoms. The following symptoms have been reported: neutropenia, anemia, thrombocytopenia, mucositis, sensory polyneuropathy, and rash. Expected complications of overdose include bone marrow suppression, manifesting as neutropenia, thrombocytopenia, and anemia. In addition, infections with or without fever, diarrhea, and/or mucositis may occur.
Treatment. If overdose is suspected, the patient should be monitored, appropriate blood tests performed, and symptomatic therapy administered as needed. Administration of calcium folinate/folic acid should be considered.
Adverse reactions.
Adverse reactions reported most frequently during administration of pemetrexed, both as monotherapy and in combination therapy, include bone marrow suppression manifested as anemia, neutropenia, leukopenia, and thrombocytopenia, as well as gastrointestinal toxicity presenting as anorexia, nausea, vomiting, diarrhea, constipation, pharyngitis, mucositis, and stomatitis. Other adverse reactions include renal toxicity, increased levels of aminotransferases, alopecia, asthenia, dehydration, rash, infection/sepsis, and neuropathy. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported rarely.
The table below shows the frequency and severity of adverse effects observed in > 5% of 168 patients with mesothelioma randomly assigned to receive cisplatin plus pemetrexed, and 163 patients with mesothelioma randomly assigned to receive cisplatin monotherapy. All patients in both treatment groups received folic acid and vitamin B12 supplementation as recommended.
Within each group, adverse reactions are listed in order of decreasing severity with frequency: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (<1/10000), frequency not known (cannot be estimated from available data).
Table 4
| Organ systems |
Frequency |
Signs* |
Pemetrexed/cisplatin (N=168) |
Cisplatin (N=163) |
|||
| toxicity of any grade (%) |
toxicity grade 3–4 (%) |
toxicity of any grade (%) |
toxicity grade 3–4 (%) |
||||
| Blood and lymphatic system disorders |
Very common |
Neutropenia/Granulocytopenia |
56.0 |
23.2 |
13.5 |
3.1 |
|
| Leukopenia |
53.0 |
14.9 |
16.6 |
0.6 |
|||
| Hemoglobin decreased |
26.2 |
4.2 |
10.4 |
0.0 |
|||
| Platelet count decreased |
23.2 |
5.4 |
8.6 |
0.0 |
|||
| Metabolism and nutrition disorders |
Common |
Dehydration |
6.5 |
4.2 |
0.6 |
0.6 |
|
| Nervous system disorders |
Very common |
Sensory neuropathy |
10.1 |
0.0 |
9.8 |
0.6 |
|
| Common |
Taste disturbance |
7.7 |
0.0*** |
6.1 |
0.0*** |
||
| Eye disorders |
Common |
Conjunctivitis |
5.4 |
0.0 |
0.6 |
0.0 |
|
| Gastrointestinal disorders |
Very common |
Diarrhea |
16.7 |
3.6 |
8.0 |
0.0 |
|
| Vomiting |
56.5 |
10.7 |
49.7 |
4.3 |
|||
| Stomatitis/Pharyngitis |
23.2 |
3.0 |
6.1 |
0.0 |
|||
| Nausea |
82.1 |
11.9 |
76.7 |
5.5 |
|||
| Anorexia |
20.2 |
1.2 |
14.1 |
0.6 |
|||
| Constipation |
11.9 |
0.6 |
7.4 |
0.6 |
|||
| Common |
Dyspepsia |
5.4 |
0.6 |
0.6 |
0.0 |
||
| Skin and subcutaneous tissue disorders |
Very common |
Rash |
16.1 |
0.6 |
4.9 |
0.0 |
|
| Alopecia |
11.3 |
0.0*** |
5.5 |
0.0*** |
|||
| Renal disorders |
Very common |
Increased creatinine |
10.7 |
0.6 |
9.8 |
1.2 |
|
| Decreased creatinine clearance** |
16.1 |
0.6 |
17.8 |
1.8 |
|||
| General disorders |
Very common |
Fatigue |
47.6 |
10.1 |
42.3 |
9.2 |
|
* Reference to National Cancer Institute, USA, CTC criteria for each grade of toxicity (version 2.0), except for the criterion "reduced creatinine clearance"**.
** This term is derived from the CTC section "Other renal/urinary disorders".
*** According to the National Cancer Institute, USA, CTC criteria (version 2.0; NCI 1998), alopecia and taste disturbances should be reported as grade 1 or 2 only.
The 5% threshold in this table was established to include all symptoms considered possibly related to pemetrexed and cisplatin.
Clinically significant CTC toxicity observed in >1% and ≤5% of patients randomly assigned to receive cisplatin and pemetrexed includes renal failure, infection, fever, febrile neutropenia, increased levels of AST, ALT and gamma-glutamyl transferase (GGT), rash, and chest pain.
Clinically significant CTC toxicity observed in ≤1% of patients randomly assigned to receive cisplatin and pemetrexed includes arrhythmia and motor neuropathy.
Table 5 shows the frequency and severity of adverse reactions observed in >5% of 265 patients randomly assigned to receive pemetrexed monotherapy with folic acid and vitamin B12, and 276 patients randomly assigned to receive docetaxel monotherapy. All patients had histologically confirmed locally advanced or metastatic non-small cell lung cancer and had received prior chemotherapy.
Table 5
| Organ systems |
Frequency |
Symptoms* |
Pemetrexed (N=265) |
Docetaxel (N=276) |
||
| any-grade toxicity (%) |
grade 3–4 toxicity (%) |
any-grade toxicity (%) |
grade 3–4 toxicity (%) |
|||
| Blood and lymphatic system |
very common |
Neutropenia/granulocytopenia |
10.9 |
5.3 |
45.3 |
40.2 |
| Leukopenia |
12.1 |
4.2 |
34.1 |
27.2 |
||
| Decreased hemoglobin levels |
19.2 |
4.2 |
22.1 |
4.3 |
||
| common |
Decreased platelet levels |
8.3 |
1.9 |
1.1 |
0.4 |
|
| Gastrointestinal system |
very common |
Nausea |
30.9 |
2.6 |
16.7 |
1.8 |
| Anorexia |
21.9 |
1.9 |
23.9 |
2.5 |
||
| Vomiting |
16.2 |
1.5 |
12.0 |
1.1 |
||
| Stomatitis/pharyngitis |
14.7 |
1.1 |
17.4 |
1.1 |
||
| Diarrhea |
12.8 |
0.4 |
24.3 |
2.5 |
||
| common |
Constipation |
5.7 |
0.0 |
4.0 |
0.0 |
|
| Hepatobiliary system |
common |
AlAT (SGPT) |
7.9 |
1.9 |
1.4 |
0.0 |
| AsAT (SGOT) |
6.8 |
1.1 |
0.7 |
0.0 |
||
| Skin and subcutaneous tissue |
very common |
Rash/desquamation |
14.0 |
0.0 |
|
0.0 |
| common |
Itching |
6.8 |
0.4 |
1.8 |
0.0 |
|
| Alopecia |
6.4 |
0.4** |
37.7 |
2.2** |
||
| General disorders |
very common |
Weakness |
34.0 |
5.3 |
35.9 |
5.4 |
| common |
Fever |
8.3 |
0.0 |
7.6 |
0.0 |
|
* Reference to National Cancer Institute, USA, CTC criteria for laboratory values for each toxicity grade (version 2.0).
** According to the National Cancer Institute, USA, CTC criteria (version 2.0; NCI 1998), alopecia should be reported as toxicity of grade 1 or 2.
The 5% threshold in this table is included to capture all symptoms considered related to pemetrexed.
Clinically significant CTC toxicities observed in ≥1% and ≤5% (common) of patients randomly selected for pemetrexed therapy include infection without neutropenia, febrile neutropenia, allergic reactions/hypersensitivity, increased creatinine levels, motor neuropathy, sensory neuropathy, erythema multiforme, and abdominal pain.
Clinically significant CTC toxicities observed in <1% (rare) of patients randomly selected for pemetrexed therapy include supraventricular arrhythmias.
Clinically significant laboratory findings of overall grade 3 and 4 toxicity were similar to the integrated phase 2 results across three pemetrexed monotherapy trials (n=164) and phase 3 results from the study described above, except for neutropenia (12.8% vs. 5.3%, respectively) and elevated alanine aminotransferase levels (15.2% vs. 1.9%, respectively). These discrepancies were likely due to differences in patient populations, as the phase 2 trials included both chemotherapy-naïve patients and those with extensive prior therapy for breast cancer and pre-existing liver metastases and/or baseline abnormalities in liver function tests.
Table 6 lists the frequency and severity of adverse reactions observed in >5% of 839 patients with non-squamous non-small cell lung cancer randomly assigned to receive pemetrexed and cisplatin, as well as in 830 patients randomly assigned to receive cisplatin and gemcitabine. All patients had a diagnosis of locally advanced or metastatic non-squamous non-small cell lung cancer, and all received full supplementation with folic acid and vitamin B12.
Table 6
| Organ systems |
Frequency |
Symptoms* |
Pemetrexed/cisplatin (N=839) |
Gemcitabine/cisplatin (N=830) |
||
| Any grade toxicity (%) |
Grade 3–4 (%) |
Any grade toxicity (%) |
Grade 3–4 (%) |
|||
| Blood and lymphatic system |
Very common |
Decreased hemoglobin |
33.0* |
|
45.7* |
9.9* |
| Neutropenia/granulocytopenia |
29.0* |
15.1* |
38.4* |
26.7* |
||
| Leukopenia |
17.8 |
4.8* |
20.6 |
7.6* |
||
| Decreased platelet count |
10.1* |
4.1* |
26.6* |
12.7* |
||
| Nervous system |
Common |
Sensory neuropathy |
8.5* |
0.0* |
12.4* |
0.6* |
| Taste disturbance |
8.1 |
0.0*** |
8.9 |
0.0*** |
||
| Gastrointestinal system |
Very common |
Nausea |
56.1 |
7.2* |
53.4 |
3.9* |
| Vomiting |
39.7 |
6.1 |
35.5 |
6.1 |
||
| Anorexia |
26.6 |
2.4* |
24.2 |
0.7* |
||
| Constipation |
21.0 |
0.8 |
19.5 |
0.4 |
||
| Stomatitis/pharyngitis |
13.5 |
0.8 |
12.4 |
0.1 |
||
| Diarrhea without colostomy |
12.4 |
1.3 |
12.8 |
1.6 |
||
| Common |
Dyspepsia/heartburn |
5.2 |
0.1 |
5.9 |
0.0 |
|
| Skin and subcutaneous tissue |
Very common |
Alopecia |
11.9* |
0*** |
21.4* |
0.5*** |
| Common |
Rash/desquamation |
6.6 |
0.1 |
8.0 |
0.5 |
|
| Renal |
Very common |
Increased creatinine |
10.1* |
0.8 |
|
0.5 |
| General disorders |
Very common |
Fatigue |
42.7 |
6.7 |
44.9 |
4.9 |
*P-value ≤ 0.05 for comparison of pemetrexed/cisplatin versus gemcitabine/cisplatin, obtained using Fisher's exact test.
** According to the National Cancer Institute, USA, CTC (version 2.0; NCI 1998), for each toxicity grade.
*** According to the National Cancer Institute, USA, CTC (version 2.0; NCI 1998), taste disturbance and alopecia should be reported as grade 1 or 2.
A 5% threshold was used in this table to include all symptoms considered related to pemetrexed.
Clinically significant toxicity observed in ≥ 1% and ≤ 5% of patients randomized to receive cisplatin and pemetrexed includes increased AST levels, increased ALT levels, infection, febrile neutropenia, renal failure, fever, dehydration, conjunctivitis, and decreased creatinine clearance.
Clinically significant toxicity observed in < 1% of patients randomized to receive cisplatin and pemetrexed includes increased GGT levels, chest pain, arrhythmia, and motor neuropathy.
Clinically significant toxicity by gender was similar across all patient groups receiving pemetrexed with cisplatin.
Table 7 shows the frequency and severity of adverse reactions observed in > 5% of the 800 patients randomized to receive pemetrexed, as well as in the 402 patients randomized to receive placebo, in the maintenance study with pemetrexed alone (study JMEN), and in the long-term maintenance study with pemetrexed alone (study PARAMOUNT). All patients had stage IIIB or IV non-small cell lung cancer and had previously received platinum-based chemotherapy. Patients received full supplementation with folic acid and vitamin B12.
Table 7
| Organ systems |
Frequency |
Symptoms* |
Pemetrexed (N=800)*** |
Placebo (N=402)*** |
||
| Any-grade toxicity (%) |
Grade 3–4 toxicity (%) |
Any-grade toxicity (%) |
Grade 3–4 toxicity (%) |
|||
| Blood and lymphatic system disorders |
Very common |
Decreased hemoglobin |
18.06 |
4.5 |
5.2 |
0.5 |
| Common |
Leukopenia |
5.8 |
1.9 |
0.7 |
0.2 |
|
| Neutropenia |
8.4 |
4.4 |
0.2 |
0.0 |
||
| Nervous system disorders |
Common |
Sensory neuropathy |
7.4 |
0.6 |
5.0 |
0.2 |
| Gastrointestinal disorders |
Very common |
Nausea |
17.3 |
0.8 |
4.0 |
0.2 |
| Anorexia |
12.8 |
1.1 |
3.2 |
0.0 |
||
| Common |
Vomiting |
8.4 |
0.3 |
1.5 |
0.0 |
|
| Stomatitis/mucositis |
6.8 |
0.8 |
1.7 |
0.0 |
||
| Hepatobiliary disorders |
Common |
ALT (SGPT) |
6.5 |
0.1 |
2.2 |
0.0 |
| AST (SGOT) |
5.9 |
0.0 |
1.7 |
0.0 |
||
| Skin and subcutaneous tissue disorders |
Common |
Rash/desquamation |
8.1 |
0.1 |
3.7 |
0.0 |
| General disorders |
Very common |
Fatigue |
24.1 |
5.3 |
10.9 |
0.7 |
| Common |
Pain |
7.6 |
0.9 |
4.5 |
0.0 |
|
| Edema |
5.6 |
0.0 |
1.5 |
0.0 |
||
| Renal disorders |
Common |
Renal disorders**** |
7.6 |
0.9 |
1.7 |
0.0 |
ALT – alanine aminotransferase; AST – aspartate aminotransferase; NCI – National Cancer Institute, USA; CTCAE – Common Terminology Criteria for Adverse Events.
* Frequency criteria: very common – ≥ 10 %; common – > 5 % and < 10 %. A 5 % threshold was used in this table to include all symptoms considered to be related to pemetrexed.
** Refers to the National Cancer Institute, USA, CTC criteria for laboratory values for each toxicity grade (version 3.0, NCI 2003). The reported frequency of events corresponds to CTCAE version 3.0 requirements.
*** The integrated adverse reactions table contains pooled data from the pemetrexed maintenance therapy studies JMEN (N=663) and PARAMOUNT (N=539).
**** General term encompassing increased blood/serum creatinine, decreased glomerular filtration rate, renal failure, and other renal and urinary system events.
Clinically significant toxicity observed in ≥1 % and ≤5% of patients randomly assigned to pemetrexed therapy includes febrile neutropenia, infection, thrombocytopenia, diarrhea, constipation, alopecia, rash/pruritus, fever (without neutropenia), eye disorders (including conjunctivitis), increased lacrimation, dizziness, and motor neuropathy.
Clinically significant toxicity observed in <1 % of patients randomly assigned to pemetrexed therapy includes allergic reactions/hypersensitivity, erythema multiforme, supraventricular arrhythmia, and pulmonary embolism.
Safety was evaluated in patients randomly assigned to pemetrexed therapy (N=800). The frequency of adverse reactions was assessed in patients who received ≤6 cycles of pemetrexed maintenance treatment (N=519) compared to those who received >6 cycles of pemetrexed treatment (N=281). An increased frequency of adverse reactions (all grades of severity) was observed with longer duration of treatment. A significant increase in the frequency of a potentially drug-related adverse event, namely grade 3 or 4 neutropenia, was observed with prolonged pemetrexed treatment (≤6 cycles – 3.3 %; >6 cycles – 6.4 %; p=0.046). No statistically significant difference in the frequency of other individual grade 3, 4, and 5 adverse events was observed with increasing treatment duration.
Serious cardiovascular and cerebrovascular events, including myocardial infarction, angina, cerebrovascular accidents, and transient ischemic attacks, were infrequently reported in clinical trials of pemetrexed, usually in combination with other cytotoxic agents. Most patients who experienced such events had pre-existing cardiovascular risk factors.
Potentially serious cases of hepatitis were rarely reported during clinical trials with pemetrexed.
Cases of pancytopenia were infrequently reported during clinical trials with pemetrexed.
Colitis (including intestinal and rectal hemorrhage, sometimes fatal, intestinal perforation, intestinal necrosis, and appendicitis) was infrequently reported during clinical trials in patients treated with pemetrexed.
Interstitial pneumonitis with respiratory failure, sometimes fatal, was infrequently reported during clinical trials in patients treated with pemetrexed.
Edema was infrequently reported in patients receiving pemetrexed treatment.
Esophagitis/radiation esophagitis was infrequently reported during clinical trials with pemetrexed.
Sepsis, sometimes fatal, was frequently reported during clinical trials with pemetrexed.
During post-marketing surveillance of pemetrexed, the following adverse reactions have been observed.
Hyperpigmentation was frequently reported.
Acute renal failure was infrequently reported, both during pemetrexed monotherapy and in combination with other chemotherapeutic agents.
Radiation pneumonitis was infrequently reported in patients who received radiation therapy before, during, or after pemetrexed treatment.
"Radiation recall" reactions were rarely reported in patients who had previously received radiation therapy.
Peripheral ischemia, sometimes leading to limb necrosis, was infrequently reported.
Bullous disorders, including Stevens-Johnson syndrome and toxic epidermal necrolysis, were rarely reported, with some cases being fatal.
Immune-mediated hemolytic anemia was rarely reported in patients receiving pemetrexed.
Anaphylactic shock was also rarely reported.
Cases of infectious and non-infectious dermatoses, involving the dermis, hypodermis, and/or subcutaneous tissue, such as acute bacterial dermohypodermitis, pseudocellulitis, and dermatitis, have been reported. The frequency of occurrence is unknown.
Exudative erythema, predominantly affecting the lower limbs, has been reported with unknown frequency.
Shelf life. 2 years.
The reconstituted solution and infusion solution maintains physicochemical stability for 24 hours at 2–8 °C.
From a microbiological standpoint, the product should be used immediately. If not used immediately, the responsibility for storage conditions and duration prior to use lies with the user; storage must not exceed 24 hours at 2–8 °C.
Storage conditions. Store in the original packaging at a temperature not exceeding 30 °C. Keep out of the reach of children.
Incompatibilities.
Pemetrexed is incompatible with diluents containing calcium, such as Ringer's solution. Compatibility studies for pemetrexed are lacking; therefore, it must not be mixed with any other medicinal product.
Packaging.
100 mg in glass vials, closed with a rubber stopper and aluminum cap with flip-off component. One vial per cardboard box.
500 mg in glass vials, closed with a rubber stopper and aluminum cap with flip-off component. One vial per cardboard box.
Prescription status. Prescription only.
Manufacturer. Shilpa Medicare Limited, India.
Manufacturer's address and place of business. Unit 4, Pharmaceutical Formulations SEZ, Plots S-20 to S-26, Pharma SEZ, TSIIC, Green Industrial Park, Polepally, Jadcherla, Mahbubnagar, Telangana, 509301, India