Pemetrexed fares

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PemetrexedPhaRes (PemetrexedPhaRes)

Composition:

Active substance: pemetrexed;

1 vial contains 100 mg or 500 mg of pemetrexed as pemetrexed disodium hemipentahydrate;

Excipients: mannitol (E 421), hydrochloric acid, sodium hydroxide.

Pharmaceutical form. Powder for concentrate for solution for infusion.

Main physicochemical properties: powder from white to light yellow or greenish-yellow color.

Pharmacotherapeutic group. Antimetabolites. Structural analogues of folic acid.

ATC code L01BA04.

Pharmacological properties.

Pharmacodynamics.

Pemetrexed is an antifolate antineoplastic 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. Polyglutamated forms accumulate within cells and are more potent inhibitors of TS and GARFT. Polyglutamation is a time- and concentration-dependent process that occurs more extensively in tumor cells than in healthy tissues. Polyglutamate metabolites have a prolonged intracellular half-life, resulting in a longer duration of drug action in 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 evaluated 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 steady volume of distribution of 9 L/m². In vitro studies showed that approximately 81% of pemetrexed is protein-bound in plasma. The extent of renal impairment does not affect protein binding. Pemetrexed undergoes limited hepatic metabolism; 70–90% of the administered dose is excreted unchanged in urine within 24 hours after administration. In vitro studies have shown that pemetrexed is actively secreted by OAT3 (organic anion transporter).

Total plasma clearance of pemetrexed is 91.8 mL/min, and the plasma elimination 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%. Systemic exposure to pemetrexed (AUC) and 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 pharmacokinetics of pemetrexed. Oral supplementation with folic acid and intramuscular supplementation with vitamin B₁₂ do not influence the pharmacokinetics of pemetrexed.

Clinical characteristics.

Indications.

Malignant pleural mesothelioma.

Pemetrexed in combination with cisplatin is indicated for the treatment of patients with malignant unresectable pleural mesothelioma.

Non-small cell lung cancer.

Pemetrexed in combination with cisplatin is indicated for the treatment of patients with locally advanced or metastatic non-squamous non-small cell lung cancer in the first-line chemotherapy setting.

Pemetrexed as monotherapy is indicated for maintenance treatment of patients with locally advanced or metastatic non-squamous non-small cell lung cancer who have not experienced disease progression following platinum-based chemotherapy.

Pemetrexed as monotherapy is indicated for the treatment of patients with locally advanced or metastatic non-squamous non-small cell lung cancer in the second-line chemotherapy setting.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Breastfeeding period.

Concomitant use of yellow fever vaccine.

Special 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. The use of gloves is recommended. If pemetrexed solution comes into contact with the skin, the skin should be washed immediately with soap and water. If pemetrexed solution comes into contact with mucous membranes, they should be rinsed thoroughly with water. Pemetrexed does not cause blistering. 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 primarily excreted unchanged by the kidneys via tubular secretion or, less frequently, glomerular filtration. Concomitant administration of nephrotoxic drugs (e.g., aminoglycosides, loop diuretics, platinum-containing agents, cyclosporine) may reduce pemetrexed clearance. Such combinations should be used with caution. If 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 combined with pemetrexed cautiously. If 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 used with caution when co-administered 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 regarding 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 NSAID use is necessary, patients should be closely monitored for signs of toxicity, particularly myelosuppression and gastrointestinal toxicity.

Pemetrexed undergoes minimal hepatic metabolism. In vitro studies using 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, cancer patients are often prescribed anticoagulant therapy. The high individual variability in coagulation status during the disease course and the potential for interaction between oral anticoagulants and antineoplastic chemotherapy agents necessitate more frequent monitoring of the international normalized ratio (INR) if oral anticoagulants are prescribed to these patients.

Concomitant use contraindicated: yellow fever vaccine – due to the risk of developing fatal generalized vaccine disease.

Concomitant use 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.

Pemetrexed can suppress bone marrow function, manifesting as neutropenia, thrombocytopenia, anemia (or pancytopenia); myelosuppression is usually the dose-limiting toxicity. Myelosuppression should be monitored in patients throughout treatment. Pemetrexed should not be administered until the absolute neutrophil count (ANC) has recovered to ≥1.5×10⁹/L and platelet count to ≥100×10⁹/L. Dose reduction in subsequent cycles is based on the following parameters obtained from the prior treatment: minimum ANC value, platelet count, and the maximum severity of non-hematological toxicity.

Lower overall toxicity and reduced incidence of hematological and non-hematological toxicities of grade III–IV, such as neutropenia, febrile neutropenia, and infection with grade III–IV neutropenia, have been observed when folic acid and vitamin B₁₂ were administered prophylactically. Therefore, patients receiving pemetrexed therapy must 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 its equivalent) may reduce the frequency and severity of skin reactions.

Clinical experience with pemetrexed in patients with creatinine clearance below 45 mL/min is limited; therefore, pemetrexed should not be administered to such patients.

Patients with mild to moderate renal impairment should avoid the use of 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.

For patients with mild to moderate renal impairment receiving pemetrexed therapy, treatment with NSAIDs having a long elimination half-life should be discontinued 5 days before, on the day of, 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. Cases of nephrogenic diabetes insipidus and renal tubular necrosis have also been reported during post-marketing studies with pemetrexed, used alone or in combination with other chemotherapeutic agents. Most of these events resolve after discontinuation of pemetrexed. Acute tubular necrosis, decreased renal function, and signs and symptoms of nephrogenic diabetes insipidus (e.g., hypernatremia) should be monitored regularly in patients.

The impact of pemetrexed in body cavity fluids, such as pleural effusion and ascites, has not been fully established. In a phase II study of pemetrexed 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 prior to administering pemetrexed to patients with significant volume 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 administered in combination with other cytotoxic agents. Most patients in whom such events occurred had pre-existing cardiovascular risk factors.

Most oncology patients are immunocompromised; therefore, concomitant use of live attenuated vaccines is not recommended.

Pemetrexed may cause genetic damage. Sexually active men are advised not to father a child during pemetrexed therapy and for 6 months after treatment. Use of contraception or abstention from sexual intercourse is recommended. 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 considered for patients on a sodium-controlled 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 malformations when administered during pregnancy. Animal studies have shown reproductive toxicity. Pemetrexed should not be used during pregnancy except in cases of strong medical necessity and only after careful assessment of benefit to the mother 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 should be discontinued during pemetrexed therapy.

Effect on ability to drive and use machines.

No studies on the effect of the medicinal product on the ability to drive or operate machinery have been conducted. However, there have been reports that pemetrexed may cause fatigue; therefore, patients should exercise caution when driving or operating machinery.

Method of Administration and Dosage.

The medicinal product should be administered under the supervision of a qualified physician experienced in the use of antineoplastic agents.

Administration in combination with cisplatin.

The recommended dose of Pemetrexed FaRes is 500 mg/m² body surface area (BSA) as an intravenous infusion over 10 minutes on day 1 of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m² BSA as a 2-hour infusion, administered approximately 30 minutes after completion of the pemetrexed infusion on day 1 of each 21-day cycle. Patients should receive appropriate antiemetic therapy. Adequate 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 FaRes is 500 mg/m² BSA 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 the 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 treatment course and for 21 days after the last dose of pemetrexed. Patients should also receive intramuscular vitamin B12 once weekly starting 1 week before the first dose of pemetrexed and then 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 checked before each administration. Before each chemotherapy cycle, a biochemical blood test should be performed to assess liver and kidney function. Absolute neutrophil count (ANC) must be ≥ 1.5 × 10⁹/L and platelet count ≥ 100 × 10⁹/L prior to initiating any chemotherapy cycle.

Creatinine clearance must be ≥ 45 mL/min.

Total bilirubin levels should not exceed 1.5 times the upper normal limit. Alkaline phosphatase (AP), ALT, and AST levels should not exceed the upper normal limit by more than 3 times. Elevations in AP, ALT, and AST levels up to 5 times the upper normal limit are acceptable if liver metastases are present.

Dose modification.

Dose adjustments prior to starting 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 the use of Pemetrexed FaRes as monotherapy or in combination with cisplatin.

Dose modification of pemetrexed (combination therapy or monotherapy) and cisplatin.

Hematological toxicity

Table 1

Parameters	Dose
Lowest value of ANC < 0.5x10⁹/L and lowest value of platelets ≥ 50x10⁹/L	75% of previous dose (for both drugs)
Lowest value of platelets < 50x10⁹/L regardless of the lowest ANC value	75% of previous dose (for both drugs)
Lowest value of platelets < 50x10⁹/L with bleeding present, regardless of the lowest ANC value	50% of previous dose (for both drugs)

and Criteria according to the National Cancer Institute Common Toxicity Criteria (CTC v2.0; NCI 1998) correspond to bleeding ≥ CTC Grade II.

If a patient develops signs of non-hematological toxicity (except neurotoxicity) ≥ Grade III, administration of Pemetrexed Pharos should be discontinued until lower levels are reached or until values corresponding to the patient's baseline prior to initiation of therapy are achieved. Therapy should be resumed according to the recommendations provided in Table 2.

Dose modification of pemetrexed (combination therapy or monotherapy) and cisplatin.

Non-hematological toxicity a,b

Table 2

	Pemetrexed dose (mg/m2)	Cisplatin dose (mg/m2)
Any grade III or IV toxicity, except mucositis	75 % of previous dose	75 % of previous dose
Any diarrhea requiring hospitalization (regardless of grade), or grade III or IV diarrhea	75 % of previous dose	75 % of previous dose
Grade III or IV mucositis	50 % of previous dose	100 % of previous dose

a According to the National Cancer Institute Common Toxicity Criteria (CTC v2.0; NCI 1998).

b Excluding neurotoxicity.

Recommended dose modification of Pemetrexed FaRes and cisplatin in case of neurotoxicity is presented in Table 3. In case of grade III or IV neurotoxicity, treatment should be discontinued.

Dose modification of Pemetrexed FaRes (combination therapy or monotherapy) and cisplatin.

Table 3

Neurotoxicity

CTCa grade	Pemetrexed Pharos 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 Common Toxicity Criteria of the National Cancer Institute, USA (CTC v2.0; NCI 1998).

Treatment with pemetrexed should be discontinued if any hematological or non-hematological toxicity of grade III or IV occurs after two dose reductions, or immediately discontinued if neurotoxicity of grade III or IV 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 younger than 65 years. No dose adjustment is required, except as recommended for all patients.

Patients with renal impairment (using the standard Cockcroft-Gault formula or glomerular filtration rate (GFR) determined by the plasma clearance method of Tc99m-DPTA). Pemetrexed is predominantly excreted unchanged by the kidneys. In clinical studies, no dose adjustment was necessary for patients with creatinine clearance ≥45 mL/min, except as recommended for all patients. The number of patients with creatinine clearance <45 mL/min was insufficient to make dosing recommendations 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 elevated bilirubin levels >1.5 times the upper limit of normal (ULN) or elevated aminotransferases >3 times ULN (without liver metastases), or >5 times ULN (with liver metastases), has not been specifically studied.

Method of administration.

Warnings regarding the preparation and administration of Pemetrexed FaRes are described in the section "Special precautions." Pemetrexed FaRes 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 FaRes are provided below.

Recommendations for administration.

1. Appropriate aseptic techniques should be used during reconstitution and subsequent dilution of pemetrexed for intravenous infusion.
2. Calculate the required dose and number of vials of Pemetrexed FaRes. Each vial contains an excess of pemetrexed to ensure the labeled dose is delivered.
3. Reconstitute the contents of the 500 mg vial with 20 mL of 0.9% sodium chloride injection solution (without preservatives) to obtain a solution containing 25 mg/mL of pemetrexed. Gently swirl each vial until the powder is completely dissolved. The resulting solution should be clear, colorless to yellow or greenish-yellow, and free of particulate matter. The pH of the reconstituted solution is 6.6–7.8. FURTHER DILUTION IS REQUIRED.
4. 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.
5. The pemetrexed infusion solution, prepared as described above, is compatible with intravenous infusion bags and administration sets made of polyvinyl chloride and polyolefin.
6. Intravenous preparations should be inspected visually for particulate matter and discoloration prior to administration. If particulate matter is present, the solution must not be used.
7. The pemetrexed solution is intended for individual use only. Unused medicinal product or waste material should be disposed of in accordance with local regulations.

Prepared solution. When prepared according to the recommended instructions, the reconstituted powder and infusion solution of Pemetrexed FaRes do not contain antimicrobial preservatives.

Chemical and physical stability of the reconstituted powder and pemetrexed infusion solution was observed for 24 hours when stored refrigerated. From a microbiological standpoint, the prepared Pemetrexed FaRes infusion solution should be used immediately. If the medicinal product is not used immediately, the user is responsible for ensuring proper storage at 2–8°C for no longer than 24 hours.

Pediatric population. There are no relevant data on the use of Pemetrexed FaRes in pediatric patients for the treatment of malignant pleural mesothelioma and non-small cell lung cancer.

Overdose.

Symptoms. Reported symptoms include neutropenia, anemia, thrombocytopenia, mucositis, sensory polyneuropathy, and rash. Expected complications of overdose include bone marrow suppression, manifesting as neutropenia, thrombocytopenia, and anemia. In addition, infection (with or without fever), diarrhea, and/or mucositis may occur.

Treatment. In case of suspected overdose, the patient should be monitored, appropriate blood tests should be performed, and symptomatic therapy should be administered as needed. The use 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 aminotransferase levels, 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. In both treatment groups, patients received folic acid and vitamin B12 supplementation as recommended.

Within each group, adverse reactions are listed in descending order of frequency as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (<1/10000), and frequency not known (cannot be estimated from available data).

Table 4

Body systems	Frequency		Signs*	Pemetrexed/Cisplatin (N=168)		Cisplatin (N=163)
				Any grade toxicity (%)	Grade III–IV toxicity (%)	Any grade toxicity (%)	Grade III–IV toxicity (%)
Blood and lymphatic system	Very common		Neutropenia/Granulocytopenia	56.0	23.2	13.5	3.1
			Leukopenia	53.0	14.9	16.6	0.6
			Decreased hemoglobin	26.2	4.2	10.4	0.0
			Decreased platelet count	23.2	5.4	8.6	0.0
Metabolism and nutrition	Common		Dehydration	6.5	4.2	0.6	0.6
Nervous system	Very common		Sensory neuropathy	10.1	0.0	9.8	0.6
	Common		Taste disturbance	7.7	0.0***	6.1	0.0***
Ophthalmologic disorders	Common		Conjunctivitis	5.4	0.0	0.6	0.0
Gastrointestinal system	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	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 toxicity grade (version 2.0), except for the criterion "decreased creatinine clearance"**.

** This term originates from the CTC category "Other renal/urinary tract disorders".

*** According to the National Cancer Institute, USA, CTC criteria (version 2.0; NCI 1998), alopecia and taste disturbances should be reported as Grade I or II.

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), urticaria, 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 events 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 locally advanced or metastatic non-small cell lung cancer and had received prior chemotherapy.

Table 5

Organ systems	Frequency	Signs*	Pemetrexed (N=265)		Docetaxel (N=276)
			Any-grade toxicity (%)	Grade III–IV toxicity (%)	Any-grade toxicity (%)	Grade III–IV 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
		Hemoglobin decrease	19.2	4.2	22.1	4.3
	Common	Thrombocyte count decrease	8.3	1.9	1.1	0.4
Gastrointestinal disorders	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 disorders	Common	ALT (SGPT)	7.9	1.9	1.4	0.0
		AST (SGOT)	6.8	1.1	0.7	0.0
Skin and subcutaneous tissue disorders	Very common	Rash/desquamation	14.0	0.0	2	0.0
	Common	Pruritus	6.8	0.4	1.8	0.0
		Alopecia	6.4	0.4**	37.7	2.2**
General disorders	Very common	Fatigue	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 based on laboratory values for each grade of toxicity (version 2.0).

** According to the National Cancer Institute, USA, CTC criteria (version 2.0; NCI 1998), alopecia should be reported as Grade I or Grade II toxicity.

A 5% threshold was used in this table to include 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 Grade III and IV overall toxicity were similar to the integrated Phase 2 results across three pemetrexed monotherapy studies (n=164) and the Phase 3 study described above, except for neutropenia (12.8% vs. 5.3%, respectively) and increased alanine aminotransferase (ALT) levels (15.2% vs. 1.9%, respectively). These discrepancies were likely due to differences in patient populations, as the Phase 2 studies included both chemotherapy-naïve patients and those with heavily pretreated breast cancer and pre-existing liver metastases and/or baseline abnormalities in liver function tests.

Table 6 shows 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, and 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

Body systems	Frequency	Symptoms*	Pemetrexed/cisplatin (N=839)		Gemcitabine/cisplatin (N=830)
			Any-grade toxicity (%)	Toxicity Grade III–IV (%)	Any-grade toxicity (%)	Toxicity Grade III–IV (%)
Blood and lymphatic system	Very common	Hemoglobin decrease	33.0*	6*	45.7*	9.9*
		Neutropenia/granulocytopenia	29.0*	15.1*	38.4*	26.7*
		Leukopenia	17.8	4.8*	20.6	7.6*
		Thrombocyte decrease	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 disorders	Very common	Creatinine increase	10.1*	0.8	9*	0.5
General disorders	Very common	Fatigue	42.7	6.7	44.9	4.9

*P-values ≤ 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 I or II.

The 5% threshold in this table was set to include all symptoms considered related to pemetrexed.

Clinically significant toxicity observed in ≥ 1% and ≤ 5% of patients randomly assigned to receive cisplatin and pemetrexed includes elevated AST levels, elevated ALT levels, infection, febrile neutropenia, renal failure, fever, dehydration, conjunctivitis, and decreased creatinine clearance.

Clinically significant toxicity observed in < 1% of patients randomly assigned to receive cisplatin and pemetrexed includes elevated GGT levels, substernal chest pain, arrhythmia, and motor neuropathy.

Clinically significant toxicity by gender was similar across all patient populations receiving pemetrexed with cisplatin.

Table 7 shows the frequency and severity of adverse reactions observed in > 5% of 800 patients randomly assigned to receive pemetrexed, as well as 402 patients randomly assigned to receive placebo, in the single-agent pemetrexed maintenance study (JMEN study), and in the long-term maintenance study with single-agent pemetrexed (PARAMOUNT study). All patients had stage IIIB or IV non-small cell lung cancer and had previously received platinum-based chemotherapy. Patients received full replacement of folic acid and vitamin B12.

Table 7

Organ systems	Frequency	Symptoms*	Pemetrexed (N=800)***		Placebo (N=402)***
			Any-grade toxicity (%)	Grade III–IV toxicity (%)	Any-grade toxicity (%)	Grade III–IV 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 threshold of 5 % was introduced in this table to include all symptoms considered related to pemetrexed.

** Refers to the National Cancer Institute (USA) Common Toxicity Criteria (CTC) for laboratory values for each toxicity grade (version 3.0, NCI 2003). The reported frequency of events corresponds to the requirements of CTCAE, version 3.0.

*** The integrated adverse reactions table includes pooled data from the pemetrexed maintenance therapy studies JMEN (N=663) and PARAMOUNT (N=539).

**** General term encompassing increased blood/serum creatinine levels, decreased glomerular filtration rate, renal failure, and other renal and urinary system disorders.

Clinically significant toxicity observed in ≥1 % and ≤ 5 % of patients randomized 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 randomized to pemetrexed therapy includes allergic reactions/hypersensitivity, erythema multiforme, supraventricular arrhythmia, and pulmonary embolism.

Safety was evaluated in patients randomized to pemetrexed therapy (N=800). The incidence 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 incidence of adverse reactions (all grades of severity) was observed with prolonged treatment duration. A significant increase in the incidence of adverse events possibly related to drug use, specifically grade III or IV neutropenia, was observed with longer treatment duration (≤ 6 cycles – 3.3 %; > 6 cycles – 6.4 %; p=0.046). No statistically significant difference in the incidence of other individual adverse events of grade III, IV, or V was observed with prolonged treatment duration.

Serious cardiovascular and cerebrovascular events, including myocardial infarction, angina pectoris, cerebrovascular accident, and transient ischemic attack, were infrequently reported during clinical trials of pemetrexed, usually in combination with other cytotoxic agents. Most patients in whom such events occurred had a history of cardiovascular risk factors.

Potentially serious cases of hepatitis were rarely reported during clinical trials.

Cases of pancytopenia were infrequently reported during clinical trials of 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 insufficiency, 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 of pemetrexed.

Sepsis, sometimes fatal, was frequently reported during clinical trials of pemetrexed.

During post-marketing surveillance of pemetrexed, the following adverse reactions have been observed.

Hyperpigmentation has been frequently reported.

Acute renal failure has been infrequently reported both during pemetrexed monotherapy and in combination with other chemotherapeutic agents (see section "Special precautions"). Cases of nephrogenic diabetes insipidus and renal tubular necrosis have been reported in post-marketing studies with unknown frequency.

Radiation pneumonitis has been infrequently reported in patients who received radiation therapy before, during, or after pemetrexed treatment.

"Radiation recall" reactions have been rarely reported in patients who previously received radiation therapy.

Peripheral ischemia, sometimes leading to limb necrosis, has been infrequently reported.

Bullous skin disorders, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been rarely reported, sometimes with fatal outcomes.

Immune-mediated hemolytic anemia has been rarely reported in patients receiving pemetrexed.

Anaphylactic shock has been rarely reported.

Cases of infectious and non-infectious diseases of the skin, subcutaneous tissue, and/or subcutis, such as acute bacterial dermohypodermitis, pseudocellulitis, and dermatitis, have been reported. The frequency is unknown.

Exudative erythema, predominantly affecting the lower limbs, has been reported. Frequency is unknown.

Shelf life. 3 years.

Storage conditions. No special storage conditions are required for this medicinal product. Keep out of reach of children.

Incompatibilities. Pemetrexed is incompatible with calcium-containing diluents, 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 or 500 mg in a vial; 1 vial per cardboard pack.

Prescription status. Prescription only.

Manufacturer.

Timoorgan Pharma GmbH.

Manufacturer's address and location of business operations.

Schiffgraben 23, Goslar, Niedersachsen, 38690, Germany.