Pexarit

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

Composition:

Active substance: pemetrexed;

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

Excipients: mannitol (Pearlitol PF), hydrochloric acid concentrated, sodium hydroxide.

Pharmaceutical form. Powder for concentrate for solution for infusion.

Main physicochemical properties: lyophilized mass or powder ranging from white to pale yellow or greenish-yellow in color.

Pharmacotherapeutic group. Antineoplastic agents. Antimetabolites. Structural analogues of folic acid. Pemetrexed. ATC code L01BA04.

Pharmacological Properties

Pharmacodynamics

Pexarit (pemetrexed) is an antitumor antifolate agent with multi-targeted activity, disrupting key folate-dependent metabolic processes essential for cellular replication.

In vitro studies have demonstrated that pemetrexed exerts multi-targeted antifolate effects by inhibiting thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), which are key folate-dependent enzymes required for the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed enters cells via both the reduced folate carrier and folate-binding membrane protein transport systems. Once inside the cell, pemetrexed is rapidly and efficiently converted into polyglutamated forms by the enzyme folylpolyglutamate synthetase. Polyglutamated forms are retained 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. Polyglutamated metabolites have a prolonged intracellular half-life, resulting in sustained drug activity within malignant cells.

Pharmacokinetics

The pharmacokinetic properties of pemetrexed were evaluated in 426 cancer patients with various solid tumors following administration as monotherapy via a 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. It is primarily excreted renally, with 70–90% of the administered dose eliminated unchanged in urine within 24 hours after administration. In vitro studies indicate that pemetrexed is actively secreted via OAT3 (organic anion transporter 3).

The 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%. 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 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-small cell non-squamous cell lung cancer in the first-line chemotherapy.

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

Pemetrexed as monotherapy is indicated for the treatment of patients with locally advanced or metastatic non-small cell non-squamous cell 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 administration of yellow fever vaccine (see section "Interaction with other medicinal products and other types of interactions").

Special precautions.

As with all 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 and thoroughly with soap and water. If pemetrexed solution comes into contact with mucous membranes, they should be thoroughly rinsed 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 types of interactions.

Pemetrexed is primarily excreted unchanged by the kidneys via tubular secretion or, less frequently, via glomerular filtration. Concomitant administration of nephrotoxic drugs (e.g., aminoglycosides, loop diuretics, platinum compounds, cyclosporine) may reduce pemetrexed clearance. Such combinations should be used with caution. If necessary, creatinine clearance should be closely monitored.

Concomitant administration 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 events. Therefore, high doses of NSAIDs or acetylsalicylic acid should be used cautiously in combination 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 (see section "Special warnings and precautions for use").

In the absence of data on potential interactions with NSAIDs having a long half-life, such as piroxicam or rofecoxib, concomitant administration 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 (see section "Special warnings and precautions for use"). 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, and CYP1A2.

Interactions common to all cytotoxic agents.

Due to the increased risk of thrombosis, oncology patients are often treated with anticoagulant therapy. The high individual variability in coagulation status during the disease course and the potential for interactions between oral anticoagulants and anticancer chemotherapy 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 (see section "Contraindications").

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., polio) (see section "Special warnings and precautions for use").

Special precautions for use.

Pemetrexed may suppress bone marrow function, manifesting as neutropenia, thrombocytopenia, anemia (or pancytopenia) (see section "Adverse reactions"); myelosuppression is usually the dose-limiting toxicity. Myelosuppression in patients must be monitored throughout treatment. Pemetrexed should not be administered to patients 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 previous treatment: the lowest ANC value, platelet count, and the most severe manifestations of non-hematological toxicity.

Lower overall toxicity and reduced incidence of grade 3/4 hematological and non-hematological toxicities, such as neutropenia, febrile neutropenia, and neutropenia-associated infection, have been observed when folic acid and vitamin B₁₂ were administered prior to treatment. Therefore, patients receiving pemetrexed therapy must receive folic acid and vitamin B₁₂ prophylactically to reduce treatment-related toxicity (see section "Dosage and administration").

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 (see section "Dosage and administration").

Clinical experience with pemetrexed in patients with creatinine clearance below 45 mL/min is limited; therefore, pemetrexed should not be administered to such patients (see section "Dosage and administration").

Patients with mild to moderate renal impairment (creatinine clearance 45–79 mL/min) should avoid taking nonsteroidal anti-inflammatory drugs (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 (see section "Interaction with other medicinal products and other forms of interaction").

Patients with mild to moderate renal impairment receiving pemetrexed therapy should discontinue NSAIDs with a long elimination half-life 5 days before, on the day of, and for 2 days after pemetrexed administration (see section "Interaction with other medicinal products and other forms of interaction").

Serious renal disorders, including acute renal failure, have been reported 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 use of pemetrexed 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 on cavity fluids such as pleural effusion and ascites has not been fully established. In a phase 2 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 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 reported 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 (see section "Adverse reactions").

Most cancer patients are immunocompromised; therefore, concomitant use of live vaccines is not recommended (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Pemetrexed may cause genetic damage. Sexually mature men should not plan fatherhood during pemetrexed therapy and for 6 months after treatment. Contraceptive measures 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 and for 6 months after completion of treatment.

Cases of radiation pneumonitis have been reported in patients who received radiotherapy before, during, or after pemetrexed therapy. These patients require special attention, and caution should be exercised when using other radiosensitizing agents.

Cases of "radiation recall" have been reported in patients who received treatment in previous weeks or years.

Excipients

Pexarit, powder for concentrate for solution for infusion 100 mg

This medicinal product contains less than 1 mmol sodium (23 mg) per vial and is therefore considered essentially "sodium-free."

Pexarit, powder for concentrate for solution for infusion 500 mg

This medicinal product contains approximately 54 mg sodium per vial, equivalent to approximately 2.7% of the WHO recommended maximum daily intake of sodium for adults (2 g). This should be taken into account for patients on a controlled sodium diet.

Use during pregnancy or breastfeeding.

Contraception in men and women.

Women of childbearing potential must use effective contraception during pemetrexed therapy and for 6 months after completion of treatment.

Pemetrexed may cause genetic damage.

Sexually mature men are advised to use effective contraception and avoid fathering a child during treatment and for up to 3 months thereafter.

Pregnancy.

There are no data on the use of pemetrexed in pregnant women. However, like other antimetabolites, pemetrexed may cause severe congenital defects when administered during pregnancy. Reproductive toxicity has been observed in animal studies. 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 (see section "Special precautions for use").

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 (see section "Contraindications").

Fertility.

Due to the potential of pemetrexed to cause irreversible infertility, men are advised to consider sperm preservation before starting treatment.

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, fatigue has been reported with pemetrexed; therefore, patients should exercise caution when driving or operating machinery.

Method of Administration and Dosage

The medicinal product Pexarit 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 Pexarit 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 approximately 30 minutes after completion of 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 administration

For the treatment of non-small cell lung cancer (NSCLC) after prior chemotherapy, the recommended dose of Pexarit 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 one day before, on the day of, and the day after pemetrexed administration. The corticosteroid dose should be equivalent to 4 mg dexamethasone orally twice daily (see section "Special Instructions").

To reduce toxicity, patients receiving pemetrexed therapy must be given vitamin supplementation (see section "Special Instructions"). Patients should take 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 (1000 mcg) during the week before the first pemetrexed dose 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 leukocyte count (WCC) and platelets should be assessed before each administration. A biochemical blood test should be performed before each chemotherapy cycle to evaluate liver and kidney function. Absolute neutrophil count (ANC) must be ≥ 1.5 × 10⁹/L and platelet count ≥ 100 × 10⁹/L prior to initiation of 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), aspartate aminotransferase (ALT), and alanine aminotransferase (AST) levels should not exceed normal limits by more than 3 times. Elevations in AP, ALT, and AST up to 5 times the upper normal limit are acceptable if liver metastases are present.

Dose modification.

Dose adjustments prior to the start of 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 Pexarit as monotherapy or in combination with cisplatin.

Table 1

Dose modification of Pexarit

(combination therapy or monotherapy) and cisplatin

Hematological toxicity

Indicators	Dose
Minimum ANC value < 0.5 × 109/l and minimum platelet value ≥ 50 × 109/l	75% of previous dose (for both drugs)
Minimum platelet value < 50 × 109/l regardless of minimum ANC value	75% of previous dose (for both drugs)
Minimum platelet value < 50 × 109/l with presence of bleeding, regardless of minimum ANC value	50% of previous dose (for both drugs)

and Criteria according to the Common Toxicity Criteria of the National Cancer Institute, USA (CTC v2.0; NCI 1998) correspond to bleeding ≥ CTC grade 2.

If a patient develops signs of non-hematological toxicity (except neurotoxicity) ≥ grade 3, administration of the medicinal product Pexarit should be discontinued until values decrease to lower levels or return to values observed prior to initiation of therapy in this patient. Therapy should be continued according to the recommendations outlined in Table 2.

Table 2

Dose modification of the medicinal product Pexarit

(combination therapy or monotherapy) and cisplatin

Non-hematological toxicitya,b

a CTC – Common Toxicity Criteria (NCI, 1998).
b Except neurotoxicity.
c Discontinue Pexarit until toxicity resolves to ≤ grade 1 or baseline.
d Reduce Pexarit dose by one dose level (see section 4.2).
e For combination therapy with cisplatin, modify cisplatin dose according to institutional guidelines.
f Monitor renal function closely; adjust hydration and diuretic regimen as needed.
g For hepatic toxicity, discontinue Pexarit until liver function tests return to ≤ grade 1 or baseline, then consider dose reduction.
h For severe skin reactions, discontinue Pexarit permanently.
i For other non-hematological toxicities, manage per clinical judgment and consider dose interruption or reduction.
j Refer to Table 1 for dose levels.
k In case of rechallenge, start at a lower dose level.
l Permanently discontinue Pexarit if toxicity recurs at reduced dose.
m Adjust dose based on severity and persistence of adverse events.
n For prolonged toxicity (> 2 weeks), consider permanent discontinuation.
o Dose modifications apply to both monotherapy and combination regimens unless otherwise specified.
p Consult prescribing information for cisplatin regarding dose adjustments.
q Monitor patients closely during dose re-escalation.
r Dose modifications should be individualized based on patient’s overall condition and tolerance.
s For grade 4 non-hematological toxicity, permanently discontinue Pexarit.
t Dose resumption after interruption should follow the guidelines in section 4.2.
u For recurrent toxicity, consider permanent discontinuation.
v Dose reduction steps are cumulative.
w In combination therapy, coordinate dose adjustments of both agents.
x For mucositis ≥ grade 3, interrupt Pexarit until resolution to ≤ grade 1, then resume at reduced dose.
y For diarrhea ≥ grade 3, discontinue Pexarit until resolution and resume at lower dose.
z For hypertension ≥ grade 3, discontinue Pexarit until controlled, then resume with caution.

	Dose of the medicinal product Pexarit (mg/m2)	Dose of cisplatin (mg/m2)
Any grade 3 or 4 toxicity, except mucositis	75 % of the previous dose	75 % of the previous dose
Any diarrhea requiring hospitalization (regardless of grade), or grade 3 or 4 diarrhea	75 % of the previous dose	75 % of the previous dose
Mucositis grade 3 or 4	50 % of the previous dose	100 % of the previous dose

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

bExcluding neurotoxicity.

Recommended dose modification of the medicinal product Pexarit and cisplatin in case of neurotoxicity is presented in Table 3. In case of grade 3 or 4 neurotoxicity, treatment should be discontinued.

Table 3

Dose modification of the medicinal product Pexarit

(combination therapy or monotherapy) and cisplatin

Neurotoxicity

CTCa grade	Pexarit drug dosage (mg/m2)	Cisplatin dosage (mg/m2)
0–1	100 % of previous dose	100 % of previous dose
2	100 % of previous dose	50 % of previous dose

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

Treatment with Pexarit 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 reactions compared to patients younger than 65 years. No dose adjustments are required other than those recommended for all patients.

Patients with renal impairment (using the standard Cockcroft-Gault formula or glomerular filtration rate (GFR) determined by serum clearance of Tc99m-DTPA). Pemetrexed is predominantly excreted unchanged by the kidneys. In clinical studies, no dose adjustments were necessary for patients with creatinine clearance ≥45 mL/min, apart from those recommended for all patients. The number of patients with creatinine clearance <45 mL/min was insufficient to make specific dosing recommendations for this patient group. Therefore, the use of pemetrexed in patients with creatinine clearance <45 mL/min is not recommended (see section "Special instructions").

Patients with hepatic impairment. No correlation has been established between AST, ALT, total bilirubin levels, 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) and/or aminotransferases >3 times ULN (without liver metastases), or >5 times ULN (with liver metastases), has not been specifically studied.

Method of administration.

Pexarit is intended for intravenous use. Pexarit should be administered as an intravenous infusion over 10 minutes on day 1 of each 21-day cycle.

Precautions regarding the preparation and administration of Pexarit are described in the section "Special precautions for handling." Recommendations for reconstitution and dilution of Pexarit are provided below.

Recommendations for use

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 Pexarit vials. Each vial contains an excess of pemetrexed to ensure the labeled dose can be withdrawn.
3. Pexarit 100 mg: Reconstitute the contents of the 100 mg vial with 4.2 mL of 0.9% sodium chloride injection solution (without preservatives) to obtain a solution containing 25 mg/mL of pemetrexed. Pexarit 500 mg: 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 shake 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 ranges from 6.6 to 7.8. FURTHER DILUTION IS REQUIRED.
4. The required volume of the reconstituted pemetrexed solution should be further diluted to a total volume of 100 mL with 0.9% sodium chloride injection solution (without preservatives) and administered as an intravenous infusion over 10 minutes.
5. The pemetrexed infusion solution prepared as described above is compatible with polyvinyl chloride infusion bags and administration sets.
6. Parenteral products 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 single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Children.

There are no relevant data on the use of Pexarit 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, monitor the patient, perform appropriate blood tests, and administer symptomatic therapy as needed. Consideration should be given to the administration of calcium folinate/folic acid.

Adverse reactions

Adverse reactions most commonly reported during pemetrexed administration, both as monotherapy and in combination therapy, include bone marrow suppression manifested as anemia, neutropenia, leukopenia, and thrombocytopenia; and gastrointestinal toxicity manifested 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. Rarely, Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.

Table 4 lists adverse events regardless of causality, associated with the use of pemetrexed either as monotherapy or in combination with cisplatin, observed in pivotal registration studies and during the post-marketing period.

Adverse reactions are listed below by MedDRA system organ classes. The following terminology was used to classify frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from available data).

Within each frequency category, adverse reactions are listed in order of decreasing severity.

Table 4

Frequency of adverse events of all grades, regardless of causality, observed in pivotal registration studies and during the post-marketing period

System organ class (MedDRA)	Very common	Common	Uncommon	Rare	Very rare	Frequency not known
Infections and infestations	Infectious pharyngitis	Sepsisb			Dermatogranuloma
Blood and lymphatic system disorders	Neutropenia Leukopenia Decreased hemoglobin levels	Febrile neutropenia Decreased platelet count	Pancytopenia	Autoimmune hemolytic anemia
Immune system disorders		Hypersensitivity		Anaphylactic shock
Metabolism and nutrition disorders		Dehydration
Nervous system disorders		Taste disturbance Peripheral motor neuropathy Peripheral sensory neuropathy Confusion	Cerebrovascular accident Ischemic stroke Intracranial hemorrhage
Eye disorders		Conjunctivitis Dry eyes Increased lacrimation Dry keratoconjunctivitis Periorbital edema Surface eye disorders
Cardiac disorders		Heart failure Arrhythmia	Angina pectoris Myocardial infarction Ischemic heart disease Supraventricular arrhythmia
Vascular disorders			Peripheral ischemiac
Respiratory, thoracic and mediastinal disorders			Pulmonary embolism Interstitial lung diseasebd
Gastrointestinal disorders	Stomatitis Anorexia Vomiting Diarrhea Nausea	Dyspepsia Constipation Abdominal pain	Rectal hemorrhage Gastrointestinal hemorrhage Intestinal perforation Esophagitis Colitise
Hepatobiliary disorders		Increased alanine aminotransferase levels Increased aspartate aminotransferase levels		Hepatitis
Skin and subcutaneous tissue disorders	Rash Desquamation of skin	Hyperpigmentation Pruritus Multiform erythema Alopecia Urticaria		Erythema	Stevens-Johnson syndromeb Toxic epidermal necrolysisb Pemphigoid Bullous dermatitis Acquired bullous epidermolysis Erythematous swellingf Pseudocellulitis Dermatitis Exema Prurigo
Renal and urinary disorders	Decreased creatinine clearance Increased blood creatinine levels	Renal failure Decreased glomerular filtration rate				Nephrogenic diabetes insipidus Renal tubular necrosis
General disorders and administration site conditions	Weakness	Pyrexia Pain Edema Chest pain Mucosal inflammation
Investigations		Increased gamma-glutamyl- transferase levels
Injury, poisoning and procedural complications			Radiation esophagitis Radiation pneumonitis	Radiation dermatitis

aWith neutropenia and without it.

bIn some cases fatal.

cSometimes leads to limb necrosis.

dWith respiratory failure.

eObserved only in combination with cisplatin.

fMostly lower limbs.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Prepared solution. Chemical and physical stability of reconstituted and infusion solutions of pemetrexed has been demonstrated for 24 hours when stored at 2 °C to 8 °C. From a microbiological standpoint, the prepared solution should be used immediately. If the prepared solution is not used immediately, the user is responsible for the storage conditions and duration prior to use, which must not exceed 24 hours at a temperature of 2 °C to 8 °C.

Storage conditions.

Store below 25 °C. Keep out of reach of children.

The prepared solution should be stored at 2–8 °C for no more than 24 hours.

Incompatibilities.

Pemetrexed is incompatible with solvents containing calcium, such as lactated Ringer's solution and Ringer's injection solution. Compatibility studies of pemetrexed are lacking; therefore, it must not be mixed with any other medicinal product.

Packaging.

One vial containing powder for concentrate for solution for infusion in a cardboard box, or one vial containing powder for concentrate for solution for infusion in a protective plastic container within a cardboard box.

Prescription category. Prescription only.

Manufacturer.

Yugia Pharma Specialities Limited.

Manufacturer's address and location of its business operations.

Survey Nos. 550, 551 and 552, Choultry Village, Shamirpet Mandal, Medchal – Malkajgiri, Medchal District, Telangana State, 500101 – India.