Pemetrexed - vista solut

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PEMETREXED-VISTA solut (PEMETREXED-VISTA solut)

Composition:

Active substance: pemetrexed;

1 ml of concentrate contains 25 mg of pemetrexed;

Excipients: L-arginine, L-cysteine, propylene glycol, citric acid, water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties:

A clear solution, from colorless or slightly yellowish, or brownish to yellowish-brown or greenish-yellow in color. Practically free from particles. In colorless glass vials with a rubber stopper and an aluminum flip-top cap. The 7 ml vial contains 4 ml of concentrate.

A clear solution, from colorless or slightly yellowish, or brownish to yellowish-brown or greenish-yellow in color. Practically free from particles. In colorless glass vials with a rubber stopper and an aluminum flip-top cap. The 20 ml vial contains 20 ml of concentrate.

A clear solution, from colorless or slightly yellowish, or brownish to yellowish-brown or greenish-yellow in color. Practically free from particles. In colorless glass vials with a rubber stopper and an aluminum flip-top cap. The 50 ml vial contains 40 ml of concentrate.

Pharmacotherapeutic group. Antineoplastic and immunomodulating agents. Antineoplastic agents. Antimetabolites. Folic acid analogues. Pemetrexed. 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 folate-binding membrane protein transport systems. Once inside the cell, pemetrexed is rapidly converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The 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 prolonged drug effect 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 studied in 426 oncology patients with various solid tumors following administration of pemetrexed 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 degree 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 indicate that pemetrexed is actively secreted by OAT3 (organic anion transporter 3).

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%. Total systemic exposure to pemetrexed (AUC) and maximum plasma concentration (Cmax) increase proportionally with dose escalation. Pemetrexed pharmacokinetics are consistent across 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

In combination with cisplatin 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 first-line chemotherapy.

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 after 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 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.

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 the pemetrexed solution comes into contact with the skin, the skin should be immediately washed with soap and water. If the pemetrexed solution contacts mucous membranes, they should be rinsed with water. Pemetrexed does not cause blistering. There is no specific antidote to manage hemorrhage resulting from pemetrexed administration. Several cases of hemorrhage attributed to pemetrexed have been reported, which were not classified by investigators as serious. Hemorrhage should be managed according to local standards.

Interaction with other medicinal products and other forms of interaction.

Pemetrexed is primarily eliminated unchanged via the kidneys through tubular secretion and, less frequently, via glomerular filtration. Concomitant administration of nephrotoxic drugs (e.g., aminoglycosides, loop diuretics, platinum agents, cyclosporine) may lead to reduced pemetrexed clearance. Such combinations should be used with caution. If necessary, creatinine clearance should be closely monitored.

Concomitant use of pemetrexed with inhibitors of OAT3 (organic anion transporter) (e.g., probenecid, penicillin, proton pump inhibitors) results in delayed pemetrexed clearance. These medicinal products should be combined with pemetrexed cautiously.

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-dose NSAIDs should be prescribed with caution when used concomitantly 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 high-dose NSAIDs (e.g., ibuprofen or acetylsalicylic acid) should be avoided for 2 days prior to pemetrexed administration, on the day of administration, and for 2 days following 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 prior to pemetrexed administration, on the day of administration, and for 2 days thereafter. 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 using 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 prescribed 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 monitoring of the international normalized ratio (INR) if oral anticoagulants are prescribed 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 may suppress bone marrow function, manifesting as neutropenia, thrombocytopenia, anemia (or pancytopenia); myelosuppression is usually the dose-limiting toxicity. Myelosuppression in patients 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 cycle: the lowest ANC value, platelet count, and the most severe non-hematological toxicity.

Lower overall toxicity, as well as reduced hematological and non-hematological toxicities of grade III–IV, such as neutropenia, febrile neutropenia, and neutropenic infection of grade III–IV, 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 its equivalent) may reduce the incidence 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 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.

For patients with mild to moderate renal impairment receiving pemetrexed therapy, NSAIDs with a prolonged 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 during 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, either alone or in combination with other chemotherapeutic agents. Most of these events resolve after discontinuation of pemetrexed. Acute tubular necrosis, decreased renal function, and symptoms of nephrogenic diabetes insipidus (e.g., hypernatremia) should be monitored regularly in patients.

The effect of pemetrexed in body cavity fluids, such as pleural effusion and ascites, 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 differences were 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 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 should not plan fatherhood during pemetrexed therapy and for 3 months after treatment. Contraceptive measures should be used or sexual intercourse should be avoided. Due to the potential of pemetrexed to cause irreversible infertility, men are advised to consider sperm preservation before starting treatment.

Women of reproductive potential should 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 radiation therapy before, during, or after pemetrexed therapy. Particular caution is required when using other radiosensitizing agents.

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

Use during pregnancy or breastfeeding.

Contraception in men and women

Women who may become pregnant must use effective contraceptive measures during pemetrexed therapy and for 6 months after completion of treatment.

Pemetrexed may cause genetic damage. Sexually active men should not plan fatherhood during pemetrexed therapy and for 3 months after treatment. Contraceptive measures should be used or sexual intercourse should be avoided.

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 revealed reproductive toxicity. Pemetrexed should not be used during pregnancy except in cases of essential need, following careful assessment of benefit to the pregnant woman and risk to the fetus.

Breastfeeding

It is unknown whether pemetrexed is excreted in human breast milk. Adverse reactions in breastfed infants cannot be excluded. Therefore, breastfeeding should be discontinued during pemetrexed therapy.

Fertility

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

Ability to affect reaction speed when driving or operating machinery.

No studies have been conducted on the effect of the drug on the ability to drive or operate machinery. 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 treatment with antineoplastic agents.

Combination with cisplatin

The recommended dose of Pemetrexed-Vista solut is 500 mg/m² body surface area (BSA) 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 BSA 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 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-Vista solut is 500 mg/m² BSA 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 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 entire course of therapy and for 21 days after the last dose of pemetrexed. Patients should also receive vitamin B12 (1000 mcg) intramuscularly once weekly for one 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 leukocyte counts and platelets, should be monitored before each administration. Biochemical blood tests to assess liver and kidney function should be performed before each chemotherapy cycle. Absolute neutrophil count (ANC) should be ≥ 1.5×10⁹/L and platelet count ≥ 100×10⁹/L prior to 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 (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels should not exceed the upper limit of normal by more than 3 times. Elevations in ALP, 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 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 pemetrexed use as monotherapy or in combination with cisplatin.

Table 1

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

Hematological toxicity

Indicators	Dose
Lowest ANC value < 0.5×109/l and lowest platelet count ≥ 50×109/l	75% of previous dose (both drugs)
Lowest platelet count < 50×109/l regardless of lowest ANC value	75% of previous dose (both drugs)
Lowest platelet count < 50×109/l in case of bleeding, regardless of lowest ANC value	50% of previous dose (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 should be discontinued until values return to lower levels or to values consistent with the patient's baseline prior to starting therapy. Therapy should be resumed according to the recommendations outlined in Table 2.

Table 2

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

Non-hematological toxicity a,b

	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, USA Common Toxicity Criteria (CTC v2.0; NCI 1998).

b Excluding neurotoxicity.

Recommended dose modifications of pemetrexed and cisplatin in the case of neurotoxicity are presented in Table 3. In case of grade III or IV neurotoxicity, treatment should be discontinued.

Table 3

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

Neurotoxicity

CTCa grade	Pemetrexed 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).

Treatment with Pemetrexed-Vista Solut should be discontinued if a patient experiences any hematological or non-hematological toxicity of grade III or IV after two dose reductions, and should be 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 reactions compared to patients under 65 years of age. No dose reduction is required other than that recommended for all patients.

Patients with renal impairment (defined by the standard Cockcroft-Gault formula or glomerular filtration rate (GFR) determined by plasma clearance of Tc99m-DTPA). Pemetrexed is primarily excreted unchanged by the kidneys. Dose adjustment was not required in clinical studies for patients with creatinine clearance ≥45 mL/min, apart from recommendations applicable to all patients. The number of patients with creatinine clearance <45 mL/min was insufficient to establish 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 pemetrexed pharmacokinetics. 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 transaminases >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-Vista Solut are provided in the section "Special precautions for handling." 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 are given 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. Each vial contains an excess of pemetrexed to ensure the labeled dose can be withdrawn. One vial contains a solution with 25 mg/mL pemetrexed.
3. The required volume of the reconstituted pemetrexed solution should be further diluted to 100 mL using 0.9% sodium chloride solution (without preservatives) and administered as an intravenous infusion over 10 minutes.
4. The pemetrexed infusion solution prepared as described above is compatible with infusion bags and administration sets made of polyvinyl chloride and polyolefin.
5. 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.
6. The pemetrexed solution is intended for single use only. Any unused medicinal product or waste material should be disposed of in accordance with current legislation.

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. 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. If overdose is suspected, the patient should be monitored, appropriate blood tests performed, and symptomatic treatment initiated as necessary. Consideration should be given to the use of calcium folinate and folic acid.

Adverse reactions.

The most commonly reported adverse reactions associated with the use of pemetrexed (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, elevated aminotransferase levels, alopecia, asthenia, dehydration, rash, infection/sepsis, and neuropathy. Rarely, Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.

Table 4 lists adverse reactions regardless of causal relationship to pemetrexed, observed during monotherapy or in combination with cisplatin, from pivotal registration studies (JMCH, JMEI, JMBD, JMEN, and PARAMOUNT) and from the post-marketing period.

Within each category, adverse reactions are listed in order of decreasing frequency: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000), very rare (< 1/10,000), and frequency not known (cannot be estimated from available data).

Table 4

Frequency of all-grade adverse reactions regardless of causal relationship from the main studies: JMEI (pemetrexed and docetaxel), JMDB (pemetrexed and cisplatin vs. gemcitabine and cisplatin), JMCH (pemetrexed and cisplatin vs. cisplatin), JMEN and PARAMOUNT (pemetrexed plus best supportive care vs. placebo plus best supportive care), and from the post-marketing period.

Organ systems	Very common	Common	Uncommon	Rare	Very rare	Frequency unknown
Infections and infestations	Infectious pharyngitis	Sepsisb			Dermohypodermitis
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, dizziness	Cerebral ischemia, ischemic stroke, intracranial hemorrhage
Eye disorders		Conjunctivitis, dry eyes, increased lacrimation, dry keratoconjunctivitis, eyelid edema, ocular surface disease
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 diseased
Gastrointestinal disorders	Stomatitis, anorexia, vomiting, diarrhea, nausea	Dyspepsia, constipation, abdominal pain	Rectal hemorrhage, gastrointestinal hemorrhage, intestinal perforation, esophagitis, colitise
Hepatobiliary disorders		Increased alanine aminotransferase, increased aspartate aminotransferase		Hepatitis
Skin and subcutaneous tissue disorders	Rash, skin desquamation	Hyperpigmentation, pruritus, erythema multiforme, alopecia, urticaria		Erythema	Stevens-Johnson syndromeb, toxic epidermal necrolysisb, pemphigoidd, bullous dermatitis, acquired bullous epidermolysis, erythema multiformef, pseudocellulitis, dermatitis, eczema, pruritus
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 and without neutropenia.

bFatal in some cases.

cSometimes leads to limb necrosis.

dWith respiratory failure.

eObserved only in combination with cisplatin.

fMostly lower limbs.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is highly important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life

For 100 mg dosage: 2 years;

for 500 mg and 1000 mg dosages: 3 years.

Reconstituted solution

Chemical and physical stability of the pemetrexed infusion solution was observed for 15 hours when stored refrigerated (from 2 to 8 °C). From a microbiological standpoint, the medicinal product should be used immediately. If not used immediately, the user is responsible for appropriate storage at 2–8 °C for no longer than 24 hours.

Storage conditions.

No special storage conditions required. Keep out of reach of children.

Incompatibilities.

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

Pemetrexed-Vista solut contains L-arginine as an excipient. L-arginine is incompatible with cisplatin, leading to cisplatin degradation.

Packaging.

4 ml (100 mg), 20 ml (500 mg), or 40 ml (1000 mg) in a vial; 1 vial per cardboard box.

Prescription category. Prescription only.

Manufacturers.

Sicor Spain, S.L.

Sicor s.r.o.

Manufacturer locations and addresses of their business operations.

C/Castello, n° 1, Sant Boi de Llobregat, Barcelona, 08830, Spain.

Brnenska 32/sr. 597, Blansko, 67801, Czech Republic.