ARMISARTE Concentrate for solution for infusion Ref.[8457] Active ingredients: Pemetrexed

Pemetrexed can suppress bone marrow function as manifested by neutropenia, thrombocytopenia and anaemia (or pancytopenia) (see section 4.8). Myelosuppression is usually the dose-limiting toxicity. Patients should be monitored for myelosuppression during therapy and pemetrexed should not be given to patients until absolute neutrophil count (ANC) returns to ≥1500 cells/mm³ and platelet count returns to ≥100,000 cells/mm³. Dose reductions for subsequent cycles are based on nadir ANC, platelet count and maximum non-haematologic toxicity seen from the previous cycle (see section 4.2).

Less toxicity and reduction in Grade ¾ haematologic and non-haematologic toxicities such as neutropenia, febrile neutropenia and infection with Grade ¾ neutropenia were reported when pretreatment with folic acid and vitamin B12 was administered. Therefore, all patients treated with pemetrexed must be instructed to take folic acid and vitamin B12 as a prophylactic measure to reduce treatment-related toxicity (see section 4.2).

Skin reactions have been reported in patients not pre-treated with a corticosteroid. Pre-treatment with dexamethasone (or equivalent) can reduce the incidence and severity of skin reactions (see section 4.2).

An insufficient number of patients has been studied with creatinine clearance of below 45 ml/min. Therefore, the use of pemetrexed in patients with creatinine clearance of <45 ml/min is not recommended (see section 4.2).

Patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 ml/min) should avoid taking non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, and acetylsalicylic acid (>1.3 g daily) for 2 days before, on the day of, and 2 days following pemetrexed administration (see section 4.5).

In patients with mild to moderate renal insufficiency eligible for pemetrexed therapy NSAIDs with long elimination half-lives should be interrupted for at least 5 days prior to, on the day of, and at least 2 days following pemetrexed administration (see section 4.5).

Serious renal events, including acute renal failure, have been reported with pemetrexed alone or in association with other chemotherapeutic agents. Many of the patients in whom these occurred had underlying risk factors for the development of renal events including dehydration or pre-existing hypertension or diabetes. Nephrogenic diabetes insipidus and renal tubular necrosis were also reported in post marketing setting with pemetrexed alone or with other chemotherapeutic agents. Most of these events resolved after pemetrexed withdrawal. Patients should be regularly monitored for acute tubular necrosis, decreased renal function and signs and symptoms of nephrogenic diabetes insipidus (e.g. hypernatraemia).

The effect of third space fluid, such as pleural effusion or ascites, on pemetrexed is not fully defined. A phase 2 study of pemetrexed in 31 solid tumour patients with stable third space fluid demonstrated no difference in pemetrexed dose normalized plasma concentrations or clearance compared to patients without third space fluid collections. Thus, drainage of third space fluid collection prior to pemetrexed treatment should be considered, but may not be necessary.

Due to the gastrointestinal toxicity of pemetrexed given in combination with cisplatin, severe dehydration has been observed. Therefore, patients should receive adequate antiemetic treatment and appropriate hydration prior to and/or after receiving treatment.

Serious cardiovascular events, including myocardial infarction and cerebrovascular events have been uncommonly reported during clinical studies with pemetrexed, usually when given in combination with another cytotoxic agent. Most of the patients in whom these events have been observed had pre-existing cardiovascular risk factors (see section 4.8).

Immunodepressed status is common in cancer patients. As a result, concomitant use of live attenuated vaccines is not recommended (see section 4.3 and 4.5).

Pemetrexed can have genetically damaging effects. Sexually mature males are advised not to father a child during the treatment and up to 6 months thereafter. Contraceptive measures or abstinence are recommended. Owing to the possibility of pemetrexed treatment causing irreversible infertility, men are advised to seek counselling on sperm storage before starting treatment.

Women of childbearing potential must use effective contraception during treatment with pemetrexed (see section 4.6).

Cases of radiation pneumonitis have been reported in patients treated with radiation either prior, during or subsequent to their pemetrexed therapy. Particular attention should be paid to these patients and caution exercised with use of other radiosensitising agents.

Cases of radiation recall have been reported in patients who received radiotherapy weeks or years previously.

Pemetrexed is mainly eliminated unchanged renally by tubular secretion and to a lesser extent by glomerular filtration. Concomitant administration of nephrotoxic drugs (e.g. aminoglycoside, loop diuretics, platinum compounds, cyclosporin) could potentially result in delayed clearance of pemetrexed. This combination should be used with caution. If necessary, creatinine clearance should be closely monitored.

Concomitant administration of substances that are also tubularly secreted (e.g. probenecid, penicillin) could potentially result in delayed clearance of pemetrexed. Caution should be made when these drugs are combined with pemetrexed. If necessary, creatinine clearance should be closely monitored.

In patients with normal renal function (creatinine clearance ≥80 ml/min), high doses of non-steroidal anti-inflammatory drugs (NSAIDs, such as ibuprofen >1600 mg/day) and acetylsalicylic acid at higher dose (≥1.3 g daily) may decrease pemetrexed elimination and, consequently, increase the occurrence of pemetrexed adverse events. Therefore, caution should be made when administering higher doses of NSAIDs or acetylsalicylic acid, concurrently with pemetrexed to patients with normal function (creatinine clearance ≥80 ml/min).

In patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 ml/min), the concomitant administration of pemetrexed with NSAIDs (e.g. ibuprofen) or acetylsalicylic acid at higher dose should be avoided for 2 days before, on the day of, and 2 days following pemetrexed administration (see section 4.4).

In the absence of data regarding potential interaction with NSAIDs having longer half-lives such as piroxicam or rofecoxib, the concomitant administration with pemetrexed in patients with mild to moderate renal insufficiency should be interrupted for at least 5 days prior to, on the day of, and at least 2 days following pemetrexed administration (see section 4.4). If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression and gastrointestinal toxicity.

Pemetrexed undergoes limited hepatic metabolism. Results from in vitro studies with human liver microsomes indicated that pemetrexed would not be predicted to cause clinically significant inhibition of the metabolic clearance of drugs metabolised by CYP3A, CYP2D6, CYP2C9, and CYP1A2.

Interactions common to all cytotoxics

Due to the increased thrombotic risk in patients with cancer, the use of anticoagulation treatment is frequent. The high intra-individual variability of the coagulation status during diseases and the possibility of interaction between oral anticoagulants and anticancer chemotherapy require increased frequency of INR (International Normalised Ratio) monitoring, if it is decided to treat the patient with oral anticoagulants.

Concomitant use contraindicated: Yellow fever vaccine: risk of fatal generalised vaccinale disease (see section 4.3).

Concomitant use not recommended: Live attenuated vaccines (except yellow fever, for which concomitant use is contraindicated): risk of systemic, possibly fatal, disease. The risk is increased in subjects who are already immunosuppressed by their underlying disease. Use an inactivated vaccine where it exists (poliomyelitis) (see section 4.4).

Contraception in males and females

Women of childbearing potential must use effective contraception during treatment with pemetrexed. Pemetrexed can have genetically damaging effects. Sexually mature males are advised not to father a child during the treatment and up to 6 months thereafter. Contraceptive measures or abstinence are recommended.

Pregnancy

There are no data from the use of pemetrexed in pregnant women but pemetrexed, like other anti-metabolites, is suspected to cause serious birth defects when administered during pregnancy. Animal studies have shown reproductive toxicity (see section 5.3). Pemetrexed should not be used during pregnancy unless clearly necessary, after a careful consideration of the needs of the mother and the risk for the foetus (see section 4.4).

Breast-feeding

It is not known whether pemetrexed is excreted in human milk and adverse reactions on the suckling child cannot be excluded. Breast-feeding must be discontinued during pemetrexed therapy (see section 4.3).

Fertility

Owing to the possibility of pemetrexed treatment causing irreversible infertility, men are advised to seek counselling on sperm storage before starting treatment.

No studies on the effects on the ability to drive and use machines have been performed. However, it has been reported that pemetrexed may cause fatigue. Therefore patients should be cautioned against driving or operating machines if this event occurs.

Summary of the safety profile

The most commonly reported undesirable effects related to pemetrexed, whether used as monotherapy or in combination, are bone marrow suppression manifested as anaemia, neutropenia, leukopenia, thrombocytopenia; and gastrointestinal toxicities, manifested as anorexia, nausea, vomiting, diarrhoea, constipation, pharyngitis, mucositis, and stomatitis. Other undesirable effects include renal toxicities, increased aminotransferases, alopecia, fatigue, dehydration, rash, infection/sepsis and neuropathy. Rarely seen events include Stevens-Johnson syndrome and Toxic epidermal necrolysis.

Tabulated list of adverse reactions

The table below provides the frequency and severity of undesirable effects that have been reported in >5% of 168 patients with mesothelioma who were randomised to receive cisplatin and pemetrexed and 163 patients with mesothelioma randomised to receive single agent cisplatin. In both treatment arms, these chemonaive patients were fully supplemented with folic acid and vitamin B₁₂.

Frequency estimate: 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 grouping, undesirable effects are presented in order of decreasing seriousness.

^* Refer to National Cancer Institute CTC version 2 for each grade of toxicity except the term "creatinine clearance decreased"
^** which is derived from the term “renal/genitourinary other”.
^*** According to National Cancer Institute CTC (v2.0; NCI 1998), taste disturbance and alopecia should only be reported as Grade 1 or 2.

For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to pemetrexed and cisplatin.

Clinically relevant CTC toxicities that were reported in ≥1% and <5% of the patients that were randomly assigned to receive cisplatin and pemetrexed include: renal failure, infection, pyrexia, febrile neutropenia, increased AST, ALT, and GGT, urticaria and chest pain.

Clinically relevant CTC toxicities that were reported in <1% of the patients that were randomly assigned to receive cisplatin and pemetrexed include arrhythmia and motor neuropathy.

The table below provides the frequency and severity of undesirable effects that have been reported in >5% of 265 patients randomly assigned to receive single agent pemetrexed with folic acid and vitamin B₁₂ supplementation and 276 patients randomly assigned to receive single agent docetaxel. All patients were diagnosed with locally advanced or metastatic non-small cell lung cancer and received prior chemotherapy.

^* Refer to National Cancer Institute CTC version 2 for each grade of toxicity.
^** According to National Cancer Institute CTC (v2.0; NCI 1998), alopecia should only be reported as Grade 1 or 2.

For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to pemetrexed.

Clinically relevant CTC toxicities that were reported in ≥1% and <5% of the patients that were randomly assigned to pemetrexed include: infection without neutropenia, febrile reaction/hypersensitivity, increased creatinine, motor neuropathy, sensory neuropathy, erythema multiforme, and abdominal pain.

Clinically relevant CTC toxicities that were reported in <1% of the patients that were randomly assigned to pemetrexed include supraventricular arrhythmias.

Clinically relevant Grade 3 and Grade 4 laboratory toxicities were similar between integrated Phase 2 results from three single agent pemetrexed studies (n=164) and the Phase 3 single agent pemetrexed study described above, with the exception of neutropenia (12.8% versus 5.3%, respectively) and alanine aminotransferase elevation (15.2% versus 1.9%, respectively). These differences were likely due to differences in the patient population, since the Phase 2 studies included both chemonaive and heavily pre-treated breast cancer patients with pre-existing liver metastases and/or abnormal baseline liver function tests.

The table below provides the frequency and severity of undesirable effects considered possibly related to study drug that have been reported in >5% of 839 patients with NSCLC who were randomized to receive cisplatin and pemetrexed and 830 patients with NSCLC who were randomized to receive cisplatin and gemcitabine. All patients received study therapy as initial treatment for locally advanced or metastatic NSCLC and patients in both treatment groups were fully supplemented with folic acid and vitamin B₁₂.

^* P-values <0.05 comparing pemetrexed/cisplatin to gemcitabine/cisplatin, using Fisher Exact test.
^** Refer to National Cancer Institute CTC (v2.0; NCI 1998) for each Grade of Toxicity.
^*** According to National Cancer Institute CTC (v2.0; NCI 1998), taste disturbance and alopecia should only be reported as Grade 1 or 2.

For the purpose of this table, a cut-off of 5% was used for inclusion of all events where the reporter considered a possible relationship to pemetrexed and cisplatin.

Clinically relevant toxicity that was reported in ≥1% and ≤5% of the patients that were randomly assigned to receive cisplatin and pemetrexed include: AST increase, ALT increase, infection, febrile neutropenia, renal failure, pyrexia, dehydration, conjunctivitis, and creatinine clearance decrease.

Clinically relevant toxicity that was reported in <1% of the patients that were randomly assigned to receive cisplatin and pemetrexed include: GGT increase, chest pain, arrhythmia, and motor neuropathy.

Clinically relevant toxicities with respect to gender were similar to the overall population in patients receiving pemetrexed plus cisplatin.

The table below provides the frequency and severity of undesirable effects considered possibly related to study drug that have been reported in >5% of 800 patients randomly assigned to receive single agent pemetrexed and 402 patients randomly assigned to receive placebo in the single-agent pemetrexed maintenance (JMEN: N=663) and continuation pemetrexed maintenance (PARAMOUNT: N=539) studies. All patients were diagnosed with Stage IIIB or IV NSCLC and had received prior platinum-based chemotherapy. Patients in both study arms were fully supplemented with folic acid and vitamin B₁₂.

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = Common Terminology Criteria for Adverse Event; NCI = National Cancer Institute; SGOT=serum glutamic oxaloacectic aminotransferase; SGPT=serum glutamic pyruvic aminotransferase.
^* Definition of frequency terms: Very common - ≥10%; Common - >5% and <10%. For the purpose of this table, a cutoff of 5% was used for inclusion of all events where the reporter considered a possible relationship to pemetrexed.
^** Refer to NCI CTCAE Criteria (Version 3.0; NCI 2003) for each grade of toxicity. The reporting rates shown are according to CTCAE version 3.0.
^*** Integrated adverse reactions table combines the results of the JMEN pemetrexed maintenance (N=663) and PARAMOUNT continuation pemetrexed maintenance (N=539) studies.
^**** Combined term includes increased serum/blood creatinine, decreased glomerular filtration rate, renal failure and renal/genitourinary-other.

Clinically relevant CTC toxicity of any grade that was reported in ≥1% and ≤5% of the patients that were randomly assigned to pemetrexed include: febrile neutropenia, infection, decreased platelets, diarrhoea, constipation, alopecia, pruritis/itching, fever (in the absence of neutropenia), ocular surface disease (including conjunctivitis), increased lacrimation, dizziness and motor neuropathy.

Clinically relevant CTC toxicity that was reported in <1% of the patients that were randomly assigned to pemetrexed include: allergic reaction/hypersensitivity, erythema multiforme, supraventricular arrhythmia and pulmonary embolism.

Safety was assessed for patients who were randomised to receive pemetrexed (N=800). The incidence of adverse reactions was evaluated for patients who received ≤6 cycles of pemetrexed maintenance (N=519), and compared to patients who received >6 cycles of pemetrexed (N=281). Increases in adverse reactions (all grades) were observed with longer exposure. A significant increase in the incidence of possibly study-drug-related Grade ¾ neutropenia was observed with longer exposure to pemetrexed (≤6 cycles: 3.3%, >6 cycles: 6.4%: p=0.046). No statistically significant differences in any other individual Grade 3/4/5 adverse reactions were seen with longer exposure.

Serious cardiovascular and cerebrovascular events, including myocardial infarction, angina pectoris, cerebrovascular accident and transient ischaemic attack have been uncommonly reported during clinical studies with pemetrexed, usually when given in combination with another cytotoxic agent. Most of the patients in whom these events have been observed had pre-existing cardiovascular risk factors.

Rare cases of hepatitis, potentially serious, have been reported during clinical studies with pemetrexed.

Pancytopenia has been uncommonly reported during clinical trials with pemetrexed.

In clinical trials, cases of colitis (including intestinal and rectal bleeding, sometimes fatal, intestinal perforation, intestinal necrosis and typhlitis) have been reported uncommonly in patients treated with pemetrexed.

In clinical trials, cases of interstitial pneumonitis with respiratory insufficiency, sometimes fatal, have been reported uncommonly in patients treated with pemetrexed.

Uncommon cases of oedema have been reported in patients treated with pemetrexed.

Oesophagitis/radiation oesophagitis has been uncommonly reported during clinical trials with pemetrexed.

Sepsis, sometimes fatal, has been commonly reported during clinical trials with pemetrexed.

During post marketing surveillance, the following adverse reactions have been reported in patients treated with pemetrexed:

Hyperpigmentation has been commonly reported.

Uncommon cases of acute renal failure have been reported with pemetrexed alone or in association with other chemotherapeutic agents (see section 4.4). Nephrogenic diabetes insipidus and renal tubular necrosis have been reported in post marketing setting with an unknown frequency.

Uncommon cases of radiation pneumonitis have been reported in patients treated with radiation either prior, during or subsequent to their pemetrexed therapy (see section 4.4).

Rare cases of radiation recall have been reported in patients who have received radiotherapy previously (see section 4.4).

Uncommon cases of peripheral ischaemia leading sometimes to extremity necrosis have been reported.

Rare cases of bullous conditions have been reported including Stevens-Johnson syndrome and Toxic epidermal necrolysis which in some cases were fatal.

Rarely, immune-mediated haemolytic anaemia has been reported in patients treated with pemetrexed.

Rare cases of anaphylactic shock have been reported.

Erythematous oedema mainly of the lower limbs has been reported with an unknown frequency. Infectious and non-infectious disorders of the dermis, the hypodermis and/or the subcutaneous tissue have been reported with an unknown frequency (e.g. acute bacterial dermo-hypodermitis, pseudocellulitis, dermatitis).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Pemetrexed is physically incompatible with diluents containing calcium, including lactated Ringer’s injection and Ringer’s injection. In the absence of other compatibility studies this medicinal product must not be mixed with other medicinal products.

Armisarte contains trometamol as an excipient. Trometamol is incompatible with cisplatin resulting in degradation of cisplatin. This medicinal product must not be mixed with other medicinal products. Intravenous lines should be flushed after administration of Armisarte.