Almetra^®

• Patients who have a history of severe hypersensitivity reaction to pemetrexed or to other drugs containing Mannitol, Hydrochloric acid and Sodium hydroxide
• Women of childbearing age unless adequate contraception is Used
• Breast­feeding
• Concomitant injection of yellow fever vaccine.

– ALMETRA® can suppress bone marrow function as manifested by neutropenia, thrombocytopenia and anaemia (or pancytopenia). Myelosuppression is usually the dose­limiting toxicity. Patients should be monitored for myelosuppression during therapy and ALMETRA® should not be given to patients until absolute neutrophil count (ANC) returns to ≥ 1500 cells/mm and platelet count returns to ≥ 100,000 cells/mm . Dose reductions for subsequent cycles are
based on nadir ANC, platelet count and maximum non­haematologic toxicity seen from the previous cycle.

– Less toxicity and reduction in Grade 3/4 haematologic and non­haematologic toxicities such as neutropenia, febrile neutropenia and infection with Grade 3/4 neutropenia were reported when pre­treatment with folic acid and vitamin B was administered. Therefore, all patients treated with ALMETRA® must be instructed to take folic acid and vitamin B as a prophylactic measure to reduce treatment­related toxicity.

– Skin reactions have been reported in patients not pre­treated with a corticosteroid. Pre­treatment with dexamethasone (or equivalent) can reduce the incidence and severity of skin reactions.

– An insufficient number of patients has been studied with creatinine clearance of below 45 ml/min. Therefore, the use of ALMETRA® in patients with creatinine clearance of < 45 ml/min is not recommended.

– Patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 ml/min) should avoid taking nonsteroidal anti­inflammatory drugs (NSAIDs) such as ibuprofen, and acetylsalicylic acid (> 1.3 g daily) for 2 days before, on the day of, and 2 days following ALMETRA® administration.

– In patients with mild to moderate renal insufficiency eligible for ALMETRA® 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 ALMETRA® administration.

– 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 pre­existing 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 ALMETRA® 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 pre­existing cardiovascular risk factors.

– Immunodepressed status is common in cancer patients. As a result, concomitant use of live attenuated vaccines is not recommended.

– ALMETRA® can have genetically damaging effects. Sexually mature males are advised not to father a child during the treatment and up to 3 months thereafter. Contraceptive measures or abstinence are recommended. Owing to the possibility of ALMETRA® 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 ALMETRA® and for 6 months following completion of treatment.

– 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.

Precautions:

– ALMETRA® should be administered under the supervision of a qualified physician experienced in the use of antineoplastic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.

– As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion solutions of ALMETRA®.

– The use of gloves is recommended. If a solution of ALMETRA® contacts the skin, wash the skin immediately and thoroughly with soap and water.

– If ALMETRA® contacts the mucous membranes, flush thoroughly with water. Several published guidelines for handling and disposal of anticancer agents are available.

– ALMETRA® is not a vesicant. There is no specific antidote for extravasation of ALMETRA®. It should be managed with local standard practice for extravasation as with other non-vesicants.

1. ALMETRA® must only be administered under the supervision of a physician qualified in the use of anti­cancer chemotherapy.
   • Dosage:

ALMETRA^® in combination use with cisplatin:

Adults: The recommended dose of ALMETRA^® is 500 mg/m² as body surface area (BSA) administered as an intravenous infusion over 10 minutes on the first day of each 21-day cycle.

 The recommended dose of cisplatin is 75 mg/m² BSA infused over 2 hours approximately 30 minutes after completion of infusion with ALMETRA^® on the first day of each 21-day cycle.

Patients must receive adequate anti-emetic treatment and appropriate hydration prior to and/or after receiving cisplatin. See cisplatin Product Information document for specific dosing advice.

Single agent use:

Adults: In patients treated for non­small cell lung cancer after prior chemotherapy, the recommended dose of ALMETRA^® is 500 mg/m² BSA administered as an intravenous infusion over 10 minutes on the first day of each 21-day cycle.

• Premedication Regimen

To reduce the incidence and severity of skin reactions, a corticosteroid should be given the day prior to, on the day of, and the day after pemetrexed administration. The corticosteroid should be equivalent to 4 mg of dexamethasone administered orally twice a day.

To reduce toxicity, patients treated with ALMETRA^® must take oral folic acid or a multivitamin containing folic acid (350 to 1000 micrograms) on a daily basis. At least 5 daily doses of folic acid must be taken during the 7-day period preceding the first dose ALMETRA^®, and dosing should continue during the full course of therapy and for 21 days after the last dose of ALMETRA^®. Patients must also receive one intramuscular injection of vitamin B12 (1000 micrograms) during the week preceding the first dose of ALMETRA^® and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as ALMETRA^®.

• Dose Adjustment and monitoring parameters during treatment:
  Monitoring

It is recommended that patients receiving ALMETRA® be monitored before each dose with a complete blood count, including a differential white cell count(WCC) and platelet count. Periodic blood chemistry tests should be collected to evaluate renal and hepatic function. Absolute neutrophil count (ANC) should be ≥ 1500 cells/mm3 and platelets ≥ 100,000 cells/mm3 prior to scheduled administration of any cycle. Creatinine clearance should be ≥ 45 ml/min. The total bilirubin should be ≤ 1.5 times upper limit of normal. Alkaline phosphatase (AP), aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT) should be ≤ 3 times upper limit of normal. Alkaline phosphatase, AST and ALT ≤ 5 times upper limit of normal is acceptable if liver has tumour involvement.

Dose Adjustments Recommendations

Dose adjustments at the start of a subsequent cycle should be based on nadir haematologic counts or maximum nonhaematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery. Upon recovery, patients should be retreated using the guidelines in Tables 1 – 3 which are suitable for using ALMETRA® as a single agent or in combination with cisplatin.

If patients develop non-haematologic toxicities ≥ Grade 3 (excluding neurotoxicity), treatment should be withheld until resolution to less than or equal to the patient’s pre-therapy value. Treatment should be resumed according to the guidelines in Table 2.

In the event of neurotoxicity, the recommended dose adjustment for ALMETRA^®  and cisplatin is documented in Table3. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is observed.

* National Cancer Institute Common Toxicity Criteria (CTC v2.0; NCI 1998)

ALMETRA® therapy should be discontinued if a patient experiences any haematologic or nonhaematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed.

• Preparation and Administration:

Reconstitution and further dilution prior to intravenous infusion is only recommended with 0.9% sodium chloride injection.

ALMETRA® is physically incompatible with diluents containing calcium, including Lactated Ringer’s Injection and Ringer’s Injection.

Co-administration of ALMETRA® with other drugs and diluents has not been studied, and therefore is not recommended.

ALMETRA® is compatible with standard polyvinyl chloride (PVC)
109 administration sets and intravenous solution bags.

Preparation for intravenous infusion administration:

1. Use appropriate aseptic technique during the reconstitution and further dilution of ALMETRA® for intravenous infusion administration.
2. Calculate the dose and the number of ALMETRA® vials needed. The vial contains an excess of pemetrexed to facilitate delivery of label amount.
3. Prior to administration, reconstitute 500 mg vials with 20 mL of 0.9% sodium chloride injection to give a solution containing 25 mg/mL ALMETRA®. Reconstitute 100 mg vials with 4.2 mL of 0.9% sodium chloride injection to give a solution containing 25 mg/mL ALMETRA®.
4. Gently swirl each vial until the powder is completely dissolved. The resulting solution is clear and ranges in colour from colourless to yellow or green-yellow without adversely affecting product quality. The pH of the reconstituted ALMETRA® solution is between 6.6 and 7.8.
5. The appropriate volume of reconstituted ALMETRA® solution should be further diluted to 100 mL with 0.9% sodium chloride injection and administered as an intravenous infusion over 10 minutes.
6. Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration. Chemical and physical stability of reconstituted and infusion solutions of ALMETRA® was demonstrated for up to 24 hours after reconstitution of the original vial when stored below 25°C. However, because ALMETRA® and the recommended diluent contain no antimicrobial preservatives, to reduce antimicrobial hazard, reconstituted and infusion solutions should be used immediately.

 Discard any unused portion. Product is for single use in one patient on one occasion only.

Like all medicines, this medicine can cause side effects, although not everybody gets them. Side effects with ALMETRA® may include:

• >10%:

Central nervous system: Fatigue (18% to 34%)

Dermatologic: Desquamation (≤14%), skin rash (≤14%)

Gastrointestinal: Nausea (12% to 31%), anorexia (19% to 22%), vomiting (6% to 16%), stomatitis (≤15%), diarrhea (5% to 13%)

Hematologic & oncologic: Anemia (15% to 19%; grades 3/4: 3% to 5%), neutropenia (6% to 11%; grades 3/4: 3% to 5%)

Respiratory: Pharyngitis (≤15%)

• 1-10%:

Cardiovascular: Edema (5%)

Central nervous system: Neuropathy (sensory: 9%; motor: ≤5%)

Dermatologic: Pruritus (7%), alopecia (6%), erythema multiforme (≤5%)

Gastrointestinal: Mucositis (≤7%), constipation (6%), abdominal pain (1% to <5%)

Hematologic & oncologic: Thrombocytopenia (8%; grades 3/4: 2%), febrile neutropenia (<5%)

Hepatic: Increased serum ALT (8% to 10%), increased serum AST (7% to 8%)

Hypersensitivity: Hypersensitivity reaction (<5%)

Infection: Infection (1% to <5%), sepsis (1%)

Ophthalmic: Conjunctivitis (≤5%), increased lacrimation (1% to <5%)

Miscellaneous: Fever (8%)

• <1%:

 postmarketing, and/or case reports: Bullous rash, colitis, depression, esophagitis, gastrointestinal obstruction, hemolytic anemia, interstitial pneumonitis, pain, pancreatitis, pulmonary embolism, radiation recall phenomenon, renal failure, Stevens-Johnson syndrome, supraventricular cardiac arrhythmia, syncope, toxic epidermal necrolysis, ventricular tachycardia

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. Please report any adverse drug reactions via contacting Cedal Nano.

ALMETRA® is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs (e.g., aminoglycoside, loop diuretics, platinum compounds, cyclosporin) could potentially result in delayed clearance of ALMETRA®. 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 ALMETRA®. 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 at higher dose (≥ 1.3 g daily) may decrease ALMETRA® elimination and, consequently, increase the occurrence of ALMETRA® adverse reactions. Therefore, caution should be made when administering higher doses of NSAIDs or acetylsalicylic acid, concurrently with ALMETRA® 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 or acetylsalicylic acid at higher dose should be avoided for 2 days before, on the day of, and 2 days following ALMETRA® administration. In the absence of data regarding potential interaction with NSAIDs having longer half-lives such as piroxicam or rofecoxib, the concomitant administration with ALMETRA® 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. If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression and gastrointestinal toxicity.

ALMETRA® 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 intra­individual 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

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).

Pregnancy

ALMETRA® 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.

Breast feeding

It is not known whether pemetrexed is excreted in human milk. Therefore, breast-feeding must be discontinued during therapy with ALMETRA®.

– Keep the medicine in the box until it is consumed.

– store the medicine at temperatures below 30° C and protect from light.

– Keep the medicine out of the reach of children and pets.

– ALMETRA® is in the form of light yellow or green-yellow lyophilized powder and after dilution it will be a clear and colorless solution or with a yellowish-green white color. After preparation, the product should be clear and free of particles, otherwise, avoid using it.

– The solution prepared for injection should be taken immediately. The maximum storage time of the prepared solution at room temperature (25° C) should not exceed 24 hours.