DESCRIPCION

El etoposide es un agente antineoplásico que actua en una fase específica del ciclo celular, utilizado en el tratamiento de una amplia variedad de tumores sólidos y cánceres hematológicos. Qimicamente es un fármaco semi-sintético derivado de la toxina podofilotoxina que se encuentra en la resina de la mandrágora. También es conocido como VP-16

Mecanismo de acción:

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Mecanismo de acción: Etoposide is active during the G2 phase of the cell cycle. Etoposide binds to a complex of DNA and topoisomerase II. Topoisomerase II is an enzyme that coils and uncoils DNA and also examines and repairs faulty sections of DNA. When DNA and topoisomerase II are bound together, etoposide will stabilize this complex and prevent further progression in the cell cycle. DNA strand breaks develop, and the cell dies.

Farmacocinética: Etoposide is partially absorbed from the GI tract. Bioavailability following an oral dose of the drug ranges from 25—75%, with a mean of 48%. Food does not alter the bioavailability. Etoposide distributes widely throughout the body tissues, and it also crosses the blood-brain barrier (5% of plasma concentrations). The highest concentration of the drug is found in the liver, spleen, kidneys, and central nervous system. Plasma-protein binding is 95%. The unbound fraction can increase in patients with hyperbilirubinemia. Patients with higher unbound fractions also have more myelosuppression. A limited amount of the drug is metabolized in the liver. Both the parent drug and metabolites can be found in bile. Approximately 30% of an administered dose is excreted in the urine.

INDICACIONES Y POSOLOGIA

Dosage For the treatment of small-cell lung cancer:

Intravenous dosage: Adults: The recommended dosage range is 35 mg/m2/day IV for 4 days to 50 mg/m2/day IV for 5 days in combination with other antineoplastics. Alternatively, etoposide 80—120 mg/m2/day IV for 3 days each month in combination with cisplatin. Courses are repeated every 3 or 4 weeks after adequate recovery from any toxicity.

Oral dosage: Adults: The recommended oral dosage is two times the IV dosage rounded to the nearest 50 mg, given once daily if the total dose is <= 400 mg/day or in divided doses if > 400 mg/day.

For the treatment of testicular cancer: Intravenous dosage: Adults: 100 mg/m2/day IV on days 1—5 in combination with bleomycin and cisplatin (BEP regimen) or 100 mg/m2/day IV on days 1, 3, and 5. Courses are repeated every 3 or 4 weeks after adequate recovery from any toxicity. For the treatment of gastric cancer†

: Intravenous dosage: Adults: Therapy has included etoposide 90—120 mg/m2/day IV three days each month in combination with other antineoplastics. For induction or consolidation treatment of acute lymphocytic leukemia

(ALL)†: Intravenous dosage: Adults and children: Commonly, etoposide is given in dosage of 100 mg/m2/day IV for 3—5 days in combination with other antineoplastics. Alternatively, etoposide 300 mg/m2 IV as a single dose is given at the beginning of therapy.

For induction or consolidation treatment of acute myelogenous leukemia (AML)† and refractory† or relapsed† acute myelogenous leukemias (AML): Intravenous dosage: Adults: Commonly, etoposide is given in dosages of 100 mg/m2/day IV for 3—5 days in combination with other antineoplastics. Children: 150 mg/m2/day IV for 2—3 days. Dosages up to 250 mg/m2/day IV for 3 days can be used for consolidation.

For the treatment of Hodgkin's disease†: Intravenous dosage: Adults and children: Treatment has included etoposide 100 mg/m2 IV on days 3—5 in combination with other antineoplastics. For the treatment of non-Hodgkin's lymphoma (NHL)†: Intravenous dosage: Adults and children: Treatment has included etoposide 100—120 mg/m2 IV on day 1 and 8 or only on day 1 every 28 days in combination with other antineoplastics.

For bone marrow ablation† therapy in combination with other agents for autologus or allogeneic bone marrow transplantation: Intravenous dosage: Adults and children: Doses of 450—750 mg/m2 IV given over 3 days in divided doses every 12 hours has been used in combination with carmustine and cyclophosphamide. With total body irradiation, a total dose of etoposide 60 mg/kg has been used.

For the treatment of neuroblastoma†: Intravenous dosage: Children: Etoposide in doses of 100 mg/m2 IV over 1 hour on days 1—5 of the treatment cycle, repeated every 4 weeks have been used

. For the treatment of malignant glioma†: Intravenous dosage: Adults and children: Regimens include etoposide 150 mg/m2 IV on days 2 and 3 of the treatment course, or 300 mg/m2 IV on the first day and then 200 mg/m2 IV once every 21—28 days.

Patients with renal impairment: CrCl 60—45 ml/min: Reduce etoposide dose by 15% CrCl 44—30 ml/min: Reduce etoposide dose by 20% CrCl <30 ml/min: Reduce etoposide dose by 25% Patients with hepatic impairment: Decrease etoposide dose by 50% in patients with a serum bilirubin of 1.5—3 mg/dl. For patients with a serum bilirubin of 3—5 mg/dl, decrease etoposide dose by 75%. Hold etoposide in patients with a serum bilirubin > 5 mg/dl. †Non-FDA-approved indications

Administration CAUTION: Observe and exercise usual precautions for handling, preparing, and administering solutions of cytotoxic drugs. NOTE: The correct dose of etoposide will vary from protocol to protocol. Clinicians should consult the appropriate references to verify the dose. Oral Administration •The oral capsules must be refrigerated. Intravenous Administration •Etoposide is administered by IV infusion. Avoid any contact with skin. Use Luer Lok® fittings to prevent accidental leakage of etoposide during administration. If contact with skin occurs, wash immediately with soap and water. •Monitor blood pressure every 15 minutes during IV infusion of etoposide concentrate. If hypotension occurs, stop the infusion and notify physician. Infusion may be restarted at a slower rate after stabilization of blood pressure with IV fluids and supportive measures. Epinephrine, an antihistamine, and resuscitation equipment should be readily available in case of an anaphylactic reaction. •Plastic devices made of acrylic or ABS (a polymer composed of acrylonitrile, butadiene and styrene) have been reported to crack and leak when used with undiluted etoposide for injection. •Store unopened vials of etoposide at room temperature. •Store unopened vials of etoposide phosphate (Etopophos®) under refrigeration. Dilution: •Etoposide concentrate for injection must be diluted before administration. Dilute the commercial injection with NS or D5W to give a concentration of 0.2—0.4 mg/ml. Crystallization is likely to occur with concentrations greater than 0.4 mg/ml. If crystals are present, discard the solution. Solutions diluted to 0.2 mg/ml etoposide are stable for 96 hours at room temperature and solutions diluted to 0.4 mg/ml are stable for 24 hours at room temperature. •Etoposide phosphate (Etopophos®) may be reconstituted with 5 or 10 ml of Sterile Water for Injection, D5W, NS, Bacteriostatic Water for Injection or Bacteriostatic Sodium Chloride for Injection to a concentration equivalent to 20 or 10 mg/ml etoposide, respectively. This solution may be given without further dilution or may be further diluted to concentrations as low as 0.1 mg/ml etoposide in either D5W or NS. Reconstituted and diluted etoposide phosphate is stable at room temperature or under refrigeration for 24 hours. •Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Intravenous infusion: •Infuse desired dose of the diluted injection slowly over 30—60 minutes or longer to avoid hypotension and bronchospasm. •Etopophos® may be infused over 5—210 minutes.

CONTRAINDICACIONES

Etoposide therapy is usually delayed if neutropenia or thrombocytopenia exist prior to administering etoposide. Bone marrow suppression constiting of an ANC below 500/mm3, or a platelet count below 50,000/mm3 contraindicates the use of etoposide until the counts have recovered. Etoposide will only delay recovery of the counts. Etoposide should be used cautiously in patients who have had previous myelosuppressive therapy such as chemotherapy or radiation therapy. Patients with an active infection should be treated prior to receiving etoposide, the dose should be reduced or discontinued in patients who develop such infections. Patients with a history of varicella zoster, other herpes infections (e.g., herpes simplex), or other viral infections are at risk for reactivation of the infection when treated with chemotherapy. Myelosuppressive effects of etoposide can increase the risk of infection or bleeding; therefore, dental work should be delayed until blood counts have returned to normal. Patients, especially those with dental disease, should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks. Etoposide is considered an irritant. Extravasation of etoposide infusions should be avoided. Patients should be closely monitored during IV infusions for signs and symptoms of extravasation. Intramuscular administration and subcutaneous administration of etoposide should be avoided due to severe local reactions. Intramuscular injections should be avoided in patients with platelet counts < 50,000/mm3 who are receiving etoposide. IM injections can cause bleeding, bruising, or hematomas in patients with etopside-induced thrombocytopenia. Etoposide is primarily renally eliminated and should be used with caution in patients with renal impairment. Dosage adjustments may be necessary to avoid toxicities, although specific guidelines are not available. Etoposide is also partially hepatically eliminated and dosage adjustments may be needed in patients with hepatic disease. Etoposide is a category D drug for use during pregnancy. Although this drug is embryotoxic in animals, there are no data on use in humans. If a woman becomes pregnant during therapy with etoposide, the patient should be informed of the potential risk to the fetus. There are no data on the drug's penetration into breast milk. Breast-feeding should be avoided during therapy with etoposide. Use care to avoid accidental exposure to etoposide during preparation, handling and administration. The use of protective gowns, gloves and goggles is recommended. Avoid ocular exposure of etoposide solutions. If exposure occurs, the eye should be rinsed immediately and thoroughly. Vaccination during chemotherapy or radiation therapy should be avoided because the antibody response is suboptimal. When chemotherapy is being planned, vaccination should precede the initiation of chemotherapy by >= 2 weeks. Those undergoing chemotherapy should not be exposed to others who have recently received the oral poliovirus vaccine (OPV). Measles-mumps-rubella (MMR) vaccination is not contraindicated for the close contacts, including health care professionals, of immunocompromised patients. Passive immunoprophylaxis with immune globulins may be indicated for immunocompromised persons instead of, or in addition to, vaccination. When exposed to a vaccine-preventable disease such as measles, severely immunocompromised children should be considered susceptible regardless of their vaccination history.

INTERACCIONES

Concomitant administration of etoposide and cisplatin can produce synergistic effects against some tumors. Cisplatin also can delay etoposide's renal clearance and prolong its therapeutic plasma concentrations. Ifosfamide also can delay etoposide's renal clearance. Cytarabine, ARA-C, and etoposide have synergistic antitumor activity of unknown mechanism. Both cyclosporine and verapamil block a pathway of etoposide resistance used by some tumor cells to escape the antitumor effects of etoposide. Thus, either agent could theoretically enhance etoposide's therapeutic activity. Although the dose of verapamil required to enhance etoposide's actions is cardiotoxic and would not be used clinically, cyclosporine can be given in doses that would enhance etoposide activity. Cyclosporine doses of 5—21 mg/kg/day have been shown to affect etoposide pharmacokinetics. Etoposide can slow cellular efflux of methotrexate and possibly increase intracellular retention time, thus enhancing methotrexate's activity. Concurrent use of etoposide with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects. The immune response of the immunocompromised patient to vaccines is decreased and higher doses or more frequent boosters may be required. Despite these dose increases, the immune response may still be suboptimal. Live virus vaccines are contraindicated during therapy with antineoplastic agents due to the potentiation of virus replication, adverse reactions to the virus, and the immunocompromised status of the patient. Those undergoing antineoplastic therapy should not be exposed to others who have recently received the oral poliovirus vaccine (OPV). Estimates for postponing vaccination vary from 3 months to 1 year following discontinuation of treatment depending of the type of antineoplastic agent used and the disease state of the patient. Due to the thrombocytopenic effects of etoposide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. Large doses of salicylates (>= 6 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Because antineoplastic agents exert their toxic effects against rapidly growing cells, such as hematopoietic progenitor cells, sargramostim, GM-CSF, and filgrastim, G-CSF, are contraindicated for use in patients within 24 hours of treatment with antineoplastic agents. Due to rapid lysis of chemosensitive cells by etoposide, serum uric acid levels may increase. This may compromise the efficacy of the uricosuric agents probenecid and sulfinpyrazone. Dosage adjustments of antigout agents may be necessary to control hyperuricemia. To prevent uric acid nephropathy in cancer chemotherapy-induced hyperuricemia, allopurinol is preferred over uricosuric agents. Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; no significant change was seen with digoxin capsules, and the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. Digoxin capsules (Lanoxicaps®) may be utilized to avoid this interaction in patients receiving antineoplastic agents and digoxin tablets. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy. Due to ritonavir inhibition of CYP3A4, drug-drug interactions may occur during concomitant administration with etoposide.

REACCIONES ADVERSAS

The primary dose-limiting adverse effect associated with etoposide chemotherapy is hematologic toxicity, the severity of which depends on the dose of the drug and the regenerative capacity of the patient's bone marrow. Signs of myelosuppression include pancytopenia, leukopenia, neutropenia, thrombocytopenia, and anemia. A patient's hematologic status should be carefully monitored during chemotherapy. The nadir is approximately day 16 and recovery day 20—22. Mild to moderate nausea/vomiting have been reported during etoposide administration, and these symptoms usually respond to antiemetics. Stomatitis also can occur but appears to be more likely in patients who have received previous radiation therapy. Anorexia, abdominal pain, and diarrhea also have been reported. Reversible alopecia occurs in as many as 20—90% of patients receiving etoposide therapy, and the severity of hair loss can be dose-related. Occasionally, rapid infusion of etoposide can cause bronchospasm and hypotension, but cardiotoxicity has not been reported. Hypotension may be more likely to occur in geriatric patients and typically subsides with discontinuance of the drug and initiation of supportive measures. The reaction may be related to rapid administration of the drug. The vehicle with solubilizers is believed to be the cause, not etoposide itself. Although rare, anaphylactoid reactions can occur following too-rapid administration of etoposide, and appropriate supportive equipment for maintaining a patent airway should always be readily available during etoposide administration. In the event of an anaphylactoid reaction, infusion of the drug should be stopped and supportive measures (epinephrine, oxygen, corticosteroids, antihistamines) begun. Fever and headache are uncommon but known reactions to etoposide. Secondary malignancy, specifically acute myelogenous leukemia, may occur after treatment with etoposide. The incidence is approximately 12% in patients receiving weekly etoposide or teniposide for maintenance therapy for acute lymphocytic leukemia. Although etoposide is not considered a vesicant, extravasation of IV infusions have been associated with an injection site reaction consisting of phlebitis, urticaria, and erythema. This toxicity is thought to be due to the Cremophor EL (polyoxyethylated castor oil) solvent used in the injection preparation.

PRESENTACION

Etoposide, VP-16 Etopophos®, Toposar®, VePesid®