Evoltra

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Overdose

There were no known overdoses of Evoltra. The highest daily dose administered to a human to date (on a mg/m² basis) has been 70 mg/m²/day x 5 days (2 pediatric ALL patients). The toxicities included in these 2 patients included Grade 4 hyperbilirubinemia, Grade 2 and 3 vomiting, and Grade 3 maculopapular rash.

In a Phase 1 study of adults with refractory and/or relapsed hematologic malignancies, the recommended pediatric dose of 52 mg/m²/day was not tolerated.

Contraindications

None

Pharmaceutical form

Concentrate for solution for infusion

Undesirable effects

The following adverse reactions are discussed in greater detail in other sections of the label:

  • Myelosuppression
  • Hemorrhage
  • Serious Infections
  • Hyperuricemia (Tumor Lysis)
  • Systemic Inflammatory Response Syndrome (SIRS) and Capillary Leak Syndrome
  • Venous Occlusive Disease of the Liver
  • Hepatotoxicity
  • Renal Toxicity
  • Enterocolitis
  • Skin Reactions
Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to Evoltra in 115 pediatric patients with relapsed or refractory Acute Lymphoblastic Leukemia (ALL) (70 patients) or Acute Myelogenous Leukemia (AML) (45 patients).

In total, 115 pediatric patients treated in clinical trials received the recommended dose of Evoltra 52 mg/m² daily x 5. The median number of cycles was 2. The median cumulative amount of Evoltra received by pediatric patients during all cycles was 540 mg.

Most common adverse reactions ( ≥ 25%): vomiting, nausea, diarrhea, febrile neutropenia, pruritus, headache, bacteremia, pyrexia, rash, tachycardia, abdominal pain, chills, fatigue, anorexia, pain in extremity, hypotension, epistaxis, and petechiae.

Table 1 lists adverse reactions by System Organ Class, including severe or life-threatening (NCI CTC Grade 3 or Grade 4), reported in ≥ 5% of the 115 patients in the 52 mg/m²/day dose group  (pooled analysis of pediatric patients with ALL and AML). More detailed information and follow-up of certain events is given below.

Table 1: Most Commonly Reported ( ≥ 5% Overall) Adverse Reactions by System Organ Class (N=115 pooled analysis)

System Organ Class* Preferred Term* ALL/AML
(N = 115)
Worst NCI Common Terminology Criteria Grade*
3 4 5
N % N % N % N %
Blood and Lymphatic System Disorders Febrile neutropenia 63 55 59 51 3 3 - -
Neutropenia 11 10 3 3 8 7 - -
Cardiac Disorders Pericardial effusion 9 8 1 1 - -
Tachycardia 40 35 6 5 - - - -
Gastrointestinal Disorders Abdominal pain 40 35 8 7 - - - -
Abdominal pain upper 9 8 1 1 - - - -
Diarrhea 64 56 14 12 - - - -
Gingival or mouth bleeding 20 17 8 7 1 1 - -
Nausea 84 73 16 14 1 1 - -
Oral mucosal petechiae 6 5 4 4 - - - -
Proctalgia 9 8 2 2 - - - -
Stomatitis 8 7 1 1 - - - -
Vomiting 90 78 9 8 1 1 - -
General Disorders and Administration Site Conditions Asthenia 12 10 1 1 1 1 - -
Chills 39 34 3 3 - - - -
Fatigue 39 34 3 3 2 2 - -
Irritability 11 10 1 1 - - - -
Mucosal inflammation 18 16 2 2 - - - -
Edema 14 12 2 2 - - - -
Pain 17 15 7 6 1 1 - -
Pyrexia 45 39 16 14 - - - -
Hepatobiliary Disorder Jaundice 9 8 2 2 - - - -
Infections and Infestations Bacteremia 10 9 10 9 - - - -
Candidiasis 8 7 1 1 - - - -
Catheter related infection 14 12 13 11 - - - -
Cellulitis 9 8 7 6 - - - -
Clostridium colitis 8 7 6 5 - - - -
Herpes simplex 11 10 6 5 - - - -
Herpes zoster 8 7 6 5 - - - -
Oral candidiasis 13 11 2 2 - - - -
Pneumonia 11 10 6 5 1 1 1 1
Sepsis, including septic shock 19 17 6 5 4 4 9 8
Staphylococcal bacteremia 7 6 5 4 1 1 - -
Staphylococcal sepsis 6 5 5 4 1 1 - -
Upper respiratory tract infection 6 5 1 1 - - - -
Metabolism and Nutrition Disorders Anorexia 34 30 6 5 8 7 - -
Musculoskeletal and Connective Tissue Disorders Arthralgia 10 9 3 3 - - - -
Back pain 12 10 3 3 - - - -
Bone pain 11 10 3 3 - - - -
Myalgia 16 14 - - - -
Pain in extremity 34 30 6 5 - - - -
Neoplasms Benign, Malignant and Unspecified (incl. cysts and polyps) Tumor lysis syndrome 7 6 7 6 - - - -
Nervous System Disorders Headache 49 43 6 5 - - - -
Lethargy 12 10 1 1 - - - -
Somnolence 11 10 1 1 - - - -
Psychiatric Disorders Agitation 6 5 1 1 - - - -
Anxiety 24 21 2 2 - - - -
Renal and Urinary Disorders Hematuria 15 13 2 2 - - - -
Respiratory Dyspnea 15 13 6 5 2 2 - -
*Thoracic and Mediastinal Disorders Epistaxis 31 27 15 13 - - - -
Pleural effusion 14 12 4 4 2 2 - -
Respiratory distress 12 10 5 4 4 4 1 1
Tachypnea 10 9 4 4 1 1 - -
Skin and Subcutaneous Erythema 13 11 - - - - - -
Tissue Disorders Palmar-plantar erythrodysesthesia syndrome 18 16 8 7 - - - -
Petechiae 30 J6 7 6 - - - -
Pruritus 49 43 1 1 - - - -
Rash 44 38 8 7 - - - -
Rash pruritic 9 8
Vascular Disorders Flushing 22 19
Hypertension 15 13 6 5 - - - -
Hypotension 33 29 13 11 9 8 - -
*Patients with more than one preferred term within a SOC are counted only once in the SOC totals. Patients with more than one occurrence of the same preferred term are counted only once within that term and at the highest severity grade.

The following less common adverse reactions have been reported in 1-4% of the 115 pediatric patients with ALL or AML:

Gastrointestinal Disorders: cecitis, pancreatitis

Hepatobiliary Disorders: hyperbilirubinemia

Immune System Disorders: hypersensitivity

Infections and Infestations: bacterial infection, Enterococcal bacteremia, Escherichia bacteremia, Escherichia sepsis, fungal infection, fungal sepsis, gastroenteritis adenovirus, infection, influenza, parainfluenza virus infection, pneumonia fungal, pneumonia primary atypical, Respiratory syncytial virus infection, sinusitis, staphylococcal infection

Investigations: blood creatinine increased

Psychiatric Disorders: mental status change

Respiratory, Thoracic and Mediastinal Disorder: pulmonary edema

Table 2 lists the incidence of treatment-emergent laboratory abnormalities after Evoltra administration at 52 mg/m² among pediatric patients with ALL and AML (N=115).

Table 2: Incidence of Treatment-Emergent Laboratory Abnormalities after Evoltra Administration

Parameter Any Grade Grade 3 or higher
Anemia (N = 114) 83% 75%
Leukopenia (N = 114) 88% 88%
Lymphopenia (N = 113) 82% 82%
Neutropenia (N = 113) 64% 64%
Thrombocytopenia (N = 114) 81% 80%
Elevated Creatinine (N = 115) 50% 8%
Elevated SGOT (N = 100) 74% 36%
Elevated SGPT (N = 113) 81% 43%
Elevated Total Bilirubin (N = 114) 45% 13%
Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Evoltra. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) reported frequency of the reaction, or (3) strength of causal connection to Evoltra.

  • Gastrointestinal disorders: Gastrointestinal hemorrhage including fatalities
  • Metabolism and nutrition disorders: hyponatremia
  • Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN)

Therapeutic indications

Evoltra® (clofarabine) Injection is indicated for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. This indication is based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Evoltra.

Pharmacokinetic properties

The population pharmacokinetics of Evoltra were studied in 40 pediatric patients aged 2 to 19 years (21 males/19 females) with relapsed or refractory acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML). At the given 52 mg/m² dose, similar concentrations were obtained over a wide range of body surface areas (BSAs). Clofarabine was 47% bound to plasma proteins, predominantly to albumin. Based on noncompartmental analysis, systemic clearance and volume of distribution at steady-state were 28.8 L/h/m² and 172 L/m², respectively. The terminal half-life was 5.2 hours. No apparent difference in pharmacokinetics was observed between patients with ALL and AML or between males and females.

No relationship between clofarabine or clofarabine triphosphate exposure and toxicity or response was found in this population.

Based on 24-hour urine collections in the pediatric studies, 49- 60% of the dose is excreted in the urine unchanged. In vitro studies using isolated human hepatocytes indicate very limited metabolism (0.2%). The pathways of non-hepatic elimination remain unknown.

Clofarabine has not been studied in patients with hepatic impairment.

Qualitative and quantitative composition

Clofarabine

Special warnings and precautions for use

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS Myelosuppression

Evoltra causes myelosuppression which may be severe and prolonged. Febrile neutropenia occurred in 55% and non-febrile neutropenia in an additional 10% of pediatric patients in clinical trials. At initiation of treatment, most patients in the clinical studies had hematological impairment as a manifestation of leukemia. Myelosuppression is usually reversible with interruption of Evoltra treatment and appears to be dosedependent. Monitor complete blood counts.

Hemorrhage

Serious and fatal hemorrhage, including cerebral, gastrointestinal and pulmonary hemorrhage, has occurred. The majority of the cases were associated with thrombocytopenia. Monitor platelets and coagulation parameters and treat accordingly.

Infections

Evoltra increases the risk of infection, including severe and fatal sepsis, and opportunistic infections. At baseline, 48% of the pediatric patients had one or more concurrent infections. A total of 83% of patients experienced at least one infection after Evoltra treatment, including fungal, viral and bacterial infections. Monitor patients for signs and symptoms of infection, discontinue Evoltra, and treat promptly.

Hyperuricemia (Tumor Lysis)

Administration of Evoltra may result in tumor lysis syndrome associated with the break-down metabolic products from peripheral leukemia cell death. Monitor patients undergoing treatment for signs and symptoms of tumor lysis syndrome and initiate preventive measures including adequate intravenous fluids and measures to control uric acid.

Systemic Inflammatory Response Syndrome (SIRS) And Capillary Leak Syndrome

Evoltra may cause a cytokine release syndrome (e.g., tachypnea, tachycardia, hypotension, pulmonary edema) that may progress to the systemic inflammatory response syndrome (SIRS) with capillary leak syndrome and organ impairment which may be fatal. Monitor patients frequently for these conditions. In clinical trials, SIRS was reported in two patients (2%); capillary leak syndrome was reported in four patients (4%). Symptoms included rapid onset of respiratory distress, hypotension, pleural and pericardial effusion, and multi-organ failure. Close monitoring for this syndrome and early intervention may reduce the risk.  Immediately discontinue Evoltra and provide appropriate supportive measures. The use of prophylactic steroids (e.g., 100 mg/m² hydrocortisone on Days 1 through 3) may be of benefit in preventing signs or symptoms of SIRS or capillary leak. Consider use of diuretics and/or albumin. After the patient is stabilized and organ function has returned to baseline, re-treatment with Evoltra can be considered with a 25% dose reduction.

Venous Occlusive Disease Of The Liver

Patients who have previously received a hematopoietic stem cell transplant (HSCT) are at higher risk for veno-occlusive disease (VOD) of the liver following treatment with clofarabine (40 mg/m²) when used in combination with etoposide (100 mg/m²) and cyclophosphamide (440 mg/m²). Severe hepatotoxic events have been reported in a combination study of clofarabine in pediatric patients with relapsed or refractory acute leukemia. Two cases (2%) of VOD in the mono-therapy studies were considered related to study drug. Monitor for and discontinue Evoltra if VOD is suspected.

Hepatotoxicity

Severe and fatal hepatotoxicity, including hepatitis and hepatic failure, has occurred with the use of Evoltra. In clinical studies, Grade 3-4 liver enzyme elevations were observed in pediatric patients during treatment with Evoltra at the following rates: elevated aspartate aminotransferase (AST) occurred in 36% of patients; elevated alanine aminotransferase (ALT) occurred in 44% of patients. AST and ALT elevations typically occurred within 10 days of Evoltra administration and returned to Grade 2 or less within 15 days. Grade 3 or 4 elevated bilirubin occurred in 13% of patients, with 2 events reported as Grade 4 hyperbilirubinemia (2%), one of which resulted in treatment discontinuation and one patient had multi-organ failure and died. Eight patients (7%) had Grade 3 or 4 elevations in serum bilirubin at the last time point measured; these patients died due to sepsis and/or multi-organ failure. Monitor hepatic function and for signs and symptoms of hepatitis and hepatic failure. Discontinue Evoltra immediately for Grade 3 or greater liver enzyme and/or bilirubin elevations.

Renal Toxicity

Evoltra may cause acute renal failure. In Evoltra treated patients in clinical studies, Grade 3 or 4 elevated creatinine occurred in 8% of patients and acute renal failure was reported as Grade 3 in three patients (3%) and Grade 4 in two patients (2%). Patients with infection, sepsis, or tumor lysis syndrome may be at increased risk of renal toxicity when treated with Evoltra.

Hematuria occurred in 13% of Evoltra treated patients overall. Monitor patients for renal toxicity and interrupt or discontinue Evoltra as necessary.

Enterocolitis

Fatal and serious cases of enterocolitis, including neutropenic colitis, cecitis, and C. difficile colitis, have occurred during treatment with clofarabine. This has occurred more frequently within 30 days of treatment, and in the setting of combination chemotherapy. Enterocolitis may lead to necrosis, perforation, hemorrhage or sepsis complications. Monitor patients for signs and symptoms of enterocolitis and treat promptly.

Skin Reactions

Serious and fatal cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported. Discontinue Clofarabine for exfoliative or bullous rash, or if SJS or TEN is suspected.

Embryo-fetal Toxicity

Evoltra can cause fetal harm when administered to a pregnant woman. Intravenous doses of clofarabine in rats and rabbits administered during organogenesis caused an increase in resorptions, malformations, and variations.

Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility

Clofarabine has not been tested for carcinogenic potential.

Clofarabine showed clastogenic activity in the in vitro mammalian cell chromosome aberration assay (CHO cells) and in the in vivo rat micronucleus assay. It did not show evidence of mutagenic activity in the bacterial mutation assay (Ames test).

Studies in mice, rats, and dogs have demonstrated dose-related adverse effects on male reproductive organs. Seminiferous tubule and testicular degeneration and atrophy were reported in male mice receiving intraperitoneal (IP) doses of 3 mg/kg/day (9 mg/m²/day, approximately 17% of clinical recommended dose on a mg/m² basis). The testes of rats receiving 25 mg/kg/day (150 mg/m²/day, approximately 3 times the recommended clinical dose on a mg/m² basis) in a 6-month IV study had bilateral degeneration of the seminiferous epithelium with retained spermatids and atrophy of interstitial cells. In a 6-month IV dog study, cell degeneration of the epididymis and degeneration of the seminiferous epithelium in the testes were observed in dogs receiving 0.375 mg/kg/day (7.5 mg/m²/day, approximately 14% of the clinical recommended dose on a mg/m² basis). Ovarian atrophy or degeneration and uterine mucosal apoptosis were observed in female mice at 75 mg/kg/day (225 mg/m²/day, approximately 4-fold of recommended human dose on a mg/m² basis), the only dose administered to female mice. The effect on human fertility is unknown.

Use In Specific Populations Pregnancy Pregnancy Category D

Evoltra (clofarabine) may cause fetal harm when administered to a pregnant woman.

Clofarabine was teratogenic in rats and rabbits. Developmental toxicity (reduced fetal body weight and increased postimplantation loss) and increased incidences of malformations and variations (gross external, soft tissue, skeletal and retarded ossification) were observed in rats receiving 54 mg/m²/day (approximately equivalent to the recommended clinical dose on a mg/m² basis), and in rabbits receiving 12 mg/m²/day (approximately 23% of the recommended clinical dose on a mg/m² basis).

There are no adequate and well-controlled studies in pregnant women using clofarabine. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with clofarabine. All patients should be advised to use effective contraceptive measures to prevent pregnancy.

Nursing Mothers

It is not known whether clofarabine or its metabolites are excreted in human milk. Because of the potential for tumorigenicity shown for clofarabine in animal studies and the potential for serious adverse reactions, women treated with clofarabine should not nurse. Female patients should be advised to avoid breastfeeding during treatment with Evoltra.

Pediatric Use

Safety and effectiveness have been established in pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia.

Geriatric Use

Safety and effectiveness of Evoltra has not been established in geriatric patients aged 65 and older.

Adults With Hematologic Malignancies

Safety and effectiveness have not been established in adults.

Renal Impairment

Reduce the Evoltra starting dose by 50% in patients with CrCL of 30 to 60 mL/min. There is insufficient information to make a dosage recommendation in patients with CrCL less than 30 mL/min or in patients on dialysis.

The pharmacokinetics of clofarabine in patients with renal impairment and normal renal function were obtained from a population pharmacokinetic analysis of three pediatric and two adult studies. In patients with CrCL 60 to less than 90 mL/min (N=47) and CrCL 30 to less than 60 mL/min (N=30), the average AUC of clofarabine increased by 60% and 140%, respectively, compared to patients with normal (N=66) renal function (CrCL greater than 90 mL/min).

Dosage (Posology) and method of administration

Recommended Dosage

Administer the recommended pediatric dose of 52 mg/m² as an intravenous infusion over 2 hours daily for 5 consecutive days.

  • Treatment cycles are repeated following recovery or return to baseline organ function, approximately every 2 to 6 weeks. The dosage is based on the patient's body surface area (BSA), calculated using the actual height and weight before the start of each cycle. To prevent drug incompatibilities, no other medications should be administered through the same intravenous line.
  • Provide supportive care, such as intravenous fluids, antihyperuricemic treatment, and alkalinize urine throughout the 5 days of Evoltra administration to reduce the effects of tumor lysis and other adverse events.
  • Discontinue Evoltra if hypotension develops during the 5 days of administration.
  • Monitor renal and hepatic function during the 5 days of Evoltra administration.
  • Monitor patients taking medications known to affect blood pressure. Monitor cardiac function during administration of Evoltra.
  • Reduce the dose by 50% in patients with creatinine clearance (CrCL) between 30 and 60 mL/min. There is insufficient information to make a dosage recommendation in patients with CrCL less than 30 mL/min.
Supportive Medications And Medications To Avoid
  • Consider prophylactic anti-emetic medications as Evoltra is moderately emetogenic.
  • Consider the use of prophylactic steroids to mitigate Systemic Inflammatory Response Syndrome (SIRS) or capillary leak syndrome (e.g., hypotension, tachycardia, tachypnea, and pulmonary edema).
  • Minimize exposure to drugs with known renal toxicity during the 5 days of Evoltra administration since the risk of renal toxicity may be increased.
  • Consider avoiding concomitant use of medications known to induce hepatic toxicity.
Dose Modifications And Reinitiation Of Therapy
  • Hematologic Toxicity
    • Administer subsequent cycles no sooner than 14 days from the starting day of the previous cycle and provided the patient's ANC is ≥ 0.75 x 109/L.
    • If a patient experiences a Grade 4 neutropenia (ANC < 0.5 x 109/L) lasting ≥ 4 weeks, reduce dose by 25% for the next cycle.
  • Non-hematologic Toxicity
    • Withhold Evoltra if a patient develops a clinically significant infection, until the infection is controlled, then restart at the full dose.
    • Withhold Evoltra for a Grade 3 non-infectious nonhematologic toxicity (excluding transient elevations in serum transaminases and/or serum bilirubin and/or nausea/vomiting controlled by antiemetic therapy). Re-institute Evoltra administration at a 25% dose reduction when resolution or return to baseline.
    • Discontinue Evoltra administration for a Grade 4 non-infectious non-hematologic toxicity.
    • Discontinue Evoltra administration if a patient shows early signs or symptoms of SIRS or capillary leak (e.g., hypotension, tachycardia, tachypnea, and pulmonary edema) occur and provide appropriate supportive measures.
    • Discontinue Evoltra administration if Grade 3 or higher increases in creatinine or bilirubin are noted. Re-institute Evoltra with a 25% dose reduction, when the patient is stable and organ function has returned to baseline. If hyperuricemia is anticipated (tumor lysis), initiate measures to control uric acid.
Reconstitution/Preparation

Evoltra should be filtered through a sterile 0.2 micron syringe filter and then diluted with 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP, prior to intravenous (IV) infusion to a final concentration between 0.15 mg/mL and 0.4 mg/mL. Use within 24 hours of preparation. Store diluted Evoltra at room temperature (15-30°C).

Incompatibilities

Do not administer any other medications through the same intravenous line.