Oforta

Dosage Forms & Strengths

injectable solution

• 25mg/mL

powder for injection

• 50mg

tablet

• 10mg

B-Cell Chronic Lymphocytic Leukemia

25 mg/sq.meter IV infusion over 30 minutes qD x5 days (up to 30 mg/sq.meter) 

40 mg/sq.meter PO x5 days

Repeat q28Days

Renal impairment

• CrCl 30-70 mL/min: reduce by 20%
• CrCl <30 mL/min: IV not recommended; PO reduce 50%

Non-Hodgkin Lymphoma (Orphan)

Treatment and management of non-Hodgkin lymphoma

Orphan indication sponsor

• Berlex Laboratories, Inc; 15049 San Pablo Avenue, P.O. Box 4099; Richmond, CA 94804-0099

Other Information

Monitor: CBC, chemistries, pulmonary function

Other Indications & Uses

Off-label: hairy cell leukemia, NHL, prolymphocytic leukemia, mycosis fungoides, Hodgkin's disease

Safety and efficacy not established

Peak plasma time: 2 hr

Vd: 96-98 L/sq.meter

Protein bound: 19-29%

Metabolites: 2-fluoro-ara-ATP

Clearance: 8.9 L/hr/sq.meter

Excretion: urine

Mechanism of Action

Fluorinated purine analog, inhibits DNA polymerase alpha

Oforta is part of the drug class:

• Purine analogues

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• pentostatin (Nipent)
• cytarabine (Cytostar-U, DepoCyt)

This is not a complete list of Oforta drug interactions. Ask your doctor or pharmacist for more information.

Tell your healthcare provider if you are breastfeeding or plan to breastfeed. It is not known if Oforta is excreted in human breastmilk or if it will harm your nursing baby.

The dose your doctor recommends will be determined based on your height and weight, your medical conditions, other medicines you take, and other factors.

The usual recommended Oforta dose is 25 mg per m² infused (injected into a vein) over 30 minutes, once daily, for five days in a row. This cycle may be repeated every 28 days.

Your doctor may recommend a lower dosage if you have kidney disease or a delay in treatment if you experience severe side effects.

Before receiving chemotherapy or radiation therapy in the future, tell your healthcare provider that you have received Oforta treatments.

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 Oforta™ in 159 patients exposed to the drug. Oforta™ was studied primarily in Study 1 in 78 patients with CLL who received prior therapy and in Study 2 in 81 patients with CLL who had not received prior therapy.

Based on experience with the intravenous and oral use of fludarabine phosphate, the most common adverse reactions include myelosuppression (neutropenia, thrombocytopenia and anemia), fever and chills, infection, and nausea and vomiting. Other commonly reported events include malaise, fatigue, anorexia, and weakness. Serious opportunistic infections have occurred in patients with CLL treated with fludarabine phosphate. The most frequently reported adverse reactions and those reactions which are more clearly related to the drug, as reported in clinical studies conducted with intravenous and oral fludarabine phosphate, are arranged below according to body system.

Hematopoietic Systems

Hematologic events (neutropenia, thrombocytopenia, and/or anemia) were reported in the majority of patients with CLL treated with fludarabine phosphate. During intravenous fludarabine phosphate treatment of 133 patients with CLL, the absolute neutrophil count decreased to less than 500/mm3 in 59% of patients, hemoglobin decreased from pretreatment values by at least 2 grams percent in 60%, and platelet count decreased from pretreatment values by at least 50% in 55%. Among 78 patients with B-CLL who were treated with Oforta™, the absolute neutrophil count decreased to less than 500/mm3 in 37% of patients, hemoglobin decreased from pretreatment values by at least 2 grams percent in 14%, and platelet count decreased from pretreatment values by at least 50% in 17% of patients. Myelosuppression may be severe, cumulative, and may affect multiple cell lines. Bone marrow fibrosis occurred in one CLL patient treated with fludarabine phosphate intravenously. In the pivotal oral fludarabine phosphate study (Study 1), there was one report of a non-fatal case of pancytopenia. Similarly, there was one case of non-fatal pancytopenia reported among the 133 patients with CLL treated with intravenous fludarabine phosphate.

Life-threatening and sometimes fatal autoimmune hemolytic anemias have been reported to occur in patients receiving fludarabine phosphate. [See Warnings and Precautions (5.2)] The majority of patients rechallenged with fludarabine phosphate developed a recurrence in the hemolytic process.

Metabolic

Tumor lysis syndrome has been reported in patients with CLL treated with fludarabine phosphate for injection. This complication may include hyperuricemia, hyperphosphatemia, hypocalcemia, metabolic acidosis, hyperkalemia, hematuria, urate crystalluria, and renal failure. The onset of this syndrome may be heralded by flank pain and hematuria.

Nervous System

Objective weakness, agitation, confusion, visual disturbances, and coma have occurred in patients with CLL treated with fludarabine phosphate at the recommended dose. Peripheral neuropathy and one case of wrist-drop have been observed with intravenous administration of fludarabine phosphate. In Study 1 for Oforta™, there was one report of severe impairment of consciousness that presented concurrent with hemolytic anemia. This patient had enrolled in the study with pre-existing peripheral neurotoxicity. [See Warnings and Precautions (5.1)]

Pulmonary System

Pneumonia, a frequent manifestation of infection in patients with CLL, was observed in two clinical trials conducted with intravenous fludarabine phosphate (16% and 22%) and in two clinical trials with Oforta™ (8% and 3%). Pulmonary hypersensitivity reactions to fludarabine phosphate characterized by dyspnea, cough and interstitial pulmonary infiltrate have been observed. In Study 1 conducted with Oforta™, severe pulmonary toxicity was reported in 5 of 78 patients, often in conjunction with respiratory or pulmonary infections and hence not regarded as isolated drug related pulmonary toxicity.

Gastrointestinal System

Gastrointestinal disturbances such as nausea and vomiting, anorexia, diarrhea, stomatitis and gastrointestinal bleeding have been reported in patients treated with fludarabine phosphate. Nausea and vomiting occurred in up to 38% of patients following treatment with Oforta™ in the clinical trials.

Cardiovascular

Edema has been frequently reported. One patient developed a pericardial effusion possibly related to treatment with Oforta™. No other severe cardiovascular events were considered to be drug related.

Genitourinary System

Hemorrhagic cystitis has been reported in patients treated intravenously with fludarabine phosphate.

Skin

Skin toxicity, consisting primarily of skin rashes, has been reported in patients treated with oral and intravenous fludarabine phosphate.

Data in Table 2 are derived from the 159 patients with CLL who received Oforta™ in Study 1 and Study 2.

Post Marketing Experience

The following adverse reactions have been identified during post approval use of Oforta™. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possibly to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hematopoietic Systems

Several instances of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes resulting in death, have been reported in post-marketing surveillance. The duration of clinically significant cytopenia in the reported cases has ranged from approximately 2 months to approximately 1 year. These episodes have occurred both in previously treated or untreated patients.

Nervous System

In post-marketing experience, cases of progressive multifocal leukoencephalopathy have been reported. Most cases had a fatal outcome. Many of these cases were confounded by prior and/or concurrent chemotherapy. The median time to onset was approximately one year.

Pulmonary System

In post-marketing experience, cases of severe pulmonary toxicity have been observed with fludarabine phosphate use which resulted in acute respiratory distress syndrome, respiratory distress, pulmonary hemorrhage, pulmonary fibrosis, and respiratory failure. After exclusion of an infectious origin, some patients experienced symptom improvement with corticosteroids.

Pentostatin

The use of Oforta™ in combination with pentostatin is not recommended due to the risk of severe pulmonary toxicity. [See Warnings and Precautions (5.6)]

Do not use Oforta if you are pregnant. It could harm the unborn baby. Use birth control to prevent pregnancy while you are taking this medicine, whether you are a man or a woman. Keep using birth control for at least 6 months after your treatment ends. Use of fludarabine by either parent may cause birth defects.

Before you take Oforta, tell your doctor if you have kidney disease, bone marrow problems, or a weak immune system.

Oforta can lower blood cells that help your body fight infections and help your blood to clot. Serious and sometimes fatal infections may occur during treatment. Call your doctor if you have unusual bruising or bleeding, or signs of infection (fever, chills, painful mouth sores, cold or flu symptoms, pale or yellowed skin, dark colored urine).

Oforta may also have harmful effects on your lungs. Call your doctor at once if you have a new or worsening cough, fever, and trouble breathing.

Oforta can affect your central nervous system during or just after treatment. Get emergency medical help if you have vision problems, confusion, agitation, changes in behavior, or a light-headed feeling (like you might pass out).

Applies to fludarabine: intravenous powder for injection, intravenous solution, oral tablet

General

In general, the most common dose-limiting toxicities have been myelosuppression (60%), fever and chills (11% to 60%, sometimes without infection), infection (33%, including serious opportunistic infections), and nausea and vomiting (36%).

General side effects including pain (up to 19%), flu syndrome (up to 8%), and decreased weight (up to 6%) have been reported.[Ref]

Hematologic

Hematologic toxicity has been reported to have occurred in the majority of patients. It presents as either neutropenia, thrombocytopenia, anemia, or a combination. Fifty-nine percent of patients develop an absolute neutrophil count of less than 500/mm3, 60% develop a hemoglobin concentration decrease by at least 2 g percent, and 55% develop a platelet count decrease by 50%. Several instances of trilineage bone marrow hypoplasia or aplasia resulting in sometimes fatal pancytopenia have been reported. Rarely, bone marrow fibrosis or clinically significant hemolytic anemia have been associated with the use of fludarabine (the active ingredient contained in Oforta) A single case of pure red cell aplasia has been reported.[Ref]

Myelosuppression may be severe, cumulative, and may affect multiple cell lines.[Ref]

Immunologic

Instances of life-threatening and sometimes fatal autoimmune hemolytic anemia have been reported after one or more cycles of treatment in patients with or without a previous history of autoimmune hemolytic anemia or a positive Coombs test and who may or may not be in remission for their disease. Steroids may be effective in controlling these hemolytic episodes. The majority of affected patients developed a recurrence upon rechallenge.

An increased incidence of infections with pathogens not commonly associated with chronic lymphocytic leukemia have been associated with the use of fludarabine (the active ingredient contained in Oforta) especially when given with corticosteroids. These have included Listeria, Pneumocystis carinii pneumonia, disseminated varicella-zoster, cytomegalovirus, and unusual fungal pathogens. Fludarabine can significantly decrease the quantity of T-helper cells.[Ref]

Immunologic side effects have been reported secondary to neutropenia which predisposes patients to infection. Pneumonia has been reported in 16% to 22% of treated patients from major clinical trials. Other, less common, infections include minor bacterial and/or fungal infections of the oropharynx, upper respiratory tract, urinary tract, and soft tissue, as well as herpes zoster infections. The risk of sepsis or life-threatening infection appears greatest during the first three courses of chemotherapy with fludarabine in patients with extensive disease.[Ref]

Gastrointestinal

Gastrointestinal side effects including nausea, vomiting, and/or diarrhea have been reported in up to 36% of patients. Anorexia, stomatitis, esophagitis, mucositis, constipation, taste disturbances, abdominal pain, and gastrointestinal bleeding have been reported in less than 30% of patients.[Ref]

Nervous system

Central and peripheral nervous system toxicities have been reported, including weakness/fatigue (asthenia) (up to 31%), headache (up to 9%), hearing disturbances (6%), paresthesias (4%), confusion (1%), visual disturbances (3%), and coma (less than 1%). In postmarketing experience, cases of progressive multifocal leukoencephalopathy have been reported. Rare cases of disabling, severe, but reversible neurologic toxicity have been reported.[Ref]

Most cases of progressive multifocal leukoencephalopathy had a fatal outcome. Many of these cases were confounded by prior and/or concurrent chemotherapy. The time to onset has ranged from a few weeks to approximately one year after initiating treatment.

The early trials of fludarabine given at high doses in the treatment of acute leukemia (up to 125 mg/m2 per day for up to 7 days) revealed evidence of severe CNS toxicity. Progressive optic neuritis, cortical blindness, seizures, and paralysis developed in some patients up to 2 months after therapy ended. Use of lower doses for low-grade lymphoid malignancy has not generally been associated with these severe side effects. However, progressive headaches, paresthesias, hemiparesis, and progressive and fatal neurologic dysfunction have rarely been associated with recommended doses.[Ref]

Respiratory

Respiratory side effects have been reported including severe cases of pulmonary toxicity which resulted in adult respiratory distress syndrome, respiratory distress, pulmonary hemorrhage, pulmonary fibrosis, respiratory failure, and death. Cough (10% to 44%), upper respiratory tract infection or pneumonia (up to 22%), dyspnea (1% to 22%), rhinitis (up to 11%), increased cough (up to 6%), bronchitis (up to 5%), and sinusitis (up to 5%) have also been reported. Diffuse interstitial pneumonitis has been reported rarely.[Ref]

Rare cases of diffuse alveolar damage have been associated with tumor lysis syndrome and the use of fludarabine.

In a clinical investigation using fludarabine injection in combination with pentostatin for the treatment of refractory chronic lymphocytic leukemia in adults, there was an unacceptably high incidence of fatal pulmonary toxicity.[Ref]

Cardiovascular

Cardiovascular side effects including peripheral edema (8%) and chest pain (up to 5%) have been reported. A single case of pericardial effusion has been associated with the use of fludarabine (the active ingredient contained in Oforta) [Ref]

Genitourinary

Genitourinary side effects including dysuria, hematuria, or proteinuria have been reported in 1% to 4% of patients. Rare cases of hemorrhagic cystitis have also been reported.[Ref]

Renal

A single case of acute renal failure secondary to mesangiocapillary glomerulonephritis has been associated with the use of fludarabine (the active ingredient contained in Oforta) in a 60-year-old man who had refractory chronic lymphocytic leukemia (CLL). This lesion has rarely been associated with CLL itself.[Ref]

Renal side effects including hemolytic uremic syndrome and acute renal failure have rarely been associated with the use of fludarabine.[Ref]

Hypersensitivity

Hypersensitivity reactions--usually skin rashes-- to fludarabine (the active ingredient contained in Oforta) are relatively rare. Corticosteroid-responsive acute interstitial pulmonary infiltrates have been reported. Extremely rare cases of anaphylaxis have been reported.[Ref]

Metabolic

TLS may result in serious metabolic problems, including hyperuricemia, hyperphosphatemia, hypocalcemia, metabolic acidosis, hyperkalemia, hematuria, urate crystalluria, renal failure, and even death. (Allopurinol before and during therapy is recommended.) The onset of this syndrome may be heralded by flank pain and hematuria.[Ref]

Metabolic side effects including tumor lysis syndrome (TLS) has been reported to have occurred in approximately 1% of patients. A single case of diffuse alveolar damage has been associated with TLS and the use of fludarabine.[Ref]

Dermatologic

Most dermatologic problems are related to allergic reactions to fludarabine (the active ingredient contained in Oforta) [Ref]

Dermatologic side effects including increased sweating (up to 14%), diaphoresis (up to 8%), skin disorder (up to 6%), and rash (up to 5%) have been reported. Alopecia has been reported only rarely.[Ref]

Oncologic

Oncologic side effects have been reported in animal studies. Fludarabine phosphate was clastogenic in vitro to Chinese hamster ovary cells (chromosome aberrations in the presence of metabolic activation and induce sister chromatid exchanges both with and without metabolic activation). In addition, fludarabine (the active ingredient contained in Oforta) phosphate was clastogenic in vivo (mouse micronucleus assay).[Ref]

Hepatic

Hepatic side effects including increased lactic dehydrogenase (up to 6%) have been reported.

Musculoskeletal

Musculoskeletal side effects including back pain (up to 9%) have been reported.

Some side effects of Oforta may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.