Treanda

Treanda is a prescription medication used to treat chronic lymphocytic leukemia (CLL). CLL is a type of cancer of the white blood cells. Treanda is also used to treat a type of non-Hodgkins lymphoma (NHL). NHL is a cancer that begins in a type of white blood cell that normally fights infection.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Serious side effects have been reported with Treanda including the following:

• Mild or serious allergic reactions. Immediately report rash, facial swelling, or difficulty breathing during or soon after infusion.
• A decrease in white blood cells, platelets, and red blood cells. Your doctor will need to conduct labd to monitor for this. Report shortness of breath, significant fatigue, bleeding, fever, or other signs of infection.
• Treanda may also cause tiredness. Avoid driving any vehicle or operating any dangerous tools or machinery if they experience this side effect.
• Report nausea, vomiting, and diarrhea so that symptomatic treatment may be provided.
• Mild rash or itching may occur during treatment with Treanda. Immediately report severe or worsening rash or itching.

Do not take Treanda if you are allergic to Treanda or to any of its ingredients.

Get emergency medical help if you have signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Serious and sometimes fatal skin reactions may occur during treatment with bendamustine. Tell your caregivers right away if you have any type of skin rash after being treated with bendamustine.

Call your doctor at once if you have:

• fever, chills, or itching during or shortly after the injection;

• pain, swelling, redness, skin changes, or signs of infection where the medicine was injected;

• severe ongoing nausea, vomiting, or diarrhea;

• pain or burning when you urinate;

• cough, chest pain, trouble breathing;

• liver problems--upper stomach pain, itching, tiredness, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);

• low blood cell counts--fever, flu symptoms, swollen glands, mouth sores, skin sores, pale skin, easy bruising, unusual bleeding;

• low potassium--leg cramps, constipation, irregular heartbeats, fluttering in your chest, extreme thirst, increased urination, muscle weakness or limp feeling;

• signs of tumor cell breakdown--lower back pain, blood in your urine, little or no urination; numbness or tingly feeling around your mouth; muscle weakness or tightness; fast or slow heart rate, weak pulse, confusion, fainting; or

• severe skin reaction--new or worsening symptoms of fever, swelling in your face or tongue, burning in your eyes, skin pain followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Common side effects may include:

• fever, cough, mouth sores, trouble breathing;

• nausea, vomiting, diarrhea, constipation;

• headache, tiredness, dizziness;

• swelling in your hands or feet;

• loss of appetite, weight loss; or

• mild skin rash.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Storage

Parenteral

2–8°C.1 Protect from light.1

Diluted solutions are stable for 24 hours when stored at 2–8°C and for 2 hours when stored at 15–30°C under normal room light conditions.1 Administration must be completed within these time periods.1

≤25°C; may be exposed to temperatures up to 30°C.1 Protect from light.1

Diluted solutions are stable for 24 hours when stored at 2–8°C and for 3 hours when stored at 15–30°C under normal room light conditions.1 Administration must be completed within these time periods.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

In the U.S.

• Bendeka
• Treanda

Available Dosage Forms:

• Powder for Solution
• Solution

Therapeutic Class: Antineoplastic Agent

Pharmacologic Class: Alkylating Agent

Chemical Class: Nitrogen Mustard

• Tell all of your health care providers that you take Treanda. This includes your doctors, nurses, pharmacists, and dentists.
• Avoid driving and doing other tasks or actions that call for you to be alert until you see how this medicine affects you.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• If you smoke, talk with your doctor.
• This medicine may lower the ability of your bone marrow to make blood cells that your body needs. This can lead to needing a blood transfusion and very bad and sometimes deadly bleeding problems or infections. Tell your doctor right away if you have signs of infection like fever, chills, or sore throat; any bruising or bleeding; or if you feel very tired or weak.
• You may bleed more easily. Be careful and avoid injury. Use a soft toothbrush and an electric razor.
• You may have more chance of getting an infection. Wash hands often. Stay away from people with infections, colds, or flu.
• Some patients have very bad side effects during the infusion. Tell your doctor if you have any bad effects during the infusion.
• Other types of cancer may rarely happen later in life.
• Very bad and sometimes deadly liver problems have happened with Treanda. Call your doctor right away if you have signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• This medicine may cause tissue damage if the drug leaks from the vein. Tell your nurse if you have any redness, burning, pain, swelling, blisters, skin sores, or leaking of fluid where the drug is going into your body.
• A very bad and sometimes deadly reaction has happened with this medicine. Most of the time, this reaction has signs like fever, rash, or swollen glands with problems in body organs like the liver, kidney, blood, heart, muscles and joints, or lungs. Talk with the doctor.
• If you are a man and have sex with a female who could get pregnant, protect her from pregnancy during care and for 3 months after care ends. Use birth control that you can trust.
• If you are a man and your sex partner gets pregnant while you take Treanda or within 3 months after your last dose, call your doctor right away.
• This medicine may affect sperm in men. This may affect being able to father a child. Talk with the doctor.
• This medicine may cause harm to the unborn baby if you take it while you are pregnant.
• Use birth control that you can trust to prevent pregnancy while taking this medicine and for 3 months after care ends.
• If you get pregnant while taking Treanda or within 3 months after your last dose, call your doctor right away.

  Chronic Lymphocytic Leukemia (CLL)

Treanda® is indicated for the treatment of patients with chronic lymphocytic leukemia. Efficacy relative to first line therapies other than chlorambucil has not been established.

  Non-Hodgkin Lymphoma (NHL)

Treanda is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

Treanda is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine. [see Warnings and Precautions (5.3)]

No formal clinical assessments of pharmacokinetic drug-drug interactions between Treanda and other drugs have been conducted. 

Bendamustine's active metabolites, gamma-hydroxy bendamustine (M3) and N-desmethyl-bendamustine (M4), are formed via cytochrome P450 CYP1A2. Inhibitors of CYP1A2 (e.g., fluvoxamine, ciprofloxacin) have potential to increase plasma concentrations of bendamustine and decrease plasma concentrations of active metabolites.  Inducers of CYP1A2 (e.g., omeprazole, smoking) have potential to decrease plasma concentrations of bendamustine and increase plasma concentrations of its active metabolites.  Caution should be used, or alternative treatments considered if concomitant treatment with CYP1A2 inhibitors or inducers is needed. 

The role of active transport systems in bendamustine distribution has not been fully evaluated. In vitro data suggest that P-glycoprotein, breast cancer resistance protein (BCRP), and/or other efflux transporters may have a role in bendamustine transport.  

Based on in vitro data, bendamustine is not likely to inhibit metabolism via human CYP isoenzymes CYP1A2, 2C9/10, 2D6, 2E1, or 3A4/5, or to induce metabolism of substrates of cytochrome P450 enzymes.

Bendamustine hydrochloride is an alkylating agent. The chemical name of bendamustine hydrochloride is 1H-benzimidazole-2-butanoic acid, 5-[bis(2-chloroethyl)amino]-1 methyl-, monohydrochloride. Its empirical molecular formula is C16H21Cl2N3O2 ∙ HCl, and the molecular weight is 394.7. Bendamustine hydrochloride contains a mechlorethamine group and a benzimidazole heterocyclic ring with a butyric acid substituent, and has the following structural formula: 

Treanda Injection (45 mg/0.5 mL or 180 mg/2 mL solution)

Treanda (bendamustine HCl) Injection is intended for intravenous infusion only after dilution with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP. It is supplied as a sterile clear colorless to yellow solution in a single-dose vial at the concentration of 90 mg/mL of bendamustine HCl. Each 0.5 mL vial contains 45 mg of bendamustine hydrochloride, 162 mg of Propylene Glycol, USP and 293 mg of N,N-Dimethylacetamide, EP. Each 2 mL vial contains 180 mg of bendamustine hydrochloride, 648 mg of Propylene Glycol, USP and 1172 mg of N,N-Dimethylacetamide, EP. An overfill of 0.2 mL is included in each vial.

Treanda for Injection (25 mg/vial or 100 mg/vial lyophilized powder)

Treanda (bendamustine HCl) for Injection is intended for intravenous infusion only after reconstitution with Sterile Water for Injection, USP, and after further dilution with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP. It is supplied as a sterile non-pyrogenic white to off-white lyophilized powder in a single-dose vial. Each 25-mg vial contains 25 mg of bendamustine hydrochloride and 42.5 mg of mannitol, USP. Each 100-mg vial contains 100 mg of bendamustine hydrochloride and 170 mg of mannitol, USP. The pH of the reconstituted solution is 2.5 - 3.5.

Chronic Lymphocytic Leukemia (CLL)

The safety and efficacy of Treanda were evaluated in an open-label, randomized, controlled multicenter trial comparing Treanda to chlorambucil.  The trial was conducted in 301 previously-untreated patients with Binet Stage B or C (Rai Stages I - IV) CLL requiring treatment.  Need-to-treat criteria included hematopoietic insufficiency, B-symptoms, rapidly progressive disease or risk of complications from bulky lymphadenopathy. Patients with autoimmune hemolytic anemia or autoimmune thrombocytopenia, Richter’s syndrome, or transformation to prolymphocytic leukemia were excluded from the study.

The patient populations in the Treanda and chlorambucil treatment groups were balanced with regard to the following baseline characteristics: age (median 63 vs. 66 years), gender (63% vs. 61% male), Binet stage (71% vs. 69% Binet B), lymphadenopathy (79% vs. 82%), enlarged spleen (76% vs. 80%), enlarged liver (48% vs. 46%), hypercellular bone marrow (79% vs. 73%), “B” symptoms (51% vs. 53%), lymphocyte count (mean 65.7x109/L vs. 65.1x109/L), and serum lactate dehydrogenase concentration (mean 370.2 vs. 388.4 U/L).  Ninety percent of patients in both treatment groups had immuno-phenotypic confirmation of CLL (CD5, CD23 and either CD19 or CD20 or both).

Patients were randomly assigned to receive either Treanda at 100 mg/m2, administered intravenously over a period of 30 minutes on Days 1 and 2 or chlorambucil at 0.8 mg/kg (Broca’s normal weight) administered orally on Days 1 and 15 of each 28-day cycle.  Efficacy endpoints of objective response rate and progression-free survival were calculated using a pre-specified algorithm based on NCI working group criteria for CLL. 

The results of this open-label randomized study demonstrated a higher rate of overall response and a longer progression-free survival for Treanda compared to chlorambucil (see Table 5). Survival data are not mature.

Table 5: Efficacy Data for CLL

CI = confidence interval

* CR was defined as peripheral lymphocyte count ≤ 4.0 x 109/L, neutrophils ≥ 1.5 x 109/L, platelets >100 x 109/L, hemoglobin > 110g/L, without transfusions, absence of palpable hepatosplenomegaly, lymph nodes ≤ 1.5 cm, < 30% lymphocytes without nodularity in at least a normocellular bone marrow and absence of “B” symptoms. The clinical and laboratory criteria were required to be maintained for a period of at least 56 days.

** nPR was defined as described for CR with the exception that the bone marrow biopsy shows persistent nodules.

† PR was defined as ≥ 50% decrease in peripheral lymphocyte count from the pretreatment baseline value, and either ≥50% reduction in lymphadenopathy, or ≥50% reduction in the size of spleen or liver, as well as one of the following hematologic improvements: neutrophils ≥ 1.5 x 109/L or 50% improvement over baseline, platelets >100 x 109/L or 50% improvement over baseline, hemoglobin >110g/L or 50% improvement over baseline without transfusions, for a period of at least 56 days.

†† PFS was defined as time from randomization to progression or death from any cause.

Kaplan-Meier estimates of progression-free survival comparing Treanda with chlorambucil are shown in Figure 1.

 Non-Hodgkin Lymphoma (NHL)

The efficacy of Treanda was evaluated in a single arm study of 100 patients with indolent B-cell NHL that had progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.  Patients were included if they relapsed within 6 months of either the first dose (monotherapy) or last dose (maintenance regimen or combination therapy) of rituximab. All patients received Treanda intravenously at a dose of 120 mg/m2, on Days 1 and 2 of a 21-day treatment cycle.  Patients were treated for up to 8 cycles.  

The median age was 60 years, 65% were male, and 95% had a baseline WHO performance status of 0 or 1. Major tumor subtypes were follicular lymphoma (62%), diffuse small lymphocytic lymphoma (21%), and marginal zone lymphoma (16%).  Ninety-nine percent of patients had received previous chemotherapy, 91% of patients had received previous alkylator therapy, and 97% of patients had relapsed within 6 months of either the first dose (monotherapy) or last dose (maintenance regimen or combination therapy) of rituximab. 

Efficacy was based on the assessments by a blinded independent review committee (IRC) and included overall response rate (complete response + complete response unconfirmed + partial response) and duration of response (DR) as summarized in Table 6.

Allergic (Hypersensitivity) Reactions

Inform patients of the possibility of mild or serious allergic reactions and to immediately report rash, facial swelling, or difficulty breathing during or soon after infusion [see Warnings and Precautions (5.3)].

Myelosuppression

Inform patients of the likelihood that Treanda will cause a decrease in white blood cells, platelets, and red blood cells, and the need for frequent monitoring of blood counts. Advise patients to report shortness of breath, significant fatigue, bleeding, fever, or other signs of infection [see Warnings and Precautions (5.1)].

Hepatotoxicity

Inform patients of the possibility of developing liver function abnormalities and serious hepatic toxicity. Advise patients to immediately contact their health care provider if signs of liver failure occur, including jaundice, anorexia, bleeding or bruising [see Warnings and Precautions (5.6)].

Fatigue

Advise patients that Treanda may cause tiredness and to avoid driving any vehicle or operating any dangerous tools or machinery if they experience this side effect [see Adverse Reactions (6.1)].

Nausea and Vomiting

Advise patients that Treanda may cause nausea and/or vomiting. Patients should report nausea and vomiting so that symptomatic treatment may be provided [see Adverse Reactions (6.1)].

Diarrhea

Advise patients that Treanda may cause diarrhea. Patients should report diarrhea to the physician so that symptomatic treatment may be provided [see Adverse Reactions (6.1)].

Rash

Advise patients that a rash or itching may occur during treatment with Treanda. Advise patients to immediately report severe or worsening rash or itching [see Warnings and Precautions (5.5)].

Pregnancy and Nursing

Treanda can cause fetal harm. Women should be advised to avoid becoming pregnant throughout treatment and for 3 months after Treanda therapy has stopped. Men receiving Treanda should use reliable contraception for the same time period. Advise patients to report pregnancy immediately. Advise patients to avoid nursing while receiving Treanda [see Use in Specific Populations (8.1)].

TRE-013

Distributed By:
Teva Pharmaceuticals USA, Inc.
North Wales, PA 19454

Treanda is a trademark of Cephalon, Inc. or its affiliates. 

©2008-2016 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd. or its affiliates.

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