Arranon

Arranon is part of the drug class:

• Purine analogues

Nelarabine is a cancer medication that interferes with the growth and spread of cancer cells in the body.

Nelarabine is used to treat T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma.

Nelarabine may also be used for purposes not listed in this medication guide.

You should not receive this medication if you are allergic to nelarabine.

To make sure you can safely receive nelarabine, tell your doctor if you have any of these other conditions:

• liver disease;

• kidney disease;

• a nerve disorder;

• a history of radiation treatment of your head, neck, or spinal cord; or

• a history of cancer medicine injected around your spinal cord.

Do not use nelarabine if you are pregnant. It could harm the unborn baby. Use effective birth control, and tell your doctor if you become pregnant during treatment.

It is not known whether nelarabine passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using nelarabine.

Acute Lymphocytic Leukemia (ALL)

Treatment of acute T-cell lymphocytic (lymphoblastic) leukemia (ALL) and T-cell lymphoblastic lymphoma in patients whose disease is refractory to or has relapsed after ≥2 prior chemotherapy regimens (designated an orphan drug by FDA for these conditions).1 2 4 6

• Prodrug of the deoxyguanosine analog ara-G, which is subsequently converted to the active 5′-triphosphate, ara-GTP.1 2 5

• Ara-GTP accumulates in leukemic blasts and incorporates into DNA, inducing fragmentation and apoptosis.1 2 5

In the U.S.

• Arranon

Available Dosage Forms:

• Solution

Therapeutic Class: Antineoplastic Agent

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of nelarabine in children .

Geriatric

Although appropriate studies on the relationship of age to the effects of nelarabine have not been performed in the geriatric population, no geriatrics-specific problems have been documented to date. However, elderly patients are more likely to have age-related kidney problems, which may require caution in patients receiving nelarabine. Also, serious nervous system problems may be more likely to occur in the elderly .

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Measles Virus Vaccine, Live
• Mumps Virus Vaccine, Live
• Rotavirus Vaccine, Live
• Rubella Virus Vaccine, Live
• Varicella Virus Vaccine

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Adenovirus Vaccine
• Bacillus of Calmette and Guerin Vaccine, Live
• Cholera Vaccine, Live
• Influenza Virus Vaccine, Live
• Pentostatin
• Poliovirus Vaccine, Live
• Smallpox Vaccine
• Typhoid Vaccine
• Yellow Fever Vaccine

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Kidney disease or
• Liver disease—May cause side effects to become worse .

• Neurologic problems—This condition may become worse .

While you are using this medicine, your doctor may want you to drink extra fluids so that you will pass more urine. This will help prevent kidney problems and keep your kidneys working well .

Nelarabine sometimes causes nausea and vomiting. However, it is very important that you continue to receive the medicine, even if you begin to feel ill. Ask your doctor for ways to lessen these effects if they bother you .

You will receive this medicine while you are in a hospital or cancer treatment center. A doctor or other trained health professional will give you this medicine. This medicine is given through a needle placed into one of your veins .

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Abdominal pain or cramps
• anxiety
• black, tarry stools
• bleeding gums
• blood in the urine or stools
• bloody nose
• blurred vision
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• change in walking and balance
• chest pain
• chills
• clumsiness or unsteadiness
• cold sweats
• coma
• convulsions
• cool, pale skin
• cough or hoarseness
• decreased or uncontrolled urination
• difficulty with breathing
• discouragement
• dizziness, faintness, or lightheadedness when getting up from a lying or sitting position suddenly
• drowsiness
• dry mouth
• fast or irregular heartbeat
• feeling sad or empty
• feeling unusually cold
• fever
• flushed, dry skin
• fruit-like breath odor
• headache
• incoordination
• increased hunger
• increased thirst
• increased urination
• irritability
• loss of appetite
• loss of interest or pleasure
• lower back, side, or stomach pain
• mood or mental changes
• muscle cramps in hands, arms, feet, legs, or face
• muscle pain
• muscle spasms (tetany) or twitching seizures
• muscle weakness
• nausea or vomiting
• nervousness
• nightmares
• numbness, tingling, pain, or weakness in hands, feet, fingertips, or mouth
• pain or tenderness around the eyes and cheekbones
• painful or difficult urination
• paralysis or severe weakness of legs
• rapid breathing
• seizures
• shakiness and unsteady walk
• shivering
• shortness of breath
• sleepiness or unusual drowsiness
• sleeplessness
• slurred speech
• small red or purple spots on skin
• sneezing
• sore throat
• sores, ulcers, or white spots on the lips or in the mouth
• stuffy or runny nose
• sunken eyes
• sweating
• swelling of hands, ankles, feet, or lower legs
• swollen glands
• tightness in chest
• trouble concentrating
• trouble sleeping
• troubled breathing with exertion
• unable to sleep
• uncontrolled bowel movements
• unexplained weight loss
• unsteadiness, trembling, or other problems with muscle control or coordination
• unusual bleeding or bruising
• unusual tiredness or weakness
• wheezing
• wrinkled skin
• yellow eyes or skin

• Change in taste
• loss of memory
• loss of taste
• problems with memory

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Back pain
• diarrhea
• difficulty having a bowel movement (stool)
• difficulty with moving
• full or bloated feeling
• joint pain
• lack or loss of strength
• muscle aching or stiffness
• pain in the arms or legs
• pressure in the stomach
• swelling of the abdomen or stomach area
• swelling or inflammation of the mouth
• swollen joints

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• If you need to store Arranon (nelarabine) at home, talk with your doctor, nurse, or pharmacist about how to store it.

      Recommended Dosage

This product is for intravenous use only.

The recommended duration of treatment for adult and pediatric patients has not been clearly established. In clinical trials, treatment was generally continued until there was evidence of disease progression, the patient experienced unacceptable toxicity, the patient became a candidate for bone marrow transplant, or the patient no longer continued to benefit from treatment.

Adult Dosage: The recommended adult dose of Arranon is 1,500 mg/m² administered intravenously over 2 hours on Days 1, 3, and 5 repeated every 21 days. Arranon is administered undiluted.

Pediatric Dosage: The recommended pediatric dose of Arranon is 650 mg/m² administered intravenously over 1 hour daily for 5 consecutive days repeated every 21 days. Arranon is administered undiluted.

      Dosage Modification

Administration of Arranon should be discontinued for neurologic adverse reactions of NCI Common Toxicity Criteria Grade 2 or greater. Dosage may be delayed for other toxicity including hematologic toxicity. [See Boxed Warning, Warnings and Precautions (5.1, 5.2).]

      Adjustment of Dose in Special Populations

Arranon has not been studied in patients with renal or hepatic dysfunction [see Use in Specific Populations (8.6, 8.7)]. No dose adjustment is recommended for patients with a creatinine clearance (CLcr) ≥50 mL/min [see Clinical Pharmacology (12.3)]. There are insufficient data to support a dose recommendation for patients with a CLcr <50 mL/min.

      Prevention of Hyperuricemia

Appropriate measures (e.g., hydration, urine alkalinization, and prophylaxis with allopurinol) must be taken to prevent hyperuricemia [see Warnings and Precautions (5.4)].

      Instructions for Handling, Preparation, and Administration

Handling: Arranon is a cytotoxic agent. Caution should be used during handling and preparation. Use of gloves and other protective clothing to prevent skin contact is recommended. Proper aseptic technique should be used. Guidelines for proper handling and disposal of anticancer drugs have been published.1-4

Preparation and Administration: Do not dilute Arranon prior to administration. The appropriate dose of Arranon is transferred into polyvinylchloride (PVC) infusion bags or glass containers and administered as a 2-hour infusion in adult patients and as a 1-hour infusion in pediatric patients.

Prior to administration, inspect the drug product visually for particulate matter and discoloration.

Stability: Arranon Injection is stable in polyvinylchloride (PVC) infusion bags and glass containers for up to 8 hours at up to 30º C.

The safety and efficacy of Arranon were evaluated in two open-label, single-arm, multicenter trials.

      Adult Clinical Trial

The safety and efficacy of Arranon in adult patients were studied in a clinical trial which included 39 treated patients, 28 who had T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LBL) that had relapsed following or was refractory to at least two prior induction regimens. A 1,500-mg/m2 dose of Arranon was administered intravenously over 2 hours on Days 1, 3, and 5 repeated every 21 days. Patients who experienced signs or symptoms of Grade 2 or greater neurologic toxicity on therapy were to be discontinued from further therapy with Arranon. Seventeen patients had a diagnosis of T-ALL and 11 had a diagnosis of T-LBL. For patients with ≥2 prior inductions, the age range was 16 to 65 years (mean: 34 years) and most patients were male (82%) and Caucasian (61%). Patients with central nervous system (CNS) disease were not eligible.

Complete response (CR) in this trial was defined as bone marrow blast counts ≤5%, no other evidence of disease, and full recovery of peripheral blood counts. Complete response without complete hematologic recovery (CR*) was also assessed. The results of the trial for patients who had received ≥2 prior inductions are shown in Table 5.

CR = Complete response.

CR* = Complete response without hematologic recovery.

a       Does not include 1 patient who was transplanted (duration of response was 156+ weeks).

The mean number of days on therapy was 56 days (range of 10 to 136 days). Time to CR plus CR* ranged from 2.9 to 11.7 weeks.

      Pediatric Clinical Trial

The safety and efficacy of Arranon in pediatric patients were studied in a clinical trial which included patients aged 21 years and younger, who had relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LBL). Eighty-four (84) patients, 39 of whom had received two or more prior induction regimens, were treated with 650 mg/m2/day of Arranon administered intravenously over 1 hour daily for 5 consecutive days repeated every 21 days (see Table 6). Patients who experienced signs or symptoms of Grade 2 or greater neurologic toxicity on therapy were to be discontinued from further therapy with Arranon.

The 84 patients ranged in age from 2.5 to 21.7 years (overall mean: 11.9 years), 52% were 3 to 12 years of age and most were male (74%) and Caucasian (62%). The majority (77%) of patients had a diagnosis of T-ALL.

Complete response (CR) in this trial was defined as bone marrow blast counts ≤5%, no other evidence of disease, and full recovery of peripheral blood counts. Complete response without full hematologic recovery (CR*) was also assessed as a meaningful outcome in this heavily pretreated population. Duration of response is reported from date of response to date of relapse, and may include subsequent stem cell transplant. Efficacy results are presented in Table 7.

CR = Complete response.

CR* = Complete response without hematologic recovery.

a       Does not include 5 patients who were transplanted or had subsequent systemic chemotherapy (duration of response in these 5 patients was 4.7 to 42.1 weeks).

The mean number of days on therapy was 46 days (range: 7 to 129 days). Median time to CR plus CR* was 3.4 weeks (95% CI: 3.0, 3.7).

Arranon Injection is supplied as a clear, colorless, sterile solution in Type I, clear glass vials with a gray bromobutyl rubber stopper (not made with natural rubber latex) and a red snap-off aluminum seal. Each vial contains 250 mg of nelarabine (5 mg nelarabine per mL) and the inactive ingredient sodium chloride (4.5 mg per mL) in 50 mL Water for Injection, USP. Vials (NDC 0078-0683-61) are available in the following carton size:

NDC 0078-0683-06 (package of 6)

Store at 25º C (77º F); excursions permitted to 15º to 30º C (59º to 86º F) [see USP Controlled Room Temperature].

You should not receive this medication if you are allergic to nelarabine.

To make sure you can safely receive nelarabine, tell your doctor if you have any of these other conditions:

• liver disease;
• kidney disease;
• a nerve disorder;
• a history of radiation treatment of your head, neck, or spinal cord; or
• a history of cancer medicine injected around your spinal cord.

FDA pregnancy category D. Do not use nelarabine if you are pregnant. It could harm the unborn baby. Use effective birth control, and tell your doctor if you become pregnant during treatment.

It is not known whether nelarabine passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using nelarabine.

Call your doctor for instructions if you miss an appointment for your nelarabine injection.

Arranon may cause serious side effects of the central nervous system, such as problems with balance, coordination, or fine motor skills. These symptoms may not go away even after you stop receiving Arranon. Talk with your doctor if you have concerns about any possible long-term side effects.

Do not use Arranon if you are pregnant. It could harm the unborn baby. You should not breast-feed while you are using nelarabine.

Before you receive Arranon, tell your doctor if you have liver or kidney disease, a nerve disorder, a history of chemotherapy or radiation treatment of your head, neck, or spinal cord.

Arranon can lower blood cells that help your body fight infections and help your blood to clot. Your blood may need to be tested often. Avoid being near people who are sick or have infections. Avoid activities that may increase your risk of bleeding injury. Tell your doctor at once if you develop signs of infection. Do not receive a "live" vaccine while you are being treated with Arranon. This medication may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Arranon may cause serious side effects of the central nervous system. These symptoms may not go away even after you stop receiving Arranon. Talk with your doctor if you have concerns about any possible long-term side effects.

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

Call your doctor at once if you have a serious side effect such as:

• confusion or clumsiness, extreme drowsiness, fainting;

• loss of balance or coordination;

• problems with walking, breathing, speech, swallowing, or eye movement;

• numbness, weakness, or prickly feeling in your fingers or toes;

• problems with buttoning clothes or picking up small items with your fingers;

• loss of movement in any part of your body;

• seizure (convulsions);

• pale skin, feeling light-headed or short of breath, rapid heart rate, trouble concentrating;

• easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;

• fever, chills, body aches, flu symptoms, sores in your mouth and throat; or

• severe shortness of breath, wheezing, gasping for breath, cough with foamy mucus, chest pain, fast or uneven heart rate.

Less serious Arranon side effects may include:

• cough;

• mild nausea, vomiting, diarrhea, or constipation;

• dizziness, drowsiness, feeling tired;

• joint or muscle pain;

• headache; or

• swelling in your hands or feet.

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.

Applies to nelarabine: intravenous solution

Hematologic

Hematologic side effects including anemia (99%), thrombocytopenia (86%), neutropenia (81%), and febrile neutropenia (12%) have been reported. A case of biopsy confirmed multifocal leukoencephalopathy has also been reported.[Ref]

Nervous system

Nervous system side effects (64%) have been reported including somnolence (23%), dizziness (21%), peripheral neurologic disorders (21%), hypoesthesia (17%), headache (15%), paresthesia (15%), ataxia (9%), depressed level of consciousness (6%), tremor (5%), amnesia (3%), dysgeusia (3%), balance disorder (2%), and sensory loss (2%). Neurologic disorders have included peripheral sensory neuropathy (13%), peripheral motor neuropathy (7%), peripheral neuropathy (5%), neuropathy (4%), demyelination, and ascending peripheral neuropathies similar in appearance to Guillain-Barre syndrome.[Ref]

Other

There were four reported additional fatalities unrelated to treatment with nelarabine (the active ingredient contained in Arranon) [Ref]

Other side effects have included reports of sometimes fatal opportunistic infections in patients receiving nelarabine. A fatal case of cerebral hemorrhage/coma/leukoencephalopathy which was thought to be related to treatment with nelarabine has also been reported.[Ref]

Gastrointestinal

Gastrointestinal side effects including nausea (41%), diarrhea (22%), vomiting (22%), constipation (21%), abdominal pain (9%), anorexia (9%), stomatitis (8%), and abdominal distention (6%) have been reported.[Ref]

General

General side effects including fatigue (50%), pyrexia (23%), asthenia (17%), peripheral edema (15%), edema (11%), pain (11%), infection (9%), rigors (8%), dehydration (7%), abnormal gait (6%), chest pain (5%), and noncardiac chest pain (5%) have been reported.[Ref]

Respiratory

Respiratory side effects including cough (25%), dyspnea (20%), pleural effusion (10%), epistaxis (8%), pneumonia (8%), exertional dyspnea (7%), sinusitis (7%), and wheezing (5%) have been reported.[Ref]

Hepatic

Hepatic side effects including increased AST (6%) have been reported.[Ref]

Metabolic

Metabolic side effects including hyperglycemia (6%) and tumor lysis syndrome have been reported.[Ref]

Musculoskeletal

Musculoskeletal side effects including myalgia (13%), arthralgia (9%), back pain (8%), muscular weakness (8%), and pain in extremity (7%) have been reported. Postmarketing reports of rhabdomyolysis and increased blood creatine phosphokinase have been received.[Ref]

Psychiatric

Psychiatric side effects including confusional state (8%), insomnia (7%), and depression (6%) have been reported.[Ref]

Cardiovascular

Cardiovascular side effects including sinus tachycardia (8%) and hypotension (8%) have been reported.[Ref]

Dermatologic

Dermatologic side effects including petechiae (12%) have been reported.[Ref]

Ocular

Ocular side effects including blurred vision (4%) has been reported.[Ref]

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