Program Suspension

Dosage Form: FOR ANIMAL USE ONLY
Program Suspension

Suspension

The once-a-month oral suspension that controls flea populations.

Introduction

Novartis Animal Health encourages you to take the time to read this package insert which describes the use of PROGRAM® (lufenuron) Suspension as a convenient monthly flea control treatment. Controlling flea infestations is very important to the health of your pet. After reading this insert, if you have any questions about Program Suspension, flea control or medical problems associated with flea infestations, consult your veterinarian, who is your pet’s healthcare expert.

Administration

TO ENSURE ADEQUATE ABSORPTION, ALWAYS ADMINISTER Program Suspension TO CATS IN CONJUNCTION WITH A NORMAL MEAL.

Program Suspension is administered by mixing into food. If the dose is not entirely consumed, redose once with the full recommended dose as soon as possible. In multiple cat households, each cat should be treated separately to ensure adequate dosing.

Program Suspension must be administered monthly, preferably on the same date each month in conjunction with a normal meal. Treatment with Program Suspension may begin at any time of the year. Treatment should continue until the end of “flea season.” If there is risk of exposure to fleas year-round, then treatment should continue the entire year without interruption. Ask you veterinarian for details concerning your geographic area and the most effective treatment schedule for your pet.

To maximize benefits from the use of Program Suspension, it is important to treat all cats within a household. All dogs within the household should be treated with PROGRAM Tablets. Fleas can reproduce on untreated cats and dogs and allow infestations to persist.

Directions for Use

Mix the entire contents of the appropriate size Program Suspension pack(s) with about two tablespoons of the cat’s food. Since Program Suspension is a liquid, it mixes easily with wet food. You can make it a special treat for your cat by mixing it with your cat’s favorite wet food.

The active ingredient in PROGRAM is excreted in high concentrations in the milk, however, no resulting adverse effects have been recognized.

Flea Infestations on Cats

Although other flea species may be found on cats, the cat flea (Ctenocephalides felis) is the predominant flea associated with infestations on cats in the United States. In addition to the common nuisance irritations associated with infestations, fleas can be responsible for medical problems in your pet such as military dermatitis, a skin reaction to flea bites. Also, fleas transmit other parasites, including tapeworms. Controlling flea infestations is important to your pet’s health while also reducing the major and minor annoyances associated with these parasites.

Lufenuron, the active ingredient of Program Suspension does not kill adult fleas but effectively breaks the flea’s life cycle by inhibiting egg development. The following diagram illustrates the flea’s life cycle and where PROGRAM acts to break this cycle:

Life Cycle of the Flea

Fleas can be a problem because they reproduce so rapidly. A single female flea may produce up to 2,000 eggs over her lifetime. Eggs hatch and can develop into adults within only three weeks. Adult female fleas feed by ingesting blood from your cat and subsequently lay eggs, which drop off your cat’s coat. Within days, larvae hatch from the eggs and live undetected in your cat’s surroundings such as the carpet, bedding, and other protected areas. Flea larvae spin a cocoon, and when appropriately stimulated, a young adult flea emerges and jumps onto your cat to continue the life cycle. After biting a Program Suspension treated cat, the female flea ingests lufenuron which is deposited in her eggs. Lufenuron prevents these eggs from hatching or developing into mature adults. This safe and convenient approach to flea control effectively breaks the flea’s life cycle and controls flea populations.

Observe the cat closely to ensure the entire dose has been consumed and then provide its normal meal. Always administer PROGRAM (lufenuron) Suspension to cats in conjunction with a normal meal as food is important for complete absorption of PROGRAM. If your cat does not consume its meal following administration of PROGRAM, try withholding the cat’s food the night before to ensure it eats a meal with PROGRAM.

Some cats have special dietary needs, so be sure to consult your veterinarian before giving your cat any new foods or before withholding food overnight.

Description

Program Suspension is available in two sizes of packs for oral administration to cats and kittens according to their weight (see Dosage section). The active ingredient of Program Suspension is lufenuron, a benzoylphenylurea derivative with the following chemical composition: N-(2,5-dichloro-4(1,1,2,3,3,3,-hexafluoropropoxy)-phenylaminocarbonyl)-2,6difluorobenzamide. Benzoylphenylurea compounds, including lufenuron, are classified as insect development inhibitors (IDIs).

As an insect development inhibitor, PROGRAM does not kill adult fleas, but effectively and safely controls flea populations on your pet through a mode of action which breaks the flea’s life cycle at the egg stage.

Indications

Program Suspension is labeled for use in cats and kittens, six weeks of age and older, for the control of flea populations.

Precautions

Program Suspension has no effect on adult fleas but acts to immediately break the flea life cycle by preventing eggs from developing into adults. However, pre-existing immature fleas in the cat’s environment may continue to develop and emerge as adults after treatment with Program Suspension. Based on results of clinical studies, this emergence generally occurs during the first 30-60 days. Therefore, if your pet already has a flea infestation before starting PROGRAM, noticeable results may not be observed until several weeks after dosing. In cooler climates, immature fleas may take longer to complete the life cycle and emerge as adults. To speed control, traditional products that kill adult fleas may be used temporarily with PROGRAM, depending on the severity of the infestation.

If a PROGRAM-treated cat comes in contact with a flea-infested environment, adult fleas may infest the treated animal. However, these adult fleas will be unable to reproduce and will soon die off. Depending on the number of adult fleas, the temporary use of conventional adulticidal insecticides may be used to control these adult fleas. Your veterinarian can recommend the most effective treatment plan for your pet.

To ensure that your pet gets the greatest benefit from Program Suspension, you must administer the dose once a month in conjunction with a normal meal. If you miss the 30-day interval, give Program Suspension to your cat immediately and resume your monthly dosing schedule. It is important to treat all cats within the household. All dogs within the household should be treated with PROGRAM Tablets. Fleas can reproduce on untreated dogs and cats and allow infestations to persist.

Dosage

Program Suspension is given orally by mixing into food, once a

month, at the recommended minimum dosage of 13.6 mg lufenuron per pound (30mg/kg) of body weight.

Recommended Dosage Schedule

Body Weight	Pack Per Month	Lufenuron Per Pack	Pack Color
Up to 10 lbs	1 Small	135 mg	Orange
11 to 20 lbs	1 Large	270 mg	Green

Cats over 20 lbs should receive the appropriate combination of packs.

Once a Month

Program Suspension will safely and effectively control flea infestations only if administered on a monthly dosing schedule. To help you remember the monthly dosing, use the enclosed reminder stickers on the appropriate dates on your calendar.

Adverse Reactions

The following adverse reactions have been reported in cats after giving PROGRAM: vomiting, depression/lethargy, anorexia (loss of appetite), diarrhea, dyspnea (labored breathing), pruritus (itchy, scratchy skin), and skin disorder.

How Supplied

Program Suspension is available in two pack sizes (see Dosage section), formulated and color-coded according to the weight of the cat. Both pack sizes are available in color-coded packages of 6 packs per carton.

Storage Conditions

Program Suspension should be stored at room temperature between 59° and 77°F (15-25°C).

Keep out of the reach of children.

Manufactured for: Novartis Animal Health US, Inc.

Greensboro, NC 27408, USA

NADA # 141-026, Approved by FDA

©2008 Novartis Animal Health US, Inc.       NAH/PRO-S/PI/2

1/08

PRINCIPAL DISPLAY PANEL

Package Label – 135 mg

PROGRAM® (LUFENURON)

Once-a-month oral suspension

For the control of flea populations in cats

Recommended for cats and kittens up to 10 lbs. in weight.

Keep this and all drugs out of the reach of children.

Manufactured for: Novartis Animal Health US, Inc. Greensboro, NC 27408 U.S.A.

NADA # 141-026 Approved by the FDA www.novartisah.com

GIVE WITH A MEAL Net contents: 6 unit dose packs, 135 mg each. Product # 50841

PRINCIPAL DISPLAY PANEL

Package Label – 270 mg

PROGRAM® (LUFENURON)

Once-a-month oral suspension

For the control of flea populations in cats

Recommended for cats 11 to 20 lbs. in weight.

Keep this and all drugs out of the reach of children.

Manufactured for: Novartis Animal Health US, Inc. Greensboro, NC 27408 U.S.A.

NADA # 141-026 Approved by the FDA www.petwellness.com

GIVE WITH A MEAL Net contents: 6 unit dose packs, 270 mg each. Product # 50845

PROGRAM  lufenuron  suspension

Product Information Product Type PRESCRIPTION ANIMAL DRUG NDC Product Code (Source) 58198-5085 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength LUFENURON (LUFENURON) LUFENURON 270 mg

Inactive Ingredients Ingredient Name Strength WATER   METHYLPARABEN   PROPYLPARABEN   GLYCERIN   CELLULOSE, MICROCRYSTALLINE   CARBOXYMETHYLCELLULOSE SODIUM

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 58198-5085-1 6 POUCH In 1 CARTON None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NADA	NADA141026	03/28/1995

PROGRAM  lufenuron  suspension

Product Information Product Type PRESCRIPTION ANIMAL DRUG NDC Product Code (Source) 58198-5084 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength LUFENURON (LUFENURON) LUFENURON 135 mg

Inactive Ingredients Ingredient Name Strength WATER   METHYLPARABEN   PROPYLPARABEN   GLYCERIN   CELLULOSE, MICROCRYSTALLINE   CARBOXYMETHYLCELLULOSE SODIUM

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 58198-5084-1 6 POUCH In 1 CARTON None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NADA	NADA141026	03/28/1995

Labeler - Novartis Animal Health US, Inc. (966985624)

Revised: 12/2010Novartis Animal Health US, Inc.

Avloclor Tablets

1. Name Of The Medicinal Product

Avloclor 250 mg Tablets

2. Qualitative And Quantitative Composition

Tablets containing 250 mg chloroquine phosphate Ph. Eur. which is equivalent to 155 mg chloroquine base.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Tablets.

4. Clinical Particulars

4.1 Therapeutic Indications

a) Treatment of malaria.

b) Prophylaxis and suppression of malaria.

c) Treatment of amoebic hepatitis and abscess.

d) Treatment of discoid and systemic lupus erythematosus.

e) Treatment of rheumatoid arthritis.

4.2 Posology And Method Of Administration

The dose should be taken after food.

a) Treatment of malaria

i) P. falciparum and P. malariae infections

Adults: A single dose of four tablets, followed by two tablets six hours later and then two tablets a day for two days.

Children: A single dose of 10mg base/kg, followed by 5mg base/kg six hours later and then 5mg base/kg a day for two days.

Age (years)	Initial dose	Second dose 6 hours after first	Dose on each of the two subsequent days
1 – 4	1 Tablet	½ Tablet	½Tablet
5 – 8	2 Tablets	1 Tablet	1 Tablet
9 -14	3 Tablets	1½ Tablets	1½ Tablets

ii) P. vivax and P. ovale infections

Adults: A single dose of four tablets, followed by two tablets six hours later and then two tablets a day for two days. Follow with a course of treatment with primaquine if a radical cure is required.

Children: A single dose of 10mg base/kg, followed by 5mg base/kg six hours later and then 5mg base/kg a day for two days. Follow with a course of treatment with primaquine if a radical cure is required.

Elderly Patients: There are no special dosage recommendations for the elderly, but it may be advisable to monitor elderly patients so that optimum dosage can be individually determined.

Hepatic or Renally Impaired Patients: Caution is necessary when giving Avloclor to patients with renal disease or hepatic disease.

b) Prophylaxis and suppression of malaria

Adults: Two tablets taken once a week, on the same day each week. Start one week before exposure to risk and continue until four weeks after leaving the malarious area.

Children: A single dose of 5mg chloroquine base/kg per week on the same day each week. Start one week before exposure to risk and continue until four weeks after leaving the malarious area.

For practical purposes, children aged over 14 years may be treated as adults. The dose given to infants and children should be calculated on their body weight and must not exceed the adult dose regardless of weight.

1 - 4 years ½ tablet

5 - 8 years 1 tablet

9 - 15 years 1½ tablets

Elderly Patients: There are no special dosage recommendations for the elderly, but it may be advisable to monitor elderly patients so that optimum dosage can be individually determined.

Hepatic or Renally Impaired Patients: Caution is necessary when giving Avloclor to patients with renal disease or hepatic disease.

c) Amoebic hepatitis

Adults: Four tablets daily for two days followed by one tablet twice daily for two or three weeks.

Elderly Patients: There are no special dosage recommendations for the elderly, but it may be advisable to monitor elderly patients so that optimum dosage can be individually determined.

Hepatic or Renally Impaired Patients: Caution is necessary when giving Avloclor to patients with renal disease or hepatic disease.

d) Lupus erythematosus

Adults: One tablet twice daily for one to two weeks followed by a maintenance dosage of one tablet daily.

Elderly Patients: There are no special dosage recommendations for the elderly, but it may be advisable to monitor elderly patients so that optimum dosage can be individually determined.

Hepatic or Renally Impaired Patients: Caution is necessary when giving Avloclor to patients with renal disease or hepatic disease.

e) Rheumatoid arthritis

Adults: The usual dosage is one tablet daily.

Elderly Patients: There are no special dosage recommendations for the elderly, but it may be advisable to monitor elderly patients so that optimum dosage can be individually determined.

Hepatic or Renally Impaired Patients: Caution is necessary when giving Avloclor to patients with renal disease or hepatic disease.

4.3 Contraindications

Known hypersensitivity to chloroquine or any other ingredients of the formulation.

Concomitant use with amiodarone. (See section 4.5)

4.4 Special Warnings And Precautions For Use

When used as malaria prophylaxis official guidelines and local information on prevalence of resistance to anti-malarial drugs should be taken into consideration.

Caution is necessary when giving Avloclor to patients with impaired hepatic function, particularly when associated with cirrhosis.

Caution is also necessary in patients with porphyria. Avloclor may precipitate severe constitutional symptoms and an increase in the amount of porphyrins excreted in the urine. This reaction is especially apparent in patients with high alcohol intake.

A small number of cases of diffuse parenchymal lung disease have been identified in patients taking chloroquine. A response after therapy with steroids has been observed in some of these cases.

Caution is necessary when giving Avloclor to patients with renal disease.

Avloclor should be used with care in patients with a history of epilepsy. Potential risks and benefits should be carefully evaluated before use in subjects on anticonvulsant therapy or with a history of epilepsy as rare cases of convulsions have been reported in association with chloroquine.

Considerable caution is needed in the use of Avloclor for long-term high dosage therapy and such use should only be considered when no other drug is available. Patients on long

Irreversible retinal damage and corneal changes may develop during long term therapy and after the drug has been discontinued. Ophthalmic examination prior to and at 3–6 monthly intervals during use is required if patients are receiving chloroquine

• at continuous high doses for longer than 12 months

• as weekly treatment for longer than 3 years

• when total consumption exceeds 1.6 g/kg (cumulative dose 100 g)

Full blood counts should be carried out regularly during extended treatment as bone marrow suppression may occur rarely. Caution is required if drugs known to induce blood disorders are used concurrently.

The use of Avloclor in patients with psoriasis may precipitate a severe attack.

Caution is advised in patients with glucose-6-phosphate dehydrogenase deficiency, as there may be a risk of haemolysis.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

If the patient is taking amiodarone then chloroquine and hydroxychloroquine may increase the risk of cardiac arrhythmias including ventricular arrhythmias, bradycardias and cardiac conduction defect. Concurrent use is contraindicated.

Antacids (aluminium, calcium and magnesium salts) and adsorbents (e.g. kaolin) may reduce the absorption of chloroquine, so should be taken well separated from Avloclor (at least four hours apart).

If the patient is taking ciclosporin then chloroquine may cause an increase in ciclosporin levels.

Pre-exposure intradermal human diploid-cell rabies vaccine should not be administered to patients taking chloroquine as this may suppress the antibody response. When vaccinated against rabies, that vaccine should precede the start of the antimalarial dosing, otherwise the effectiveness of the vaccine might be reduced.

Chloroquine significantly reduces levels of praziquantel. Caution is therefore advised during co-administration. Prescribers may consider increasing the dose of praziquantel if the patient does not respond to the initial dose.

Other antimalarials:	increased risk of convulsion with mefloquine.
Cardiac glycosides:	hydroxychloroquine and possibly chloroquine increase plasma concentration of digoxin.
Parasympathomimetics:	chloroquine and hydroxychloroquine have potential to increase symptoms of myasthenia gravis and thus diminish effect of neostigmine and pyridostigmine.
Ulcer healing drugs:	cimetidine inhibits metabolism of chloroquine (increased plasma concentration).

4.6 Pregnancy And Lactation

Pregnancy

Avloclor should not be used during pregnancy unless, in the judgement of the physician, potential benefit outweighs the risk.

Short-term malaria prophylaxis:

Malaria in pregnant women increases the risk of maternal death, miscarriage, still-birth and low birth weight with the associated risk of neonatal death. Travel to malarious areas should be avoided during pregnancy but, if this is not possible, women should receive effective prophylaxis.

Long-term high dose:

There is evidence to suggest that Avloclor given to women in high doses throughout pregnancy can give rise to foetal abnormalities including visual loss, ototoxicity and cochlear-vestibular dysfunction.

Lactation

Although Avloclor is excreted in breast milk, the amount is too small to be harmful when used for malaria prophylaxis but as a consequence is insufficient to confer any benefit on the infant. Separate chemoprophylaxis for the infant is required. However, when long-term high doses are used for rheumatoid disease, breast feeding is not recommended.

4.7 Effects On Ability To Drive And Use Machines

Defects in visual accommodation may occur on first taking Avloclor and patients should be warned regarding driving or operating machinery.

4.8 Undesirable Effects

The adverse reactions which may occur at doses used in the prophylaxis or treatment of malaria are generally not of a serious nature. Where prolonged high dosage is required, i.e. in the treatment of rheumatoid arthritis, adverse reactions can be of a more serious nature.

Cardiovascular: hypotension and ECG changes (at high doses) cardiomyopathy.

Central nervous system: convulsions and psychotic reactions including hallucinations (rare), anxiety, personality changes.

Eye disorders: retinal degeneration, macular defects of colour vision, pigmentation, optic atrophy scotomas, field defects, blindness, corneal opacities and pigmented deposits, blurring of vision, difficulty in accommodation, diplopia.

Gastro-intestinal: gastro-intestinal disturbances, nausea, vomiting, diarrhoea, abdominal cramps.

General: headache.

Haematological: bone marrow depression, aplastic anaemia, agranulocytosis, thrombocytopenia, neutropenia.

Hepatic: Changes in liver function, including hepatitis and abnormal liver function tests, have been reported rarely.

Hypersensitivity: allergic and anaphylactic reactions, including urticaria, angioedema and vasculitis.

Hearing disorders: tinnitus, reduced hearing, nerve deafness.

Muscular: neuromyopathy and myopathy.

Respiratory: diffuse parenchymal lung disease.

Skin: macular, urticarial and purpuric skin eruptions, occasional depigmentation or loss of hair, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, precipitation of psoriasis, pruritus, photosensitivity, lichen-planus type reaction, pigmentation of the skin and mucous membranes (long term use).

4.9 Overdose

Chloroquine is highly toxic in overdose and children are particularly susceptible. The chief symptoms of overdosage include circulatory collapse due to a potent cardiotoxic effect, respiratory arrest and coma. Symptoms may progress rapidly after initial nausea and vomiting. Cardiac complications may occur without progressively deepening coma.

Death may result from circulatory or respiratory failure or cardiac arrhythmia. If there is no demonstrable cardiac output due to arrhythmias, asystole or electromechanical dissociation, external chest compression should be persisted with for as long as necessary, or until adrenaline and diazepam can be given (see below).

Gastric lavage should be carried out urgently, first protecting the airway and instituting artificial ventilation where necessary. There is a risk of cardiac arrest following aspiration of gastric contents in more serious cases. Activated charcoal left in the stomach may reduce absorption of any remaining chloroquine from the gut. Circulatory status (with central venous pressure measurement), respiration, plasma electrolytes and blood gases should be monitored, with correction of hypokalaemia and acidosis if indicated. Cardiac arrhythmias should not be treated unless life threatening; drugs with quinidine-like effects should be avoided. Intravenous sodium bicarbonate 1-2mmol/kg over 15 minutes may be effective in conduction disturbances, and DC shock is indicated for ventricular tachycardia and ventricular fibrillation.

Early administration of the following has been shown to improve survival in cases of serious poisoning:

1. Adrenaline infusion 0.25micrograms/kg/min initially, with increments of 0.25micrograms/kg/min until adequate systolic blood pressure (more than 100mg/Hg) is restored; adrenaline reduces the effects of chloroquine on the heart through its inotropic and vasoconstrictor effects.

2. Diazepam infusion (2mg/kg over 30 minutes as a loading dose, followed by 1-2mg/kg/day for up to 2-4 days). Diazepam may minimise cardiotoxicity.

Acidification of the urine, haemodialysis, peritoneal dialysis or exchange transfusion have not been shown to be of value in treating chloroquine poisoning. Chloroquine is excreted very slowly, therefore cases of overdosage require observation for several days.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

The mode of action of chloroquine on plasmodia has not been fully elucidated. Chloroquine binds to and alters the properties of DNA. Chloroquine also binds to ferriprotoporphyrin IX and this leads to lysis of the plasmodial membrane.

In suppressive treatment, chloroquine inhibits the erythrocytic stage of development of plasmodia. In acute attacks of malaria, it interrupts erythrocytic schizogony of the parasite. Its ability to concentrate in parasitised erythrocytes may account for the selective toxicity against the erythrocytic stages of plasmodial infection.

5.2 Pharmacokinetic Properties

Studies in volunteers using single doses of chloroquine phosphate equivalent to 300mg base have found peak plasma levels to be achieved within one to six hours. These levels are in the region of 54 - 102microgram/litre, the concentration in whole blood being some 4 to 10 times higher. Following a single dose, chloroquine may be detected in plasma for more than four weeks. Mean bioavailability from tablets of chloroquine phosphate is 89%. Chloroquine is widely distributed in body tissues such as the eyes, kidneys, liver, and lungs where retention is prolonged. The elimination of chloroquine is slow, with a multi exponential decline in plasma concentration. The initial distribution phase has a half-life of 2-6 days while the terminal elimination phase is 10-60 days. Approximately 50-70% of chloroquine in plasma is bound to the plasma proteins.

The principal metabolite is monodesethylchloroquine, which reaches a peak concentration of 10-20 microgram/litre within a few hours. Mean urinary recovery, within 3-13 weeks, is approximately 50% of the administered dose, most being unchanged drug and the remainder as metabolite. Chloroquine may be detected in urine for several months.

5.3 Preclinical Safety Data

Avloclor has been widely used for many years in clinical practice. There is no animal data which adds significant information relevant to the prescriber, to that covered elsewhere in this document.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Magnesium stearate Ph. Eur.

Maize starch Ph. Eur.

6.2 Incompatibilities

None have been reported or are known.

6.3 Shelf Life

5 years.

6.4 Special Precautions For Storage

Do not store above 30°C. Protect from light and moisture.

6.5 Nature And Contents Of Container

HDPE bottle of 100's and PVC/Aluminium Foil Blister Pack of 20's

6.6 Special Precautions For Disposal And Other Handling

No special instructions.

7. Marketing Authorisation Holder

AstraZeneca UK Limited

600 Capability Green,

Luton, LU1 3LU, UK

8. Marketing Authorisation Number(S)

PL 17901/0003

9. Date Of First Authorisation/Renewal Of The Authorisation

18^th June 2000/4^th June 2005

10. Date Of Revision Of The Text

6^th July 2010

sunitinib malate

soo-NI-ti-nib MAL-ate

Oral route(Capsule)

Hepatotoxicity has been observed in clinical trials and postmarketing experience. This hepatotoxicity may be severe, and deaths have been reported .

Commonly used brand name(s)

In the U.S.

• Sutent

Available Dosage Forms:

• Capsule

Therapeutic Class: Antineoplastic Agent

Pharmacologic Class: Sunitinib

Uses For sunitinib malate

Sunitinib belongs to the group of medicines known as antineoplastics. It is used to treat a gastrointestinal stromal tumor (GIST) after a medicine called imatinib did not work very well. It may also be used when patients are not able to take imatinib. GIST is a group of cancer cells that start growing in the wall of the stomach, intestines, or rectum. Sunitinib is also used to treat advanced (late-stage) kidney cancer.

Sunitinib is also used to treat a type of pancreatic cancer called pancreatic neuroendocrine tumor (pNET), that cannot be surgically removed and is locally advanced or metastatic (cancer that has spread).

Sunitinib interferes with the growth of cancer cells, which are eventually destroyed. Since the growth of normal body cells may also be affected by sunitinib, other effects will also occur. Some of these may be serious and must be reported to your doctor. Other effects, like hair loss, may not be serious but may cause concern. Some effects may not occur for months or years after the medicine is used.

Before you begin treatment with sunitinib, you and your doctor should talk about the benefits sunitinib malate will do as well as the risks of using it.

sunitinib malate is available only with your doctor's prescription.

Before Using sunitinib malate

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 sunitinib malate, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to sunitinib malate 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 have not been performed on the relationship of age to the effects of sunitinib in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of sunitinib in the elderly.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	D	Studies in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy in a life threatening situation or a serious disease, may outweigh the potential risk.

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 taking sunitinib malate, 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 sunitinib malate 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.

• Dronedarone


• Fluconazole


• Mesoridazine


• Pimozide


• Posaconazole


• Sparfloxacin


• Thioridazine

Using sunitinib malate 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.

• Alfuzosin


• Amiodarone


• Amitriptyline


• Amoxapine


• Apomorphine


• Arsenic Trioxide


• Asenapine


• Astemizole


• Atazanavir


• Azithromycin


• Boceprevir


• Bretylium


• Carbamazepine


• Chloroquine


• Chlorpromazine


• Ciprofloxacin


• Cisapride


• Citalopram


• Clarithromycin


• Clomipramine


• Clozapine


• Conivaptan


• Crizotinib


• Dasatinib


• Desipramine


• Dexamethasone


• Disopyramide


• Dofetilide


• Dolasetron


• Droperidol


• Erythromycin


• Flecainide


• Gatifloxacin


• Gemifloxacin


• Granisetron


• Halofantrine


• Haloperidol


• Ibutilide


• Iloperidone


• Imipramine


• Indinavir


• Itraconazole


• Ketoconazole


• Lapatinib


• Levofloxacin


• Lopinavir


• Lumefantrine


• Mefloquine


• Methadone


• Mitotane


• Moxifloxacin


• Nefazodone


• Nelfinavir


• Nilotinib


• Norfloxacin


• Nortriptyline


• Octreotide


• Ofloxacin


• Ondansetron


• Paliperidone


• Pazopanib


• Perflutren Lipid Microsphere


• Phenobarbital


• Phenytoin


• Procainamide


• Prochlorperazine


• Promethazine


• Propafenone


• Protriptyline


• Quetiapine


• Quinidine


• Quinine


• Ranolazine


• Rifabutin


• Rifampin


• Rifapentine


• Ritonavir


• Salmeterol


• Saquinavir


• Sodium Phosphate


• Sodium Phosphate, Dibasic


• Sodium Phosphate, Monobasic


• Solifenacin


• Sorafenib


• Sotalol


• St John's Wort


• Telavancin


• Telithromycin


• Terfenadine


• Tetrabenazine


• Toremifene


• Trazodone


• Trifluoperazine


• Trimipramine


• Vandetanib


• Vardenafil


• Vemurafenib


• Voriconazole


• Ziprasidone

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. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Other Medical Problems

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

• Bleeding problems or


• Bradycardia (very slow heart beat), history of or


• Congestive heart failure, history of or


• Heart disease (e.g., cardiomyopathy), history of or


• Heart rhythm problems (e.g., QT prolongation), history of or


• Hypertension (high blood pressure) or


• Hyperthyroidism (overactive thyroid) or


• Hypothyroidism (underactive thyroid) or


• Kidney problems (other than cancer) or


• Liver problems or


• Seizures or


• Stomach ulcers—Use with caution. May make these conditions worse.

• Hypokalemia (low potassium in the blood) or


• Hypomagnesemia (low magnesium in the blood)—May cause side effects to become worse.

• Infection, severe or


• Surgery or


• Trauma—These conditions may cause adrenal gland problems.

Proper Use of sunitinib malate

Your doctor will tell you how much of sunitinib malate to use and how often. Your dose may need to be changed several times in order to find out what works best for you. Do not use more medicine or use it more often than your doctor tells you to.

You may take sunitinib malate with or without food. Do not open the capsules.

sunitinib malate comes with a Medication Guide and a patient information leaflet. Read and follow the instructions carefully. Ask your doctor if you have any questions.

Dosing

The dose of sunitinib malate will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of sunitinib malate. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (capsules):
  
  • For the treatment of GIST and kidney cancer:
    
    • Adults—50 milligrams (mg) once a day for 4 weeks. This is followed by 2 weeks without medicine. Your doctor may tell you to repeat this cycle.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  
  • For advanced pancreatic cancer or pancreatic neuroendocrine tumor (pNET):
    
    • Adults—37.5 milligrams (mg) once a day. Your doctor may increase your dose as needed. However, the dose is usually not more than 50 mg per day.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

sunitinib malate needs to be given on a fixed schedule. If you miss a dose, call your doctor, home health caregiver, or treatment clinic for instructions.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using sunitinib malate

It is very important that your doctor check your progress at regular visits to see if the medicine is working properly. Blood tests may be needed to check for unwanted effects.

If you are a woman who can get pregnant, your doctor may do tests to make sure you are not pregnant before starting sunitinib treatment.

Using sunitinib malate while you are pregnant can harm your unborn baby. Use an effective form of birth control to keep from getting pregnant. If you think you have become pregnant while using the medicine, tell your doctor right away.

Before you have any medical tests, tell the medical doctor in charge that you are using sunitinib malate. The results of some tests may be affected by sunitinib malate.

Cancer medicines can cause nausea or vomiting in most people, sometimes even after receiving medicines to prevent it. Ask your doctor or nurse about other ways to control these unwanted effects.

Sunitinib can temporarily lower the number of white blood cells in your blood, increasing the chance of getting an infection. It can also lower the number of platelets, which are necessary for proper blood clotting. If this occurs, there are certain precautions you can take, especially when your blood count is low, to reduce the risk of infection or bleeding:

• If you can, avoid people with infections. Check with your doctor immediately if you think you are getting an infection or if you get a fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination.


• Check with your doctor immediately if you notice any unusual bleeding or bruising; black, tarry stools; blood in the urine or stools; or pinpoint red spots on your skin.


• Be careful when using a regular toothbrush, dental floss, or toothpick. Your medical doctor, dentist, or nurse may recommend other ways to clean your teeth and gums. Check with your medical doctor before having any dental work done.


• Do not touch your eyes or the inside of your nose unless you have just washed your hands and have not touched anything else in the meantime.


• Be careful not to cut yourself when you are using sharp objects such as a safety razor or fingernail or toenail cutters.


• Avoid contact sports or other situations where bruising or injury could occur.

Check with your doctor right away if you have pain or tenderness in the upper stomach; pale stools; dark urine; loss of appetite; nausea; unusual tiredness or weakness; or yellow eyes or skin. These could be symptoms of a serious liver problem.

Check with your doctor right away if you are rapidly gaining weight or have shortness of breath; chest pain or discomfort; extreme tiredness or weakness; irregular breathing; uneven heartbeats; or excessive swelling of the hands, wrist, ankles, or feet. These may be symptoms of a heart problem.

sunitinib malate can cause changes in the heart rhythm, such as a condition called QT prolongation. It may change the way your heart beats and cause fainting or dizziness. Call your doctor right away if you have any symptoms of heart rhythm problems, such as fast, pounding, or irregular heartbeats.

sunitinib malate may also increase your risk of bleeding and cause delay in wound healing. Check with your doctor immediately if you notice any unusual bleeding or bruising; black, tarry stools; blood in the urine or stools; or pinpoint red spots on your skin.

Make sure any doctor or dentist who treats you knows that you are using sunitinib malate. You may need to stop using sunitinib malate several days before having surgery or medical tests.

Grapefruit and grapefruit juice may cause you to have too much of sunitinib malate in the blood. You should not eat grapefruit or drink grapefruit juice while you are taking sunitinib malate.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal (e.g., St. John's Wort) or vitamin supplements.

sunitinib malate Side Effects

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:

More common

• Bleeding gums


• bloating or swelling of the face, arms, hands, fingers, lower legs, or feet


• blurred vision


• chest pain


• chills


• confusion


• coughing up blood


• cracked lips


• decreased urination


• decreased urine output


• diarrhea


• difficulty with breathing or swallowing


• dilated neck veins


• dizziness


• dry mouth


• extreme fatigue


• fainting


• fast, slow, or irregular heartbeat


• fever


• headache


• increase in heart rate


• increased menstrual flow or vaginal bleeding


• irregular breathing


• labored breathing


• lightheadedness


• nervousness


• nosebleeds


• paralysis


• pounding in the ears


• prolonged bleeding from cuts


• rapid breathing


• rapid weight gain


• red or black, tarry stools


• red or dark brown urine


• shortness of breath


• sores, ulcers, or white spots on the lips, tongue, or inside the mouth


• sunken eyes


• swelling or inflammation of the mouth


• thirst


• tightness in the chest


• tingling of the hands or feet


• troubled breathing


• unusual tiredness or weakness


• unusual weight gain or loss


• wheezing


• wrinkled skin


• yellow eyes or skin

Less common

• Constipation


• depressed mood


• dry skin and hair


• feeling cold


• hair loss


• hoarseness or husky voice


• indigestion


• loss of appetite


• muscle cramps and stiffness


• nausea


• pain in the chest, groin, or legs, especially the calves


• pain in the stomach, side, or abdomen, possibly radiating to the back


• severe, sudden headache


• slurred speech


• sudden loss of coordination


• sudden, severe weakness or numbness in the arm or leg


• sudden, unexplained shortness of breath


• vision changes


• vomiting

Rare

• Back pain


• chest discomfort


• cloudy or bloody urine


• convulsions


• darkening of the skin


• drowsiness


• general feeling of tiredness or weakness


• irregular or slow heart rate


• light-colored stools


• mental depression


• skin rash


• stomach pain, continuing


• swelling of the face, feet, or lower legs

Incidence not known

• Cough


• dark-colored urine


• decreased frequency or amount of urine


• increased thirst


• lower back or side pain


• muscle cramps or spasms


• muscular pain, tenderness, wasting, or weakness


• painful or difficult urination


• pale skin


• sore throat


• sudden, severe chest pain


• unusual bleeding or bruising


• weight gain

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:

More common

• Abdominal or stomach pain


• acid or sour stomach


• belching


• blistering, peeling, redness, or swelling of the palms, hands, or bottoms of the feet


• change in color of the treated skin


• change in taste


• difficulty with moving


• discouragement


• excess air or gas in the stomach or intestines


• feeling sad or empty


• full feeling


• hair color changes


• hair loss or thinning of the hair


• heartburn


• irritability


• joint pain


• lack of appetite


• lack or loss of strength


• loss of interest or pleasure


• muscle aches or pains


• numbness, pain, tingling, or unusual sensations in the palms of the hands or bottoms of the feet


• pain or burning in the throat


• passing gas


• sleeplessness


• stomach discomfort, upset, or pain


• swollen joints


• trouble concentrating


• trouble sleeping


• unable to sleep

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.

See also: sunitinib malate side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More sunitinib malate resources

• Sunitinib malate Side Effects (in more detail)
• Sunitinib malate Dosage
• Sunitinib malate Use in Pregnancy & Breastfeeding
• Sunitinib malate Drug Interactions
• Sunitinib malate Support Group
• 7 Reviews for Sunitinib malate - Add your own review/rating

Compare sunitinib malate with other medications

• Gastrointestinal Stromal Tumor
• Pancreatic Cancer
• Renal Cell Carcinoma

CeeNU

Dosage Form: capsule, gelatin coated
CeeNU®

(lomustine)

Capsules

Warnings

CeeNU (lomustine) should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents.

Bone marrow suppression, notably thrombocytopenia and leukopenia, which may contribute to bleeding and overwhelming infections in an already compromised patient, is the most common and severe of the toxic effects of CeeNU (see WARNINGS and ADVERSE REACTIONS).

Since the major toxicity is delayed bone marrow suppression, blood counts should be monitored weekly for at least 6 weeks after a dose (see ADVERSE REACTIONS). At the recommended dosage, courses of CeeNU should not be given more frequently than every 6 weeks.

The bone marrow toxicity of CeeNU is cumulative and therefore dosage adjustment must be considered on the basis of nadir blood counts from prior dose (see dosage adjustment table under DOSAGE AND ADMINISTRATION).

CeeNU Description

CeeNU® (lomustine) (CCNU) is one of the nitrosoureas used in the treatment of certain neoplastic diseases. It is 1-(2-chloro-ethyl)-3-cyclohexyl-1-nitrosourea. It is a yellow powder with the empirical formula of C9H16ClN3O2 and a molecular weight of 233.71. CeeNU is soluble in 10% ethanol (0.05 mg per mL) and in absolute alcohol (70 mg per mL). CeeNU is relatively insoluble in water (<0.05 mg per mL).

It is relatively un-ionized at a physiological pH.

Inactive ingredients in CeeNU Capsules are magnesium stearate and mannitol.

The structural formula is:

CeeNU is available in 10 mg, 40 mg, and 100 mg capsules for oral administration.

CeeNU - Clinical Pharmacology

Although it is generally agreed that CeeNU alkylates DNA and RNA, it is not cross resistant with other alkylators. As with other nitrosoureas, it may also inhibit several key enzymatic processes by carbamoylation of amino acids in proteins.

CeeNU may be given orally. Following oral administration of radioactive CeeNU at doses ranging from 30 mg/m2 to 100 mg/m2, about half of the radioactivity given was excreted in the urine in the form of degradation products within 24 hours.

The serum half-life of the metabolites ranges from 16 hours to 2 days. Tissue levels are comparable to plasma levels at 15 minutes after intravenous administration.

Because of the high lipid solubility and the relative lack of ionization at physiological pH, CeeNU crosses the blood-brain barrier quite effectively. Levels of radioactivity in the CSF are 50% or greater than those measured concurrently in plasma.

Indications and Usage for CeeNU

CeeNU has been shown to be useful as a single agent in addition to other treatment modalities, or in established combination therapy with other approved chemotherapeutic agents in the following:

Brain tumors—both primary and metastatic, in patients who have already received appropriate surgical and/or radiotherapeutic procedures.

Hodgkin’s disease—secondary therapy in combination with other approved drugs in patients who relapse while being treated with primary therapy, or who fail to respond to primary therapy.

Contraindications

CeeNU should not be given to individuals who have demonstrated a previous hypersensitivity to it.

Warnings

Since the major toxicity is delayed bone marrow suppression, blood counts should be monitored weekly for at least 6 weeks after a dose (see ADVERSE REACTIONS). At the recommended dosage, courses of CeeNU should not be given more frequently than every 6 weeks.

The bone marrow toxicity of CeeNU is cumulative and therefore dosage adjustment must be considered on the basis of nadir blood counts from prior dose (see dosage adjustment table under DOSAGE AND ADMINISTRATION).

Pulmonary toxicity from CeeNU appears to be dose related (see ADVERSE REACTIONS).

Long-term use of nitrosoureas has been reported to be possibly associated with the development of secondary malignancies.

Liver and renal function tests should be monitored periodically (see ADVERSE REACTIONS).

Pregnancy Category D

CeeNU can cause fetal harm when administered to a pregnant woman. CeeNU is embryotoxic and teratogenic in rats and embryotoxic in rabbits at dose levels equivalent to the human dose. There are no adequate and well controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking (receiving) 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.

Precautions

General

In all instances where the use of CeeNU is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risks of toxic effects or adverse reactions. Most such adverse reactions are reversible if detected early. When such effects or reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgment of the physician. Reinstitution of CeeNU therapy should be carried out with caution and with adequate consideration of the further need for the drug and alertness as to possible recurrence of toxicity.

Information for Patients

Patients receiving CeeNU should be given the following information and instructions by the physician:

1. Patients should be told that CeeNU is an anticancer drug and belongs to the group of medicines known as alkylating agents.  


2. In order to provide the proper dose of CeeNU, patients should be aware that there may be 2 or more different types and colors of capsules in the container dispensed by the pharmacist.  


3. Patients should be told that CeeNU is given as a single oral dose and will not be repeated for at least 6 weeks.  


4. Patients should be told that nausea and vomiting usually last less than 24 hours, although loss of appetite may last for several days.  


5. If any of the following reactions occur, notify the physician: fever, chills, sore throat, unusual bleeding or bruising, shortness of breath, dry cough, swelling of feet or lower legs, mental confusion, or yellowing of eyes and skin.  


6. Patients should be told to wear gloves when handling CeeNU Capsules.

Laboratory Tests

Due to delayed bone marrow suppression, blood counts should be monitored weekly for at least 6 weeks after a dose.

Baseline pulmonary function studies should be conducted along with frequent pulmonary function tests during treatment. Patients with a baseline below 70% of the predicted Forced Vital Capacity (FVC) or Carbon Monoxide Diffusing Capacity (DLCO) are particularly at risk.

Since CeeNU may cause liver dysfunction, it is recommended that liver function tests be monitored periodically.

Renal function tests should also be monitored periodically.

Carcinogenesis, Mutagenesis, Impairment of Fertility

CeeNU is carcinogenic in rats and mice, producing a marked increase in tumor incidence in doses approximating those employed clinically. Nitrosourea therapy does have carcinogenic potential in humans (see ADVERSE REACTIONS). CeeNU also affects fertility in male rats at doses somewhat higher than the human dose.

Pregnancy

Pregnancy Category D

See WARNINGS.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from CeeNU, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

See ADVERSE REACTIONS: Pulmonary Toxicity and DOSAGE AND ADMINISTRATION.

Geriatric Use

No data from clinical studies of CeeNU are available for patients 65 years of age and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Lomustine and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored.

Adverse Reactions

Hematologic Toxicity

The most frequent and most serious toxicity of CeeNU is delayed myelosuppression. It usually occurs 4 to 6 weeks after drug administration and is dose related. Thrombocytopenia occurs at about 4 weeks postadministration and persists for 1 to 2 weeks. Leukopenia occurs at 5 to 6 weeks after a dose of CeeNU and persists for 1 to 2 weeks. Approximately 65% of patients receiving 130 mg/m2 develop white blood counts below 5000 wbc/mm3. Thirty-six percent developed white blood counts below 3000 wbc/mm3. Thrombocytopenia is generally more severe than leukopenia. However, both may be dose-limiting toxicities.

CeeNU may produce cumulative myelosuppression, manifested by more depressed indices or longer duration of suppression after repeated doses.

The occurrence of acute leukemia and bone marrow dysplasias have been reported in patients following long-term nitrosourea therapy.

Anemia also occurs, but is less frequent and less severe than thrombocytopenia or leukopenia.

Pulmonary Toxicity

Pulmonary toxicity characterized by pulmonary infiltrates and/or fibrosis has been reported rarely with CeeNU. Onset of toxicity has occurred after an interval of 6 months or longer from the start of therapy with cumulative doses of CeeNU usually greater than 1100 mg/m2. There is 1 report of pulmonary toxicity at a cumulative dose of only 600 mg.

Delayed onset pulmonary fibrosis occurring up to 17 years after treatment has been reported in patients who received related nitrosoureas in childhood and early adolescence (1-16 years) combined with cranial radiotherapy for intracranial tumors. There appeared to be some late reduction of pulmonary function of all long-term survivors. This form of lung fibrosis may be slowly progressive and has resulted in death in some cases. In this long-term study of carmustine, all those initially treated at less than 5 years of age died of delayed pulmonary fibrosis.

Gastrointestinal Toxicity

Nausea and vomiting may occur 3 to 6 hours after an oral dose and usually last less than 24 hours. Prior administration of antiemetics is effective in diminishing and sometimes preventing this side effect. Nausea and vomiting can also be reduced if CeeNU is administered to fasting patients.

Hepatotoxicity

A reversible type of hepatic toxicity, manifested by increased transaminase, alkaline phosphatase, and bilirubin levels, has been reported in a small percentage of patients receiving CeeNU.

Nephrotoxicity

Renal abnormalities consisting of progressive azotemia, decrease in kidney size, and renal failure have been reported in patients who received large cumulative doses after prolonged therapy with CeeNU. Kidney damage has also been reported occasionally in patients receiving lower total doses.

Other Toxicities

Stomatitis, alopecia, optic atrophy, and visual disturbances, such as blindness, have been reported infrequently.

Neurological reactions, such as disorientation, lethargy, ataxia, and dysarthria have been noted in some patients receiving CeeNU. However, the relationship to medication in these patients is unclear.

Overdosage

Accidental overdose with lomustine has been reported, including fatal cases. Accidental overdose has been associated with bone marrow suppression, abdominal pain, diarrhea, vomiting, anorexia, lethargy, dizziness, abnormal hepatic function, cough, and shortness of breath.

No proven antidotes have been established for CeeNU overdosage. In case of overdose, appropriate supportive measures should be taken.

CeeNU Dosage and Administration

The recommended dose of CeeNU in adult and pediatric patients as a single agent in previously untreated patients is 130 mg/m2 as a single oral dose every 6 weeks (see PRECAUTIONS: Information for Patients and HOW SUPPLIED: Directions to the Pharmacist). In individuals with compromised bone marrow function, the dose should be reduced to 100 mg/m2 every 6 weeks. When CeeNU is used in combination with other myelosuppressive drugs, the doses should be adjusted accordingly.

Doses subsequent to the initial dose should be adjusted according to the hematologic response of the patient to the preceding dose. The following schedule is suggested as a guide to dosage adjustment:

Nadir After Prior Dose		Percentage of Prior Dose to be Given
Leukocytes (/mm3)	Platelets (/mm3)
≥4000	≥100,000	100%
3000–3999	75,000–99,999	100%
2000–2999	25,000–74,999	70%
<2000	<25,000	50%

A repeat course of CeeNU should not be given until circulating blood elements have returned to acceptable levels (platelets above 100,000/mm3; leukocytes above 4000/mm3), and this is usually in 6 weeks. Adequate number of neutrophils should be present on a peripheral blood smear. Blood counts should be monitored weekly and repeat courses should not be given before 6 weeks because the hematologic toxicity is delayed and cumulative.

How is CeeNU Supplied

CeeNU® (lomustine) Capsules are available in individual bottles of 20 capsules each.

NDC 0015-3032-20	100 mg capsules (Green/Green)
NDC 0015-3031-20	40 mg capsules (White/Green)
NDC 0015-3030-20	10 mg capsules (White/White)

Stability

CeeNU Capsules are stable for the lot life indicated on package labeling when stored in well-closed containers at 25°C (77°F); excursions permitted to 15°C–30°C (59°F–86°F) [see USP Controlled Room Temperature]. Avoid excessive heat (over 40°C, 104°F).

Directions to the Pharmacist

The total dose prescribed by the physician can be obtained (to within 10 mg) by determining the appropriate combination of capsule strengths. Only the appropriate number of CeeNU capsules required for a single administration should be dispensed.

The appropriate number of capsules of each size should be placed in a single vial. Each color-coded capsule is imprinted with the dose in milligrams. In order to provide the proper dose of CeeNU, patients should be aware that there may be 2 or more different types and colors of capsules in the container. Patients should be told that CeeNU is taken as a single oral dose and will not be repeated for at least 6 weeks.

Caution should be exercised when handling CeeNU Capsules. Procedures for proper handling and disposal of anticancer drugs should be utilized. Several guidelines on this subject have been published.1-4 To minimize the risk of dermal exposure, always wear impervious gloves when handling bottles containing CeeNU Capsules. CeeNU Capsules should not be broken. Personnel should avoid exposure to broken capsules. If contact occurs, wash immediately and thoroughly. More information is available in the references listed below.

REFERENCES

1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.


2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html


3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006;63:1172-1193.


4. Polovich M, White JM, Kelleher LO, eds. 2005. Chemotherapy and biotherapy guidelines and recommendations for practice. 2nd ed. Pittsburgh, PA: Oncology Nursing Society.

Manufactured for:

Bristol-Myers Squibb Company

Princeton, NJ 08543 USA

Made in Italy


1050973A5

Rev October 2010

-----------------------------------------

REPRESENTATIVE PACKAGING

See How Supplied section for a complete list of available packages of CeeNU Capsules.

NDC 0015-3030-20

20 CAPSULES

CeeNU® (lomustine)

Rx only

10 mg per capsule

Caution: Dispense One Dose

Bristol-Myers Squibb

CeeNU  lomustine  capsule, gelatin coated

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0015-3032 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength lomustine (lomustine) lomustine 100 mg

Inactive Ingredients Ingredient Name Strength magnesium stearate   mannitol

Product Characteristics Color GREEN Score no score Shape CAPSULE Size 19mm Flavor Imprint Code Bristol;3032;100;mg Contains

Packaging # NDC Package Description Multilevel Packaging 1 0015-3032-20 1 BOTTLE In 1 CARTON contains a BOTTLE 1 20 CAPSULE In 1 BOTTLE This package is contained within the CARTON (0015-3032-20)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA017588	12/15/2008

CeeNU  lomustine  capsule, gelatin coated

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0015-3031 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength lomustine (lomustine) lomustine 40 mg

Inactive Ingredients Ingredient Name Strength magnesium stearate   mannitol

Product Characteristics Color GREEN, WHITE Score no score Shape CAPSULE Size 18mm Flavor Imprint Code Bristol;3031;40;mg Contains

Packaging # NDC Package Description Multilevel Packaging 1 0015-3031-20 1 BOTTLE In 1 CARTON contains a BOTTLE 1 20 CAPSULE In 1 BOTTLE This package is contained within the CARTON (0015-3031-20)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA017588	12/15/2008

CeeNU  lomustine  capsule, gelatin coated

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0015-3030 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength lomustine (lomustine) lomustine 10 mg

Inactive Ingredients Ingredient Name Strength magnesium stearate   mannitol

Product Characteristics Color WHITE Score no score Shape CAPSULE Size 16mm Flavor Imprint Code Bristol;3030;10;mg Contains

Packaging # NDC Package Description Multilevel Packaging 1 0015-3030-20 1 BOTTLE In 1 CARTON contains a BOTTLE 1 20 CAPSULE In 1 BOTTLE This package is contained within the CARTON (0015-3030-20)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA017588	12/15/2008

Labeler - E.R. Squibb & Sons, L.L.C. (968242821)

Revised: 10/2010E.R. Squibb & Sons, L.L.C.