Online PLR Article Directory Eritrea: June 2012

Wednesday, June 27, 2012

Altinac

Generic Name: tretinoin topical (TRET in oin)

Brand Names: Altinac, Atralin, Avita, Renova, Retin A Micro Gel, Retin-A, Tretin-X

What is Altinac (tretinoin topical)?

Tretinoin is a topical (applied to the skin) form of vitamin A that helps the skin renew itself.

The Retin-A and Avita brands of tretinoin are used to treat acne. The Renova brand of tretinoin is used to reduce the appearance of fine wrinkles and mottled skin discoloration, and to make rough facial skin feel smoother.

Tretinoin topical may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about Altinac (tretinoin topical)?

Avoid exposure to sunlight or artificial UV rays (sunlamps or tanning beds). Tretinoin topical can make your skin more sensitive to sunlight and sunburn may result. Use a sunscreen (minimum SPF 15) and wear protective clothing if you must be out in the sun. Avoid getting this medication in your eyes, mouth, and nose, or on your lips. If it does get into any of these areas, wash with water. Do not use tretinoin topical on sunburned, windburned, dry, chapped, irritated, or broken skin. Also avoid using this medication in wounds or on areas of eczema. Wait until these conditions have healed before using tretinoin topical. Use this medication for as many days as it has been prescribed for you even if you think it is not working. It may take weeks or months of use before you notice improvement in your skin. If you are using tretinoin topical to treat acne, your condition may get slightly worse for a short time when you first start using the medication. Call your doctor if skin irritation becomes severe or if your acne does not improve within 8 to 12 weeks.

What should I discuss with my healthcare provider before using Altinac (tretinoin topical)?

FDA pregnancy category C. It is not known whether tretinoin topical is harmful to an unborn baby. Before taking this medication, tell your doctor if you are pregnant or plan to become pregnant during treatment. Tretinoin topical can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I use Altinac (tretinoin topical)?

Use tretinoin topical exactly as your doctor has prescribed it for you. Using more medicine or applying it more often than prescribed will not make it work any faster, and may increase side effects. Do not use this medication for longer than your doctor has prescribed.

Wash your hands before and after applying tretinoin topical. Before applying, clean and dry the skin area to be treated.

Applying tretinoin topical to wet skin may cause skin irritation. If you use Renova, wait at least 20 minutes after washing your face before applying a thin layer of the medication.

Do not wash the treated area for at least 1 hour after applying tretinoin topical. Avoid the use of other skin products on the treated area for at least 1 hour following application of tretinoin topical.

Applying an excessive amount of tretinoin gel may result in "pilling" of the medication. If this occurs, use a thinner layer of gel with the next application.

Tretinoin topical should be used as part of a complete skin care program that includes avoiding sunlight and using an effective sunscreen and protective clothing.

Use this medication for as many days as it has been prescribed for you even if you think it is not working. It may take weeks or months of use before you notice improvement in your skin. If you are using tretinoin topical to treat acne, your condition may get slightly worse for a short time when you first start using the medication. Call your doctor if skin irritation becomes severe or if your acne does not improve within 8 to 12 weeks. Store tretinoin topical at room temperature away from moisture and heat. The gel formulations of Retin-A are flammable, keep them away from open flame.

What happens if I miss a dose?

Use the medication as soon as you remember. If it is almost time for the next dose, skip the missed dose and wait until your next regularly scheduled dose. Do not apply extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine. Tretinoin topical is not expected to cause overdose symptoms.

What should I avoid while using Altinac (tretinoin topical)?

Avoid using skin products that can cause irritation, such as harsh soaps, shampoos, or skin cleansers, hair coloring or permanent chemicals, hair removers or waxes, or skin products with alcohol, spices, astringents, or lime. Do not use other medication skin products unless your doctor has told you to.

Your skin may be more sensitive to weather extremes such as cold and wind while using this medicine.

Altinac (tretinoin topical) side effects

Stop using this medication and get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Less serious side effects may include burning, warmth, stinging, tingling, itching, redness, swelling, dryness, peeling, irritation, or discolored skin.

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.

What other drugs will affect Altinac (tretinoin topical)?

Do not use skin products that contain benzoyl peroxide, sulfur, resorcinol, or salicylic acid unless otherwise directed by your doctor. These products can cause severe skin irritation if used with tretinoin topical.

The following drugs can interact with tretinoin topical, which can make your skin more sensitive to natural and artificial sunlight. Before using this medication, tell your doctor if you are using any of these:

a diuretic (water pill);

tetracycline (Sumycin, Panmycin, Robitet), minocycline (Minocin), doxycycline (Doryx, Vibramycin), demeclocycline (Declomycin), and others;

an antibiotic such as ciprofloxacin (Cipro), ofloxacin (Floxin), and others;

a sulfa drug such as Bactrim, Septra, Cotrim, and others; or

chlorpromazine (Thorazine), prochlorperazine (Compazine), fluphenazine (Permitil, Prolixin), promethazine (Phenergan, Promethegan), perphenazine (Trilafon), and others.

This list is not complete and there may be other drugs that can affect tretinoin topical. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

More Altinac resources

Altinac Side Effects (in more detail)
Altinac Use in Pregnancy & Breastfeeding
Altinac Drug Interactions
Altinac Support Group
0 Reviews for Altinac - Add your own review/rating

Atralin Topical Advanced Consumer (Micromedex) - Includes Dosage Information

Atralin Consumer Overview

Avita Prescribing Information (FDA)

Avita Cream MedFacts Consumer Leaflet (Wolters Kluwer)

Refissa Prescribing Information (FDA)

Renova Emollient Cream MedFacts Consumer Leaflet (Wolters Kluwer)

Renova Consumer Overview

Retin-A Prescribing Information (FDA)

Tretin-X Cream MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Altinac with other medications

Acne
Lichen Sclerosus
Necrobiosis Lipoidica Diabeticorum
Photoaging of the Skin

Where can I get more information?

Your pharmacist can provide more information about tretinoin topical.

See also: Altinac side effects (in more detail)

Fluzone

Pronunciation: IN-floo-EN-za
Generic Name: Influenza Virus Vaccine
Brand Name: Examples include Afluria and Fluzone

Fluzone is used for:

Protecting against certain strains of influenza (flu).

Fluzone is a vaccine. It works by stimulating the body to produce antibodies against certain types of the flu virus, which helps your body to fight the infection.

Do NOT use Fluzone if:

you are allergic to any ingredient in Fluzone, including egg proteins, or to egg products

you have had a severe allergic reaction (eg, rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue) to a prior flu vaccination

Contact your doctor or health care provider right away if any of these apply to you.

Before using Fluzone:

Some medical conditions may interact with Fluzone. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

if you are pregnant, planning to become pregnant, or are breast-feeding

if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement

if you have allergies to medicines, foods, or other substances

if you are allergic to neomycin, polymyxin, rubber, latex, or thimerosal (a preservative)

if you have a fever, cold, respiratory tract infection, or other infection or recent illness

if you have asthma or other breathing problems, a nervous system disorder, or blood or bleeding problems (eg, hemophilia, low blood platelet levels)

if you have cancer or immune system problems (eg, HIV, weakened immune system)

if you are receiving radiation treatment or chemotherapy

if you have a history of Guillain-BarrÃ© syndrome

Some MEDICINES MAY INTERACT with Fluzone. Tell your health care provider if you are taking any other medicines, especially any of the following:

Anticoagulants (eg, warfarin) because the risk of bleeding at the injection site may be increased

Digoxin because its effects may be increased or decreased by certain brands of Fluzone

Corticosteroids (eg, prednisone) or other medicines that may weaken the immune system because they may decrease Fluzone's effectiveness. Ask your doctor if you are unsure if any of your medicines may weaken the immune system

Phenytoin or theophylline because the risk of their side effects may be increased by Fluzone

This may not be a complete list of all interactions that may occur. Ask your health care provider if Fluzone may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Fluzone:

Use Fluzone as directed by your doctor. Check the label on the medicine for exact dosing instructions.

Fluzone is usually given once a year in September, October, or November.

Fluzone is given as an injection at your doctor's office, hospital, or clinic. Contact your health care provider if you have any questions.

Certain influenza vaccines are approved for use in children. Some children may need to receive more than 1 dose of the vaccine. Discuss your child's flu vaccine history with your doctor. Be sure to follow the vaccination schedule provided by your doctor.

Do not use Fluzone if it contains particles, is cloudy or discolored, or if the vial is cracked or damaged.

If you miss a dose of Fluzone, contact your doctor right away.

Ask your health care provider any questions you may have about how to use Fluzone.

Important safety information:

If you have a fever, cold, respiratory tract infection, or other illness, contact your doctor before you receive Fluzone. You may need to receive your injection at a later time.

Fluzone is not a cure for the flu. It must be given before you are exposed to the flu in order to be effective.

Fluzone contains killed viruses. It cannot cause you to develop the flu.

Fluzone is only effective for 1 flu season. You will need to receive the flu vaccine each year.

Fluzone is not effective against all strains of the flu virus. It may also not protect everyone who receives it.

Fluzone does not protect against other respiratory viruses.

Tell your doctor if you will be receiving any other vaccines.

Some of these products contain thimerosal (a preservative). If you have ever had an allergic reaction to thimerosal, ask your pharmacist if your product has thimerosal in it.

The tip cap of some of these products may contain natural rubber latex. If you have ever had an allergic reaction to latex, ask your pharmacist if your product has latex in it.

Tell your doctor or dentist that you have used Fluzone before you receive any medical or dental care, emergency care, or surgery.

Use Fluzone with caution in the ELDERLY; its effectiveness may be decreased in elderly patients.

Fever or seizures accompanied with fever have occurred in CHILDREN using certain brands of Fluzone, especially in children who are younger than 5 years old. Contact your doctor if you have questions about this information.

Caution is advised when using Fluzone in CHILDREN; they may be more sensitive to its effects, especially fever, muscle pain, and general body discomfort.

Fluzone should be used with extreme caution in CHILDREN younger than 6 months old; safety and effectiveness in these children have not been confirmed.

Some brands of Fluzone are not approved for use in CHILDREN younger than 18 years old. If the patient is a child, check with your doctor to determine whether this brand is approved for children.

PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Fluzone while you are pregnant. It is not known if Fluzone is found in breast milk. If you are or will be breast-feeding while you use Fluzone, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Fluzone:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Back pain; chills or shivering; cough; diarrhea; general body discomfort; headache; irritability; mild bruising, pain, redness, swelling, or tenderness at the injection site; mild fever; muscle aches; sore throat; stuffy nose.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); decreased movement of the face muscles; decreased movement or sensation in the arm or shoulder; loss of appetite; muscle weakness; numbness or tingling of the hands or feet; seizures; severe or persistent headache or fever; vision changes; vomiting.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Fluzone side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of Fluzone:

Fluzone is usually handled and stored by a health care provider. If you are using Fluzone at home, store Fluzone as directed by your pharmacist or health care provider. Keep this product, as well as syringes and needles, out of the reach of children and away from pets.

General information:

If you have any questions about Fluzone, please talk with your doctor, pharmacist, or other health care provider.

Fluzone is to be used only by the patient for whom it is prescribed. Do not share it with other people.

If your symptoms do not improve or if they become worse, check with your doctor.

Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Fluzone. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

More Fluzone resources

Fluzone Side Effects (in more detail)
Fluzone Use in Pregnancy & Breastfeeding
Fluzone Drug Interactions
Fluzone Support Group
0 Reviews for Fluzone - Add your own review/rating

Compare Fluzone with other medications

Influenza Prophylaxis

Sunday, June 24, 2012

Salmonella Gastroenteritis Medications

Drugs associated with Salmonella Gastroenteritis

The following drugs and medications are in some way related to, or used in the treatment of Salmonella Gastroenteritis. This service should be used as a supplement to, and NOT a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners.

Topics under Salmonella Gastroenteritis

Salmonella Enteric Fever (6 drugs)

Drug List:

Cipro

Cipro-I-V

Cipro-Xr-Extended-Release-Tablets

Friday, June 22, 2012

Moexipril Hydrochloride

Class: Angiotensin-Converting Enzyme Inhibitors
VA Class: CV800
Chemical Name: (3S-(2(R*(R*)),3R*))-2-(2-((1 - (Ethoxycarbonyl) - 3 - phenylpropyl)amino) - 1 - oxopropyl) - 1,2,3,4 - tetrahydro - 6,7 - dimethoxy - 3 - isoquinolinecarboxylic acid monohydrochloride
Molecular Formula: C₂₇H₃₄N₂O₇•ClH
CAS Number: 82586-52-5
Brands: Univasc, Uniretic

May cause fetal and neonatal morbidity and mortality if used during pregnancy.¹ ¹¹⁰ ¹¹¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

If pregnancy is detected, discontinue as soon as possible.¹ ¹¹¹

Introduction

Nonsulfhydryl ACE inhibitor.¹

Uses for Moexipril Hydrochloride

Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents).¹

One of several preferred initial therapies in hypertensive patients with heart failure, post-MI, high coronary disease risk, diabetes mellitus, chronic renal failure, and/or cerebrovascular disease.⁹⁵

Can be used as monotherapy for initial management of uncomplicated hypertension;¹ however, thiazide diuretics are preferred by JNC 7.⁹⁵

CHF

Management of symptomatic CHF†, usually in conjunction with cardiac glycosides, diuretics, and β-adrenergic blocking agents.¹⁰ ¹¹ ¹² ¹⁴ ⁹⁴ ⁹⁶

Diabetic Nephropathy

A first-line agent in the treatment of diabetic nephropathy† in hypertensive patients with diabetes mellitus.¹⁰⁰ ¹⁰¹ ¹⁰²

Moexipril Hydrochloride Dosage and Administration

General

Moexipril/hydrochlorothiazide fixed combination should not be used for initial treatment of hypertension.⁸³

Administration

Oral Administration

Administer orally once or twice daily 1 hour before meals.¹ ³ ¹⁸ ⁸³

Dosage

Available as moexipril hydrochloride; dosage expressed in terms of the salt.¹ ⁸³

Adults

Hypertension

Oral

Initially, 7.5 mg once daily as monotherapy.¹ ³ ⁵ ¹⁸ ⁹⁵

In patients currently receiving diuretic therapy, discontinue diuretic, if possible, 2–3 days before initiating moexipril.¹ ⁸ ⁹ ¹⁰ ¹¹ ¹² ¹³ ¹⁴ ³⁷ ⁴⁶ May cautiously resume diuretic therapy if BP not controlled adequately with moexipril alone.¹ ²⁸ ²⁹ ³⁰ ³⁹ If diuretic cannot be discontinued, increase sodium intake and give lower initial moexipril dose (3.75 mg) under close medical supervision.¹ ⁸ ¹⁰ ¹¹ ¹² ¹³ ¹⁴ ⁸³ ⁸⁴

Usual dosage: 7.5–30 mg daily, given in 1 dose or 2 divided doses.¹ ⁸³ ⁹⁵

If effectiveness diminishes toward end of dosing interval in patients treated once daily, consider increasing dosage or administering drug in 2 divided doses.¹

Moexipril/Hydrochlorothiazide Combination Therapy

Oral

If BP is not adequately controlled by monotherapy with moexipril, can switch to the fixed-combination preparation containing moexipril hydrochloride 7.5 mg and hydrochlorothiazide 12.5 mg, moexipril hydrochloride 15 mg and hydrochlorothiazide 12.5 mg, or moexipril hydrochloride 15 mg and hydrochlorothiazide 25 mg.⁸³ Adjust dosage of either or both drugs according to patient’s response.⁸³

Prescribing Limits

Adults

Hypertension

Oral

Usually, maximum 30 mg daily.¹ Dosages >60 mg daily have not been extensively evaluated in hypertensive patients.¹ ⁵

Special Populations

Renal Impairment

Hypertension

Oral

Initially, 3.75 mg once daily in patients with severe renal impairment (Cl_cr ≤40 mL/minute); titrate until BP is controlled or to maximum of 15 mg daily.¹

Moexipril/hydrochlorothiazide fixed combination is not recommended in patients with severe renal impairment.⁸³

Volume- and/or Salt-depleted Patients

Correct volume and/or salt depletion prior to initiation of therapy or initiate therapy under close medical supervision using lower initial dosage.¹

Cautions for Moexipril Hydrochloride

Contraindications

Known hypersensitivity (e.g., history of angioedema) to moexipril or another ACE inhibitor.¹ ⁸³

Warnings/Precautions

Warnings

Hypotension

Possible symptomatic hypotension, particularly in volume- and/or salt-depleted patients (e.g., those with restricted salt intake, treated with diuretics, undergoing dialysis, with nausea or vomiting, or with CHF).¹ Risk of marked hypotension, sometimes associated with oliguria and azotemia, and rarely acute renal failure and death in patients with CHF with or without associated renal insufficiency.¹

Hypotension may occur in patients undergoing surgery or during anesthesia with agents that produce hypotension; recommended treatment is fluid volume expansion.¹

To minimize potential for hypotension, consider recent antihypertensive therapy, extent of BP elevation, sodium intake, fluid status, and other clinical conditions.¹ May minimize potential for hypotension by withholding diuretic therapy and/or increasing sodium intake for 2–3 days prior to initiation of moexipril.¹

Transient hypotension is not a contraindication to additional doses; may reinstate therapy cautiously after BP is stabilized (e.g., with volume expansion).¹

Initiate therapy in patients with CHF (with or without associated renal insufficiency) under close medical supervision; monitor closely for first 2 weeks following initiation of moexipril or any increase in moexipril or diuretic dosage.¹

Hematologic Effects

Neutropenia and agranulocytosis reported with captopril; risk of neutropenia appears to depend principally on degree of renal impairment and presence of collagen vascular disease (e.g., systemic lupus erythematosus, scleroderma); risk with moexipril is unknown.¹ ⁸³

Consider monitoring leukocytes in patients with collagen vascular disease, especially if renal impairment exists.¹ ⁸³

Fetal/Neonatal Morbidity and Mortality

Possible fetal and neonatal morbidity and mortality when used during pregnancy.¹ ¹¹¹ (See Boxed Warning.) Such potential risks occur throughout pregnancy, especially during the second and third trimesters.¹¹¹

Also may increase the risk of major congenital malformations when administered during the first trimester of pregnancy.¹¹⁰ ¹¹¹

Discontinue as soon as possible when pregnancy is detected, unless continued use is considered lifesaving.¹ ¹¹⁰ ¹¹¹ Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy.⁷⁵

Hepatic Effects

Clinical syndrome that usually is manifested initially by cholestatic jaundice and may progress to fulminant hepatic necrosis (occasionally fatal) reported rarely with ACE inhibitors.¹

If jaundice or marked elevation of liver enzymes occurs, discontinue drug and monitor patient.¹

Sensitivity Reactions

Anaphylactoid reactions and/or angioedema possible; if associated with laryngeal edema, may be fatal.¹ ⁸³ Immediate medical intervention (e.g., epinephrine) for involvement of tongue, glottis, or larynx.¹ ⁸³ Intestinal angioedema possible; consider in differential diagnosis of patients who develop abdominal pain.¹ ⁸³

Anaphylactoid reactions reported in patients receiving ACE inhibitors while undergoing LDL apheresis with dextran sulfate absorption¹ ⁵¹ ⁵² ⁸³ or following initiation of hemodialysis that utilized high-flux membrane.¹ ⁴⁷ ⁴⁸ ⁴⁹ ⁸³

Life-threatening anaphylactoid reactions reported in at least 2 patients receiving ACE inhibitors while undergoing desensitization treatment with hymenoptera venom.¹ ⁸³

Contraindicated in patients with a history of angioedema associated with ACE inhibitors.¹ ⁸³

General Precautions

Renal Effects

Transient increases in BUN and S_cr possible, especially in patients with preexisting renal impairment or those receiving concomitant diuretic therapy.¹ ⁸³ Possible increases in BUN and S_cr in patients with unilateral or bilateral renal artery stenosis; generally reversible following discontinuance of ACE inhibitors and/or diuretic.¹ ⁸³

Possible oliguria, progressive azotemia, and, rarely, acute renal failure and/or death in patients with severe CHF.¹ ⁸³

Closely monitor renal function following initiation of therapy in such patients.¹ ⁸³ Some patients may require dosage reduction or discontinuance of ACE inhibitor or diuretic and/or adequate sodium repletion.¹ ⁸³

Hyperkalemia

Possible hyperkalemia, especially in patients with renal impairment or diabetes mellitus and those receiving drugs that can increase serum potassium concentration (e.g., potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes).¹ (See Specific Drugs under Interactions.)

Monitor serum potassium concentration carefully in these patients.¹

Cough

Persistent and nonproductive cough; resolves after drug discontinuance.¹

Use of Fixed Combinations

When used in fixed combination with hydrochlorothiazide, consider the cautions, precautions, and contraindications associated with hydrochlorothiazide.⁸³

Specific Populations

Pregnancy

Category C (1st trimester); Category D (2nd and 3rd trimesters).¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions and see Boxed Warning.)

Lactation

Not known whether moexipril is distributed into milk.¹ Caution advised if used in nursing women.¹

Pediatric Use

Safety and efficacy not established.¹

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.¹ Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.¹

Renal Impairment

Systemic exposure to moexipril and moexiprilat may be increased.¹ Initial dosage adjustment recommended in patients with severe renal impairment.¹ (See Renal Impairment under Dosage and Administration.)

Moexipril/hydrochlorothiazide fixed combination is not recommended in patients with severe renal impairment.⁸³

Blacks

BP reduction may be smaller in black patients compared with nonblack patients; however, no apparent population difference during combined therapy with ACE inhibitor and thiazide diuretic.²⁵ ⁸³ ⁹² ⁹³ ⁹⁵ ¹⁰⁸ ¹⁰⁹ Use in combination with a diuretic.²⁵ ⁸³ ⁸⁶ ⁹⁵

Higher incidence of angioedema reported with ACE inhibitors in blacks compared with other races.¹

Common Adverse Effects

Cough, dizziness, diarrhea, flu syndrome, fatigue, pharyngitis, flushing, rash, myalgia.¹

Interactions for Moexipril Hydrochloride

Specific Drugs

Drug	Interaction	Comments
Anticoagulants, oral	Clinically important interaction not observed¹
Cimetidine	Clinically important interaction not observed¹
Digoxin	Clinically important interaction not observed¹
Diuretics	Increased hypotensive effect¹	If possible, discontinue diuretic before initiating moexipril¹ (see Dosage under Dosage and Administration)
Diuretic, potassium-sparing (amiloride, spironolactone, triamterene)	Enhanced hyperkalemic effect¹	Use with caution; monitor serum potassium concentrations frequently¹
Lithium	Increased serum lithium concentrations; possible toxicity¹	Use with caution; monitor serum lithium concentration frequently¹
Potassium supplements or potassium-containing salt substitutes.	Enhanced hyperkalemic effect¹	Use with caution; monitor serum potassium concentrations frequently¹

Moexipril Hydrochloride Pharmacokinetics

Absorption

Bioavailability

About 13% of oral dose is absorbed.¹ Peak plasma concentration of moexiprilat is achieved within about 1.5 hours.¹

Onset

Following a single oral dose, antihypertensive effects are observed within about 1 hour with peak BP reduction at 3–6 hours.¹

During chronic therapy, maximum antihypertensive effect with any dose is achieved after 4 weeks.¹

Duration

Antihypertensive effect of a single dose persists for about 24 hours.¹

Food

Food reduces peak plasma concentration of moexipril; administer 1 hour before meals.¹

Special Populations

In patients with cirrhosis, peak plasma concentration and AUC of moexipril following a single oral dose were increased, while peak plasma concentration of moexiprilat was decreased and AUC of moexiprilat was increased.¹

In patients with renal impairment, increased moexipril and moexiprilat concentrations.¹

Distribution

Extent

Not known whether distributed into milk.¹

Plasma Protein Binding

Moexiprilat: 50%.¹

Elimination

Metabolism

Metabolized in the liver, principally to an active metabolite, moexiprilat.¹

Elimination Route

Following oral administration, eliminated in feces (53%), principally as moexiprilat, and to a lesser extent in urine (13%).¹

Following IV administration, eliminated principally in urine, as moexiprilat (40%) and moexipril (26%), and to lesser extent in feces (about 20%, mainly as moexiprilat).¹

Half-life

Moexiprilat: 12 hours.¹

Special Populations

In patients with renal impairment (Cl_cr 10–40 mL/minute), threefold to fourfold increase in moexiprilat half-life.¹

Stability

Storage

Oral

Tablets

Tight containers at 15–30°C.¹

ActionsActions

Prodrug; not pharmacologically active until hydrolyzed in the liver to moexiprilat.¹

Suppresses the renin-angiotensin-aldosterone system.¹

Advice to Patients

Risk of angioedema, anaphylactoid reactions, or other sensitivity reactions.¹ Importance of reporting sensitivity reactions (e.g., edema of face, eyes, lips, tongue, or extremities; hoarseness; swallowing or breathing with difficulty) immediately to clinician and of discontinuing the drug.¹

Importance of reporting signs of infection (e.g., sore throat, fever).¹

Risk of hypotension.¹ Importance of informing clinicians promptly if lightheadedness or fainting occurs.¹

Importance of adequate fluid intake; risk of volume depletion with excessive perspiration, dehydration, vomiting, or diarrhea.¹

Risks of use during pregnancy.¹ ¹¹⁰ ¹¹¹ (See Boxed Warning.)

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (including salt substitutes containing potassium).¹

Importance of taking moexipril 1 hour before meals.¹

Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.¹

Importance of advising patients of other important precautionary information.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Moexipril Hydrochloride
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	7.5 mg*	Moexipril Hydrochloride Tablets	Teva
			Univasc (scored)	Schwarz
		15 mg*	Moexipril Hydrochloride Tablets	Teva
			Univasc (scored)	Schwarz

Moexipril Hydrochloride Combinations
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	7.5 mg with Hydrochlorothiazide 12.5 mg	Uniretic (scored)	Schwarz
		15 mg with Hydrochlorothiazide 12.5 mg	Uniretic (scored)	Schwarz
		15 mg with Hydrochlorothiazide 25 mg	Uniretic (scored)	Schwarz

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Moexipril HCl 15MG Tablets (WATSON LABS): 30/$41.99 or 90/$109.98

Moexipril HCl 7.5MG Tablets (WATSON LABS): 30/$40.99 or 90/$100.97

Moexipril-Hydrochlorothiazide 15-12.5MG Tablets (WATSON LABS): 100/$109.98 or 300/$315.96

Moexipril-Hydrochlorothiazide 15-25MG Tablets (WATSON LABS): 30/$36.99 or 90/$89.97

Moexipril-Hydrochlorothiazide 7.5-12.5MG Tablets (TEVA PHARMACEUTICALS USA): 30/$37.99 or 90/$95.97

Uniretic 15-12.5MG Tablets (SCHWARZ PHARMA): 30/$84.99 or 90/$228.98

Uniretic 15-25MG Tablets (SCHWARZ PHARMA): 30/$84.99 or 90/$228.98

Uniretic 7.5-12.5MG Tablets (SCHWARZ PHARMA): 30/$84.99 or 90/$231.97

Univasc 15MG Tablets (SCHWARZ PHARMA): 30/$91.99 or 90/$244.97

Univasc 7.5MG Tablets (SCHWARZ PHARMA): 30/$61.99 or 90/$164.97

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions April 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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39. Hodsman GP, Brown JJ, Cumming AMM et al. Enalapril in treatment of hypertension with renal artery stenosis: changes in blood pressure, renin, angiotensin I and II, renal function, and body composition. Am J Med. 1984; 77:52-60.

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41. Hricik DE, Browning PJ, Kopelman R et al. Captopril-induced renal insufficiency in patients with bilateral renal-artery stenoses or renal-artery stenosis in a solitary kidney. N Engl J Med. 1983; 308:373-6. [IDIS 164635] [PubMed 6337327]

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44. Cody RJ. Clinical and hemodynamic experience with enalapril in congestive heart failure. Am J Cardiol. 1985; 55:36-40.

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47. US Food and Drug Administration. Severe allergic reactions associated with dialysis and ACE inhibitors. FDA Med Bull. 1992; 22:4.

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49. Tielemans C, Madhoun P, Lenaers M et al. Anaphylactoid reactions during hemodialysis on AN69 membranes in patients receiving ACE inhibitors. Kidney Int. 1990; 38:982-4. [PubMed 2266684]

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51. Olbricht CJ, Schaumann D, Fischer D. Anaphylactoid reactions, LDL apheresis with dextran sulphate, and ACE inhibitors. Lancet. 1992; 340:908-9. [IDIS 303757] [PubMed 1357312]

52. Keller C, Grützmacher P, Bahr F et al. LDL-apheresis with dextran sulphate and anaphylactoid reactions to ACE inhibitors. Lancet. 1993; 341:60-1. [IDIS 307728] [PubMed 8093314]

53. Merck & Co. Vaseretic (enalapril maleate–hydrochlorothiazide) prescribing information. West Point, PA; 1994 Feb.

54. Merck & Co. Vasotec I.V. Enalaprilat (enalapril) prescribing information. West Point, PA; 1994 Apr.

55. Heel RC, Brogden RN, Speight TM et al. Captopril: a preliminary review of its pharmacological properties and therapeutic efficacy. Drugs. 1980; 20:409-52. [IDIS 134943] [PubMed 7009133]

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57. Frohlich ED, Cooper RA, Lewis EJ. Review of the overall experience of captopril in hypertension. Arch Intern Med. 1984; 144:1441-4. [IDIS 186955] [PubMed 6233948]

58. Vlasses PH, Larijani GE, Conner DP et al. Enalapril, a nonsulfhydryl angiotensin-converting enzyme inhibitor. Clin Pharm. 1985; 4:27-40. [IDIS 195925] [PubMed 2982541]

59. Bünning P. Inhibition of angiotensin converting enzyme by 2-[N-[(S)-1-carboxy-3-phenylpropyl]-l -alanyl]- (1S,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498 Diacid). Arzneimittelforschung. 1984; 34:1406-10. [PubMed 6097266]

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61. Reviewers’ comments (personal observations) on enalapril; 1986 Nov.

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64. Webb D, Benjamin N, Collier J et al. Enalapril-induced cough. Lancet. 1986; 2:1094. [IDIS 222959] [PubMed 2877240]

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Thursday, June 21, 2012

Fludara

Fludarabine phosphate

Dosage Form: injection, powder, lyophilized, for solution
Fludara®

Fludarabine phosphate

FOR INJECTION

FOR INTRAVENOUS USE ONLY

Rx Only

WARNING:

Fludara FOR INJECTION should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy. Fludara FOR INJECTION can severely suppress bone marrow function. When used at high doses in dose-ranging studies in patients with acute leukemia, Fludara FOR INJECTION was associated with severe neurologic effects, including blindness, coma, and death. This severe central nervous system toxicity occurred in 36% of patients treated with doses approximately four times greater (96 mg/m2/day for 5-7 days) than the recommended dose. Similar severe central nervous system toxicity, including coma, seizures, agitation and confusion, has been reported in patients treated at doses in the range of the dose recommended for chronic lymphocytic leukemia.

In a clinical investigation using Fludara FOR INJECTION in combination with pentostatin (deoxycoformycin) for the treatment of refractory chronic lymphocytic leukemia (CLL), there was an unacceptably high incidence of fatal pulmonary toxicity. Therefore, the use of Fludara FOR INJECTION in combination with pentostatin is not recommended.

Fludara Description

Fludara FOR INJECTION contains Fludarabine phosphate, a fluorinated nucleotide analog of the antiviral agent vidarabine, 9-β-D-arabinofuranosyladenine (ara-A) that is relatively resistant to deamination by adenosine deaminase. Each vial of sterile lyophilized solid cake contains 50 mg of the active ingredient Fludarabine phosphate, 50 mg of mannitol, and sodium hydroxide to adjust pH to 7.7. The pH range for the final product is 7.2-8.2. Reconstitution with 2 mL of Sterile Water for Injection, USP, results in a solution containing 25 mg/mL of Fludarabine phosphate intended for intravenous administration.

The chemical name for Fludarabine phosphate is 9H-Purin-6-amine, 2-fluoro-9-(5-0-phosphono-β-D-arabino-furanosyl) (2-fluoro-ara-AMP). The molecular formula of Fludarabine phosphate is C10H13FN5O7P (MW 365.2) and the structure is:

Fludara - Clinical Pharmacology

Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A and then phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, 2-fluoro-ara-ATP. This metabolite appears to act by inhibiting DNA polymerase alpha, ribonucleotide reductase and DNA primase, thus inhibiting DNA synthesis. The mechanism of action of this antimetabolite is not completely characterized and may be multi-faceted.

Phase I studies in humans have demonstrated that Fludarabine phosphate is rapidly converted to the active metabolite, 2-fluoro-ara-A, within minutes after intravenous infusion. Consequently, clinical pharmacology studies have focused on 2-fluoro-ara-A pharmacokinetics. After the five daily doses of 25 mg 2-fluoro-ara-AMP/m2 to cancer patients infused over 30 minutes, 2-fluoro-ara-A concentrations show a moderate accumulation. During a 5-day treatment schedule, 2-fluoro-ara-A plasma trough levels increased by a factor of about 2. The terminal half-life of 2-fluoro-ara-A was estimated as approximately 20 hours. In vitro, plasma protein binding of Fludarabine ranged between 19% and 29%.

A correlation was noted between the degree of absolute granulocyte count nadir and increased area under the concentration x time curve (AUC).

Special Populations

Pediatric Patients

Limited pharmacokinetic data for Fludara FOR INJECTION are available from a published study of children (ages 1-21 years) with refractory acute leukemias or solid tumors (Children’s Cancer Group Study 097). When Fludara FOR INJECTION was administered as a loading dose over 10 minutes immediately followed by a 5-day continuous infusion, steady-state conditions were reached early.

Patients with Renal Impairment

The total body clearance of the principal metabolite 2-fluoro-ara-A correlated with the creatinine clearance, indicating the importance of the renal excretion pathway for the elimination of the drug. Renal clearance represents approximately 40% of the total body clearance. Patients with creatinine clearance 30-79 mL/min should have their Fludara FOR INJECTION dose reduced and be monitored closely for excessive toxicity. Due to insufficient data, Fludara FOR INJECTION should not be administered to patients with creatinine clearance less than 30 mL/min. (See DOSAGE AND ADMINISTRATION section).

Clinical Studies

Two single-arm, open-label studies of Fludara FOR INJECTION have been conducted in adult patients with CLL refractory to at least one prior standard alkylating-agent containing regimen. In a study conducted by M.D. Anderson Cancer Center (MDAH), 48 patients were treated with a dose of 22-40 mg/m2 daily for 5 days every 28 days. Another study conducted by the Southwest Oncology Group (SWOG) involved 31 patients treated with a dose of 15-25 mg/m2 daily for 5 days every 28 days. The overall objective response rates were 48% and 32% in the MDAH and SWOG studies, respectively. The complete response rate in both studies was 13%; the partial response rate was 35% in the MDAH study and 19% in the SWOG study. These response rates were obtained using standardized response criteria developed by the National Cancer Institute CLL Working Group and were achieved in heavily pretreated patients. The ability of Fludara FOR INJECTION to induce a significant rate of response in refractory patients suggests minimal cross-resistance with commonly used anti-CLL agents.

The median time to response in the MDAH and SWOG studies was 7 weeks (range of 1 to 68 weeks) and 21 weeks (range of 1 to 53 weeks), respectively. The median duration of disease control was 91 weeks (MDAH) and 65 weeks (SWOG). The median survival of all refractory CLL patients treated with Fludara FOR INJECTION was 43 weeks and 52 weeks in the MDAH and SWOG studies, respectively.

Rai stage improved to Stage II or better in 7 of 12 MDAH responders (58%) and in 5 of 7 SWOG responders (71%) who were Stage III or IV at baseline. In the combined studies, mean hemoglobin concentration improved from 9.0 g/dL at baseline to 11.8 g/dL at the time of response in a subgroup of anemic patients. Similarly, average platelet count improved from 63,500/mm3 to 103,300/mm3 at the time of response in a subgroup of patients who were thrombocytopenic at baseline.

Indications and Usage for Fludara

Fludara FOR INJECTION is indicated for the treatment of adult patients with B-cell chronic lymphocytic leukemia (CLL) who have not responded to or whose disease has progressed during treatment with at least one standard alkylating-agent containing regimen. The safety and effectiveness of Fludara FOR INJECTION in previously untreated or non-refractory patients with CLL have not been established.

Contraindications

Fludara FOR INJECTION is contraindicated in those patients who are hypersensitive to this drug or its components.

Warnings

(See BOXED WARNINGS)

Dose Dependent Neurologic Toxicities

There are clear dose-dependent toxic effects seen with Fludara FOR INJECTION. Dose levels approximately 4 times greater (96 mg/m2/day for 5 to 7 days) than that recommended for CLL (25 mg/m2/day for 5 days) were associated with a syndrome characterized by delayed blindness, coma and death. Symptoms appeared from 21 to 60 days following the last dose. Thirteen of 36 patients (36%) who received Fludara FOR INJECTION at high doses (96 mg/m2/day for 5 to 7 days) developed this severe neurotoxicity. Similar severe central nervous system toxicity, including coma, seizures, agitation and confusion, has been reported in patients treated at doses in the range of the dose recommended for chronic lymphocytic leukemia.

In postmarketing experience neurotoxicity has been reported to occur either earlier or later than in clinical trials (range 7 to 225 days).

The effect of chronic administration of Fludara FOR INJECTION on the central nervous system is unknown; however, patients have received the recommended dose for up to 15 courses of therapy.

Bone Marrow Suppression

Severe bone marrow suppression, notably anemia, thrombocytopenia and neutropenia, has been reported in patients treated with Fludara FOR INJECTION. In a Phase I study in adult solid tumor patients, the median time to nadir counts was 13 days (range, 3-25 days) for granulocytes and 16 days (range, 2-32) for platelets. Most patients had hematologic impairment at baseline either as a result of disease or as a result of prior myelosuppressive therapy. Cumulative myelosuppression may be seen. While chemotherapy-induced myelosuppression is often reversible, administration of Fludara FOR INJECTION requires careful hematologic monitoring.

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

Autoimmune Reactions

Instances of life-threatening and sometimes fatal autoimmune phenomena such as hemolytic anemia, autoimmune thrombocytopenia/thrombocytopenic purpura (ITP), Evans syndrome, and acquired hemophilia have been reported to occur after one or more cycles of treatment with Fludara FOR INJECTION in patients with or without a previous history of autoimmune hemolytic anemia or a positive Coombs' test and who may or may not be in remission from their disease. Steroids may or may not be effective in controlling these hemolytic episodes. The majority of patients rechallenged with Fludara FOR INJECTION developed a recurrence in the hemolytic process. The mechanism(s) which predispose patients to the development of this complication has not been identified. Patients undergoing treatment with Fludara FOR INJECTION should be evaluated and closely monitored for hemolysis. Discontinuation of therapy with Fludara FOR INJECTION is recommended in case of hemolysis.

Transfusion Associated Graft-Versus-Host Disease

Transfusion-associated graft-versus-host disease has been observed after transfusion of non-irradiated blood in Fludara FOR INJECTION treated patients. Fatal outcome as a consequence of this disease has been reported. Therefore, to minimize the risk of transfusion-associated graft-versus-host disease, patients who require blood transfusion and who are undergoing, or who have received, treatment with Fludara FOR INJECTION should receive irradiated blood only.

Pulmonary Toxicity

In a clinical investigation using Fludara FOR INJECTION in combination with pentostatin (deoxycoformycin) for the treatment of refractory chronic lymphocytic leukemia (CLL) in adults, there was an unacceptably high incidence of fatal pulmonary toxicity. Therefore, the use of Fludara FOR INJECTION in combination with pentostatin is not recommended.

Pregnancy Category D

Based on its mechanism of action, Fludarabine phosphate can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of Fludara FOR INJECTION in pregnant women. Fludarabine administered to rats and rabbits during organogenesis caused an increase in resorptions, skeletal and visceral malformations and decreased fetal body weights. If Fludara FOR INJECTION is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

Male Fertility and Reproductive Outcomes

Males with female sexual partners of childbearing potential should use contraception during and after cessation of Fludara FOR INJECTION therapy. Fludarabine may damage testicular tissue and spermatozoa. Possible sperm DNA damage raises concerns about loss of fertility and genetic abnormalities in fetuses. The duration of this effect is uncertain. [See PRECAUTIONS, Impairment of Fertility]

Precautions

General

Fludara FOR INJECTION is a potent antineoplastic agent with potentially significant toxic side effects. Patients undergoing therapy should be closely observed for signs of hematologic and nonhematologic toxicity. Periodic assessment of peripheral blood counts is recommended to detect the development of anemia, neutropenia and thrombocytopenia.

In patients with impaired state of health, Fludara FOR INJECTION should be given with caution and after careful risk/benefit consideration. This applies especially for patients with severe impairment of bone marrow function (thrombocytopenia, anemia, and/or granulocytopenia), immunodeficiency or with a history of opportunistic infection. Prophylactic treatment should be considered in patients at increased risk of developing opportunistic infections.

Fludara FOR INJECTION may reduce the ability to drive or use machines, since fatigue, weakness, visual disturbances, confusion, agitation and seizures have been observed.

Tumor Cell Lysis

Tumor lysis syndrome has been associated with Fludara FOR INJECTION treatment. This syndrome has been reported in CLL patients with large tumor burden. Since Fludara FOR INJECTION can induce a response as early as the first week of treatment, precautions should be taken in those patients at risk of developing this complication.

Renal Impairment

Fludara FOR INJECTION must be administered cautiously in patients with renal impairment. The total body clearance of 2-fluoro-ara-A has been shown to be directly correlated with creatinine clearance. Patients with creatinine clearance 30-79 mL/min should have their Fludara FOR INJECTION dose reduced and be monitored closely for excessive toxicity. Fludara FOR INJECTION should not be administered to patients with creatinine clearance less than 30 mL/min. (See DOSAGE AND ADMINISTRATION section).

In patients aged 65 years or older, creatinine clearance should be measured before start of treatment.

Laboratory Tests

During treatment, the patient’s hematologic profile (particularly neutrophils and platelets) should be monitored regularly to determine the degree of hematopoietic suppression.

Drug Interactions

The use of Fludara FOR INJECTION in combination with pentostatin is not recommended due to the risk of fatal pulmonary toxicity (see WARNINGS section).

Carcinogenesis

No animal carcinogenicity studies with Fludara FOR INJECTION have been conducted.

Mutagenesis

Fludarabine phosphate was not mutagenic to bacteria (Ames test) or mammalian cells (HGRPT assay in Chinese hamster ovary cells) either in the presence or absence of metabolic activation. Fludarabine phosphate was clastogenic in vitro to Chinese hamster ovary cells (chromosome aberrations in the presence of metabolic activation) and induced sister chromatid exchanges both with and without metabolic activation. In addition, Fludarabine phosphate was clastogenic in vivo (mouse micronucleus assay) but was not mutagenic to germ cells (dominant lethal test in male mice).

Impairment of Fertility

Studies in mice, rats and dogs have demonstrated dose-related adverse effects on the male reproductive system. Observations consisted of a decrease in mean testicular weights in mice and rats with a trend toward decreased testicular weights in dogs and degeneration and necrosis of spermatogenic epithelium of the testes in mice, rats and dogs. The possible adverse effects on fertility in humans have not been adequately evaluated.

Pregnancy

Pregnancy Category D (see WARNINGS section).

Based on its mechanism of action, Fludarabine phosphate can cause fetal harm when administered to a pregnant woman. There are not adequate and well-controlled studies of Fludarabine phosphate in pregnant women. Fludarabine phosphate was embryolethal and teratogenic in rats and rabbits. If Fludara FOR INJECTION is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

In rats, repeated intravenous doses of Fludarabine phosphate at 2.4 times and 7.2 times the recommended human IV dose (25 mg/m2) administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations (cleft palate, exencephaly, and fetal vertebrae deformities) and decreased fetal body weights. Maternal toxicity was not apparent at 2.4 times the human IV dose, and was limited to slight body weight decreases at 7.2 times the human IV dose. In rabbits, repeated intravenous doses of Fludarabine phosphate at 3.8 times the human IV dose administered during organogenesis increased embryo and fetal lethality as indicated by increased resorptions and a decrease in live fetuses. A significant increase in malformations including cleft palate, hydrocephaly, adactyly, brachydactyly, fusions of the digits, diaphragmatic hernia, heart/great vessel defects, and vertebrae/rib anomalies were seen in all dose levels (≥ 0.5 times the human IV dose).

Nursing Mothers

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

Pediatric Use

Data submitted to the FDA was insufficient to establish efficacy in any childhood malignancy. Fludara FOR INJECTION was evaluated in 62 pediatric patients (median age 10, range 1-21) with refractory acute leukemia (45 patients) or solid tumors (17 patients). The Fludara FOR INJECTION regimen tested for pediatric acute lymphocytic leukemia (ALL) patients was a loading bolus of 10.5 mg/m2/day followed by a continuous infusion of 30.5 mg/m2/day for 5 days. In 12 pediatric patients with solid tumors, dose-limiting myelosuppression was observed with a loading dose of 8 mg/m2/day followed by a continuous infusion of 23.5 mg/m2/day for 5 days. The maximum tolerated dose was a loading dose of 7 mg/m2/day followed by a continuous infusion of 20 mg/m2/day for 5 days. Treatment toxicity included bone marrow suppression. Platelet counts appeared to be more sensitive to the effects of Fludara FOR INJECTION than hemoglobin and white blood cell counts. Other adverse events included fever, chills, asthenia, rash, nausea, vomiting, diarrhea, and infection. There were no reported occurrences of peripheral neuropathy or pulmonary hypersensitivity reaction.

Vaccination

During and after treatment with Fludara FOR INJECTION, vaccination with live vaccines should be avoided.

Disease Progression

Richter’s syndrome has been reported in CLL patients.

Adverse Reactions

Very common adverse events include myelosuppression (neutropenia, thrombocytopenia and anemia), fever and chills, fatigue, weakness, infection, pneumonia, cough, nausea, vomiting, and diarrhea. Other commonly reported events include malaise, mucositis and anorexia. Serious opportunistic infections (such as latent viral reactivation, herpes zoster virus, Epstein-Barr virus, and progressive multifocal leukoencephalopathy) have occurred in CLL patients treated with Fludara FOR INJECTION. Adverse events and those reactions which are more clearly related to the drug are arranged below according to body system.

Hematopoietic Systems

Hematologic events (neutropenia, thrombocytopenia, and/or anemia) were reported in the majority of CLL patients treated with Fludara FOR INJECTION. During Fludara FOR INJECTION treatment of 133 patients with CLL, the absolute neutrophil count decreased to less than 500/mm3 in 59% of patients, hemoglobin decreased from pretreatment values by at least 2 grams percent in 60%, and platelet count decreased from pretreatment values by at least 50% in 55%. Myelosuppression may be severe, cumulative, and may affect multiple cell lines. Bone marrow fibrosis occurred in one CLL patient treated with Fludara FOR INJECTION.

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

Life-threatening and sometimes fatal autoimmune phenomena such as hemolytic anemia, autoimmune thrombocytopenia/thrombocytopenic purpura (ITP), Evans syndrome, and acquired hemophilia have been reported to occur in patients receiving Fludara FOR INJECTION (see WARNINGS section). The majority of patients rechallenged with Fludara FOR INJECTION developed a recurrence in the hemolytic process.

In post-marketing experience, cases of myelodysplastic syndrome and acute myeloid leukemia, mainly associated with prior, concomitant or subsequent treatment with alkylating agents, topoisomerase inhibitors, or irradiation have been reported.

Infections

Serious and sometimes fatal infections, including opportunistic infections and reactivations of latent viral infections such as VZV (herpes zoster), Epstein-Barr virus and JC virus (progressive multifocal leukoencephalopathy) have been reported in patients treated with Fludara FOR INJECTION.

Rare cases of Epstein-Barr virus (EBV) associated lymphoproliferative disorders have been reported in patients treated with Fludara FOR INJECTION.

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

Of the 133 adult CLL patients in the two trials, there were 29 fatalities during study, approximately 50% of which were due to infection.

Metabolic

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

Nervous System

(see WARNINGS section)

Objective weakness, agitation, confusion, seizures, visual disturbances, optic neuritis, optic neuropathy, blindness and coma have occurred in CLL patients treated with Fludara FOR INJECTION at the recommended dose. Peripheral neuropathy has been observed in patients treated with Fludara FOR INJECTION and one case of wrist-drop was reported. There have been additional reports of cerebral hemorrhage though the frequency is not known.

Pulmonary System

Pneumonia, a frequent manifestation of infection in CLL patients, occurred in 16% and 22% of those treated with Fludara FOR INJECTION in the MDAH and SWOG studies, respectively. Pulmonary hypersensitivity reactions to Fludara FOR INJECTION characterized by dyspnea, cough and interstitial pulmonary infiltrate have been observed.

In post-marketing experience, cases of severe pulmonary toxicity have been observed with Fludara FOR INJECTION use which resulted in ARDS, respiratory distress, pulmonary hemorrhage, pulmonary fibrosis, pneumonitis and respiratory failure. After an infectious origin has been excluded, some patients experienced symptom improvement with corticosteroids.

Gastrointestinal System

Gastrointestinal disturbances such as nausea and vomiting, anorexia, diarrhea, stomatitis and gastrointestinal bleeding and hemorrhage have been reported in patients treated with Fludara FOR INJECTION. Elevations of pancreatic enzyme levels have also been reported.

Cardiovascular

Edema has been frequently reported. One patient developed a pericardial effusion possibly related to treatment with Fludara FOR INJECTION. There have been additional reports of heart failure and arrhythmia though the frequency is rare. No other severe cardiovascular events were considered to be drug related.

Genitourinary System

Rare cases of hemorrhagic cystitis have been reported in patients treated with Fludara FOR INJECTION.

Skin

Skin toxicity, consisting primarily of skin rashes, has been reported in patients treated with Fludara FOR INJECTION. Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis and pemphigus have been reported, with fatal outcomes in some cases.

Neoplasms

Worsening or flare-up of pre-existing skin cancer lesions, as well as new onset of skin cancer, has been reported in patients during or after treatment with Fludara FOR INJECTION.

Hepatobiliary Disorders

Elevations of hepatic enzyme levels have been reported.

Data in the following table are derived from the 133 patients with CLL who received Fludara FOR INJECTION in the MDAH and SWOG studies.

PERCENT OF CLL PATIENTS REPORTING NONHEMATOLOGIC ADVERSE EVENTS
ADVERSE EVENTS	MDAH (N=101)	SWOG (N=32)
ANY ADVERSE EVENT	88%	91%
BODY AS A WHOLE	72	84
FEVER	60	69
CHILLS	11	19
FATIGUE	10	38
INFECTION	33	44
PAIN	20	22
MALAISE	8	6
DIAPHORESIS	1	13
ALOPECIA	0	3
ANAPHYLAXIS	1	0
HEMORRHAGE	1	0
HYPERGLYCEMIA	1	6
DEHYDRATION	1	0
NEUROLOGICAL	21	69
WEAKNESS	9	65
PARESTHESIA	4	12
HEADACHE	3	0
VISUAL DISTURBANCE	3	15
HEARING LOSS	2	6
SLEEP DISORDER	1	3
DEPRESSION	1	0
CEREBELLAR SYNDROME	1	0
IMPAIRED MENTATION	1	0
PULMONARY	35	69
COUGH	10	44
PNEUMONIA	16	22
DYSPNEA	9	22
SINUSITIS	5	0
PHARYNGITIS	0	9
UPPER RESPIRATORY INFECTION	2	16
ALLERGIC PNEUMONITIS	0	6
EPISTAXIS	1	0
HEMOPTYSIS	1	6
BRONCHITIS	1	0
HYPOXIA	1	0
GASTROINTESTINAL	46	63
NAUSEA/VOMITING	36	31
DIARRHEA	15	13
ANOREXIA	7	34
STOMATITIS	9	0
GI BLEEDING	3	13
ESOPHAGITIS	3	0
MUCOSITIS	2	0
LIVER FAILURE	1	0
ABNORMAL LIVER FUNCTION TEST	1	3
CHOLELITHIASIS	0	3
CONSTIPATION	1	3
DYSPHAGIA	1	0
CUTANEOUS	17	18
RASH	15	15
PRURITUS	1	3
SEBORRHEA	1	0
GENITOURINARY	12	22
DYSURIA	4	3
URINARY INFECTION	2	15
HEMATURIA	2	3
RENAL FAILURE	1	0
ABNORMAL RENAL FUNCTION TEST	1	0
PROTEINURIA	1	0
HESITANCY	0	3
CARDIOVASCULAR	12	38
EDEMA	8	19
ANGINA	0	6
CONGESTIVE HEART FAILURE	0	3
ARRHYTHMIA	0	3
SUPRAVENTRICULAR TACHYCARDIA	0	3
MYOCARDIAL INFARCTION	0	3
DEEP VENOUS THROMBOSIS	1	3
PHLEBITIS	1	3
TRANSIENT ISCHEMIC ATTACK	1	0
ANEURYSM	1	0
CEREBROVASCULAR ACCIDENT	0	3
MUSCULOSKELETAL	7	16
MYALGIA	4	16
OSTEOPOROSIS	2	0
ARTHRALGIA	1	0
TUMOR LYSIS SYNDROME	1	0

More than 3000 adult patients received Fludara FOR INJECTION in studies of other leukemias, lymphomas, and other solid tumors. The spectrum of adverse effects reported in these studies was consistent with the data presented above.

Overdosage

High doses of Fludara FOR INJECTION (see WARNINGS section) have been associated with an irreversible central nervous system toxicity characterized by delayed blindness, coma and death. High doses are also associated with severe thrombocytopenia and neutropenia due to bone marrow suppression. There is no known specific antidote for Fludara FOR INJECTION overdosage. Treatment consists of drug discontinuation and supportive therapy.

Fludara Dosage and Administration

Usual Dose

The recommended adult dose of Fludara FOR INJECTION is 25 mg/m2 administered intravenously over a period of approximately 30 minutes daily for five consecutive days. Each 5 day course of treatment should commence every 28 days. Dosage may be decreased or delayed based on evidence of hematologic or nonhematologic toxicity. Physicians should consider delaying or discontinuing the drug if neurotoxicity occurs.

A number of clinical settings may predispose to increased toxicity from Fludara FOR INJECTION. These include advanced age, renal impairment, and bone marrow impairment. Such patients should be monitored closely for excessive toxicity and the dose modified accordingly.

The optimal duration of treatment has not been clearly established. It is recommended that three additional cycles of Fludara FOR INJECTION be administered following the achievement of a maximal response and then the drug should be discontinued.

Renal Impairment

Adjustments to the starting dose are recommended to provide appropriate drug exposure in patients with creatinine clearance 30-79 mL/min, as estimated by the Cockroft-Gault equations. These adjustments are based on a pharmacokinetic study in patients with renal impairment. Fludara FOR INJECTION should not be administered to patients with creatinine clearance less than 30 mL/min.

Starting Dose Adjustment for Renal Impairment

Creatinine Clearance	Starting Dose
≥ 80 mL/min	25 mg/m2(full dose)
50 - 79 mL/min	20 mg/m2
30 - 49 mL/min	15 mg/m2
< 30 mL/min	do not administer

Renally impaired patients should be monitored closely for excessive toxicity and the dose modified accordingly.

Preparation of Solutions

Fludara FOR INJECTION should be prepared for parenteral use by aseptically adding Sterile Water for Injection, USP. When reconstituted with 2 mL of Sterile Water for Injection, USP, the solid cake should fully dissolve in 15 seconds or less; each mL of the resulting solution will contain 25 mg of Fludarabine phosphate, 25 mg of mannitol, and sodium hydroxide to adjust the pH to 7.7. The pH range for the final product is 7.2-8.2. In clinical studies, the product has been d