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Thursday, October 6, 2016

Amoxil

Generic Name: penicillin (Oral route, Injection route, Intravenous route, Intramuscular route)

Commonly used brand name(s)

In the U.S.

Amoxil

Bactocill

Bicillin L-A

Cloxapen

Crysticillin

Dynapen

Geocillin

Nafcil

Pfizerpen

Pipracil

Principen

Staphcillin

Ticar

Veetids

In Canada

Amoxil Pediatric

Ampicillin Sodium

Apo-Amoxi

Apo-Amoxi Sugar-Free

Apo-Cloxi

Apo-Pen-Vk

Gen-Amoxicillin

Med Amoxicillin

Nadopen V 200

Nadopen V 400

Novamoxin

Available Dosage Forms:

Powder for Suspension

Tablet

Tablet, Chewable

Tablet for Suspension

Tablet, Extended Release

Capsule

Powder for Solution

Suspension

Solution

Syrup

Uses For Amoxil

Penicillins are used to treat infections caused by bacteria. They work by killing the bacteria or preventing their growth.

There are several different kinds of penicillins. Each is used to treat different kinds of infections. One kind of penicillin usually may not be used in place of another. In addition, penicillins are used to treat bacterial infections in many different parts of the body. They are sometimes given with other antibacterial medicines (antibiotics). Some of the penicillins may also be used for other problems as determined by your doctor. However, none of the penicillins will work for colds, flu, or other virus infections.

Penicillins are available only with your doctor's prescription.

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although these uses are not included in product labeling, penicillins are used in certain patients with the following medical conditions:

Chlamydia infections in pregnant women—Amoxicillin and ampicillin

Gas gangrene—Penicillin G

Helicobacter pylori-associated gastritis or peptic ulcer disease—Amoxicillin

Leptospirosis—Ampicillin and penicillin G

Lyme disease—Amoxicillin and penicillin V

Typhoid fever—Amoxicillin and ampicillin

Before Using Amoxil

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to medicines in this group 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

Many penicillins have been used in children and, in effective doses, are not expected to cause different side effects or problems in children than they do in adults.

Some strengths of the chewable tablets of amoxicillin contain aspartame, which is changed by the body to phenylalanine, a substance that is harmful to patients with phenylketonuria.

Geriatric

Penicillins have been used in the elderly and have not been shown to cause different side effects or problems in older people than they do in younger adults.

Pregnancy

Penicillins have not been studied in pregnant women. However, penicillins have been widely used in pregnant women and have not been shown to cause birth defects or other problems in animal studies.

Breast Feeding

Penicillins pass into the breast milk. Even though only small amounts may pass into breast milk, allergic reactions, diarrhea, fungus infections, and skin rash may occur in nursing babies.

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 any of these medicines, 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 medicines in this class 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.

Cyclosporine

Methotrexate

Vecuronium

Venlafaxine

Interactions with Food/Tobacco/Alcohol

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

Proper Use of penicillin

This section provides information on the proper use of a number of products that contain penicillin. It may not be specific to Amoxil. Please read with care.

Penicillins (except bacampicillin tablets, amoxicillin, penicillin V, pivampicillin, and pivmecillinam) are best taken with a full glass (8 ounces) of water on an empty stomach (either 1 hour before or 2 hours after meals) unless otherwise directed by your doctor.

For patients taking amoxicillin, penicillin V, pivampicillin, and pivmecillinam:

Amoxicillin, penicillin V, pivampicillin, and pivmecillinam may be taken on a full or empty stomach.

The liquid form of amoxicillin may also be taken by itself or mixed with formulas, milk, fruit juice, water, ginger ale, or other cold drinks. If mixed with other liquids, take immediately after mixing. Be sure to drink all the liquid to get the full dose of medicine.

For patients taking bacampicillin:

The liquid form of this medicine is best taken with a full glass (8 ounces) of water on an empty stomach (either 1 hour before or 2 hours after meals) unless otherwise directed by your doctor.

The tablet form of this medicine may be taken on a full or empty stomach.

For patients taking penicillin G by mouth:

Do not drink acidic fruit juices (for example, orange or grapefruit juice) or other acidic beverages within 1 hour of taking penicillin G since this may keep the medicine from working properly.

For patients taking the oral liquid form of penicillins:

This medicine is to be taken by mouth even if it comes in a dropper bottle. If this medicine does not come in a dropper bottle, use a specially marked measuring spoon or other device to measure each dose accurately. The average household teaspoon may not hold the right amount of liquid.

Do not use after the expiration date on the label. The medicine may not work properly after that date. If you have any questions about this, check with your pharmacist.

For patients taking the chewable tablet form of amoxicillin:

Tablets should be chewed or crushed before they are swallowed.

To help clear up your infection completely, keep taking this medicine for the full time of treatment, even if you begin to feel better after a few days. If you have a ”strep” infection, you should keep taking this medicine for at least 10 days. This is especially important in ”strep” infections. Serious heart problems could develop later if your infection is not cleared up completely. Also, if you stop taking this medicine too soon, your symptoms may return.

This medicine works best when there is a constant amount in the blood or urine. To help keep the amount constant, do not miss any doses. Also, it is best to take the doses at evenly spaced times, day and night . For example, if you are to take four doses a day, the doses should be spaced about 6 hours apart. If this interferes with your sleep or other daily activities, or if you need help in planning the best times to take your medicine, check with your health care professional.

Make certain your health care professional knows if you are on a low-sodium (low-salt) diet. Some of these medicines contain enough sodium to cause problems in some people.

Dosing

The dose medicines in this class 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 these medicines. 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.

The number of tablets or teaspoonfuls of suspension 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 taking a penicillin.

For amoxicillin:
- For bacterial infections:
  - For oral dosage forms (capsules, oral suspension, tablets, and chewable tablets):
    - Adults, teenagers, and children weighing more than 40 kilograms (kg) (88 pounds)—250 to 500 milligrams (mg) every eight hours or 500 to 875 mg every twelve hours, depending on the type and severity of the infection.
    - Neonates and infants up to 3 months of age—Dose is based on body weight and must be determined by your doctor. The usual dose is 15 mg per kg (6.8 mg per pound) of body weight or less every twelve hours.
    - Infants 3 months of age and older and children weighing up to 40 kg (88 lbs.)—Dose is based on body weight and must be determined by your doctor. The usual dose is 6.7 to 13.3 mg per kg (3 to 6 mg per pound) of body weight every eight hours or 12.5 to 22.5 mg per kg (5.7 to 10.2 mg per pound) of body weight every twelve hours.
      - For duodenal ulcers (associated with Helicobacter pylori bacterial infection):
        For oral dosage forms (capsules, oral suspension, tablets, and chewable tablets):
        Adults: 1000 mg twice a day every twelve hours for fourteen days, along with the two other medicines, clarithromycin and lansoprazole, as directed by your doctor.
        
        Teenagers and children: Use and dose must be determined by your doctor.
        For dual medicine therapy—
        Adults: 1000 mg three times a day every eight hours for fourteen days, along with the other medicine, lansoprazole, as directed by your doctor.
        
        Teenagers and children: Use and dose must be determined by your doctor.

For ampicillin:
- For bacterial infections:
  - For oral dosage forms (capsules and oral suspension):
    - Adults, teenagers, and children weighing more than 20 kilograms (kg) (44 pounds)—250 to 500 milligrams (mg) every six hours.
    - Infants and children weighing up to 20 kg (44 pounds)—Dose is based on body weight and must be determined by your doctor. The usual dose is 12.5 to 25 mg per kg (5.7 to 11.4 mg per pound) of body weight every six hours; or 16.7 to 33.3 mg per kg (7.6 to 15 mg per pound) of body weight every eight hours.
      - For injection dosage form:
        Adults, teenagers, and children weighing more than 20 kg (44 pounds)—250 to 500 mg, injected into a vein or muscle every three to six hours.
        
        Infants and children weighing up to 20 kg (44 pounds)—Dose is based on body weight and must be determined by your doctor. The usual dose is 12.5 mg per kg (5.7 mg per pound) of body weight, injected into a vein or muscle every six hours.

For bacampicillin:
- For bacterial infections:
  - For oral dosage forms (oral suspension and tablets):
    - Adults, teenagers, and children weighing more than 25 kilograms (kg) (55 pounds)—400 to 800 milligrams (mg) every twelve hours.
    - Children weighing up to 25 kg (55 pounds)—Bacampicillin tablets are not recommended for use in children weighing up to 25 kg (55 pounds). The dose of the oral suspension is based on body weight and must be determined by your doctor. The usual dose is 12.5 to 25 mg per kg (5.7 to 11.4 mg per pound) of body weight every twelve hours.

For carbenicillin:
- For bacterial infections:
  - For oral dosage form (tablets):
    - Adults and teenagers—500 milligrams (mg) to 1 gram every six hours.
    - Children—Dose must be determined by your doctor.
      - For injection dosage form:
        Adults and teenagers—Dose is based on body weight and must be determined by your doctor. The usual dose is 50 to 83.3 mg per kilogram (kg) (22.8 to 37.9 mg per pound) of body weight, injected into a vein or muscle every four hours.
        
        Older infants and children—Dose is based on body weight and must be determined by your doctor. The usual dose is 16.7 to 75 mg per kg (7.6 to 34 mg per pound) of body weight, injected into a vein or muscle every four to six hours.

For cloxacillin:
- For bacterial infections:
  - For oral dosage form (capsules and oral solution):
    - Adults, teenagers, and children weighing more than 20 kilograms (kg) (44 pounds)—250 to 500 milligrams (mg) every six hours.
    - Infants and children weighing up to 20 kg (44 pounds)—Dose is based on body weight and must be determined by your doctor. The usual dose is 6.25 to 12.5 mg per kg (2.8 to 5.7 mg per pound) of body weight every six hours.
      - For injection dosage form:
        Adults, teenagers, and children weighing more than 20 kg—250 to 500 mg, injected into a vein every six hours.
        
        Infants and children weighing up to 20 kg (44 pounds)—Dose is based on body weight and must be determined by your doctor. The usual dose is 6.25 to 12.5 mg per kg (2.8 to 5.7 mg per pound) of body weight, injected into a vein every six hours.

For dicloxacillin:
- For bacterial infections:
  - For oral dosage form (capsules and oral suspension):
    - Adults, teenagers, and children weighing more than 40 kilograms (kg) (88 pounds)—125 to 250 milligrams (mg) every six hours.
    - Infants and children weighing up to 40 kg (88 pounds)—Dose is based on body weight and must be determined by your doctor. The usual dose is 3.1 to 6.2 mg per kg (1.4 to 2.8 mg per pound) of body weight every six hours.

For flucloxacillin:
- For bacterial infections:
  - For oral dosage form (capsules and oral suspension):
    - Adults, teenagers, and children more than 12 years of age and weighing more than 40 kilograms (kg) (88 pounds)—250 to 500 milligrams (mg) every six hours.
    - Children less than 12 years of age and weighing up to 40 kg (88 pounds)—125 to 250 mg every six hours; or 6.25 to 12.5 mg per kg (2.8 to 5.7 mg per pound) of body weight every six hours.
    - Infants up to 6 months of age—Dose is based on body weight and must be determined by your doctor. The usual dose is 6.25 mg per kg (2.8 mg per pound) of body weight every six hours.

For methicillin:
- For bacterial infections:
  - For injection dosage form:
    - Adults, teenagers, and children weighing more than 40 kilograms (kg) (88 pounds)—1 gram injected into a muscle every four to six hours; or 1 gram injected into a vein every six hours.
    - Children weighing up to 40 kg (88 pounds)—Dose is based on body weight and must be determined by your doctor. The usual dose is 25 milligrams (mg) per kg (11.4 mg per pound) of body weight, injected into a vein or muscle every six hours.

For mezlocillin:
- For bacterial infections:
  - For injection dosage form:
    - Adults and teenagers—Dose is based on body weight and must be determined by your doctor. The usual dose is 33.3 to 87.5 milligrams (mg) per kilogram (kg) (15.1 to 39.8 mg per pound) of body weight, injected into a vein or muscle every four to six hours; or 3 to 4 grams every four to six hours.
    - Infants over 1 month of age and children up to 12 years of age—Dose is based on body weight and must be determined by your doctor. The usual dose is 50 mg per kg (22.7 mg per pound) of body weight, injected into a vein or muscle every four hours.

For nafcillin:
- For bacterial infections:
  - For oral dosage form (capsules and tablets):
    - Adults and teenagers—250 milligrams (mg) to 1 gram every four to six hours.
    - Older infants and children—Dose is based on body weight and must be determined by your doctor. The usual dose is 6.25 to 12.5 mg per kilogram (kg) (2.8 to 5.7 mg per pound) of body weight every six hours.
    - Newborns—Dose is based on body weight and must be determined by your doctor. The usual dose is 10 mg per kg (4.5 mg per pound) of body weight every six to eight hours.
      - For injection dosage form:
        Adults and teenagers—500 mg to 2 grams injected into a vein or muscle every four to six hours.
        
        Infants and children—Dose is based on body weight and must be determined by your doctor. The usual dose is 10 to 25 mg per kg (4.5 to 11.4 mg per pound) of body weight, injected into a muscle every twelve hours; or 10 to 40 mg per kg (4.5 to 18.2 mg per pound) of body weight, injected into a vein every four to eight hours.

For oxacillin:
- For bacterial infections:
  - For oral dosage form (capsules and oral solution):
    - Adults, teenagers, and children weighing more than 40 kilograms (kg) (88 pounds)—500 milligrams (mg) to 1 gram every four to six hours.
    - Children weighing up to 40 kg (88 pounds)—Dose is based on body weight and must be determined by your doctor. The usual dose is 12.5 to 25 mg per kg (5.7 to 11.4 mg per pound) of body weight every six hours.
      - For injection dosage form:
        Adults, teenagers, and children weighing more than 40 kg (88 pounds)—250 mg to 1 gram injected into a vein or muscle every four to six hours.
        
        Children weighing up to 40 kg (88 pounds)—Dose is based on body weight and must be determined by your doctor. The usual dose is 12.5 to 25 mg per kg (5.7 to 11.4 mg per pound) of body weight, injected into a vein or muscle every four to six hours.
        
        Premature infants and newborns—Dose is based on body weight and must be determined by your doctor. The usual dose is 6.25 mg per kg (2.8 mg per pound) of body weight, injected into a vein or muscle every six hours.

For penicillin G:
- For bacterial infections:
  - For oral dosage form (oral solution, oral suspension, and tablets):
    - Adults and teenagers—200,000 to 500,000 Units (125 to 312 milligrams [mg]) every four to six hours.
    - Infants and children less than 12 years of age—Dose is based on body weight and must be determined by your doctor. The usual dose is 4167 to 30,000 Units per kilogram (kg) (189 to 13,636 Units per pound) of body weight every four to eight hours.
      - For benzathine injection dosage form:
        Adults and teenagers—1,200,000 to 2,400,000 Units injected into a muscle as a single dose.
        
        Infants and children—300,000 to 1,200,000 Units injected into a muscle as a single dose; or 50,000 Units per kg (22,727 Units per pound) of body weight injected into a muscle as a single dose.
        For injection dosage forms (potassium and sodium salts):
        Adults and teenagers—1,000,000 to 5,000,000 Units, injected into a vein or muscle every four to six hours.
        
        Older infants and children—Dose is based on body weight and must be determined by your doctor. The usual dose is 8333 to 25,000 Units per kg (3788 to 11,363 Units per pound) of body weight, injected into a vein or muscle every four to six hours.
        
        Premature infants and newborns—Dose is based on body weight and must be determined by your doctor. The usual dose is 30,000 Units per kg (13,636 Units per pound) of body weight, injected into a vein or muscle every twelve hours.
        For procaine injection dosage form:
        Adults and teenagers—600,000 to 1,200,000 Units injected into a muscle once a day.
        
        Children—Dose is based on body weight and must be determined by your doctor. The usual dose is 50,000 Units per kg (22,727 Units per pound) of body weight, injected into a muscle once a day.

For penicillin V:
- For bacterial infections:
  - For the benzathine salt oral dosage form (oral solution):
    - Adults and teenagers—200,000 to 500,000 Units every six to eight hours.
    - Children—100,000 to 250,000 Units every six to eight hours.
      - For the potassium salt oral dosage forms (oral solution, oral suspension, and tablets):
        Adults and teenagers—125 to 500 milligrams (mg) every six to eight hours.
        
        Children—Dose is based on body weight and must be determined by your doctor. The usual dose is 2.5 to 16.7 mg per kilogram (kg) (1.1 to 7.6 mg per pound) of body weight every four to eight hours.

For piperacillin:
- For bacterial infections:
  - For injection dosage form:
    - Adults and teenagers—3 to 4 grams, injected into a vein or muscle every four to six hours.
    - Infants and children—Dose must be determined by your doctor.

For pivampicillin:
- For bacterial infections:
  - For oral dosage form (oral suspension):
    - Adults, teenagers, and children 10 years of age and older—525 to 1050 milligrams (mg) two times a day.
    - Children 7 to 10 years of age—350 mg two times a day.
    - Children 4 to 6 years of age—262.5 mg two times a day.
    - Children 1 to 3 years of age—175 mg two times a day.
    - Infants 3 to 12 months of age—Dose is based on body weight and must be determined by your doctor. The usual dose is 20 to 30 mg per kilogram (kg) (9.1 to 13.6 mg per pound) of body weight two times a day.
      - For oral dosage form (tablets):
        Adults, teenagers, and children 10 years of age and older—500 mg to 1 gram two times a day.
        
        Children up to 10 years of age—Dose must be determined by your doctor.

For pivmecillinam:
- For bacterial infections:
  - For oral dosage form (tablets):
    - Adults, teenagers, and children weighing more than 40 kilograms (kg) (88 pounds)—200 milligrams (mg) two to four times a day for three days.
    - Children up to 40 kg (88 pounds)—Dose must be determined by your doctor.

For ticarcillin:
- For bacterial infections:
  - For injection dosage form:
    - Adults, teenagers, and children weighing more than 40 kilograms (kg) (88 pounds)—3 grams injected into a vein every four hours; or 4 grams injected into a vein every six hours.
    - Children up to 40 kg (88 pounds)—Dose is based on body weight and must be determined by your doctor. The usual dose is 33.3 to 75 milligrams (mg) per kg (15 to 34 mg per pound) of body weight, injected into a vein every four to six hours.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

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.

Precautions While Using Amoxil

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

Penicillins may cause diarrhea in some patients.

Check with your doctor if severe diarrhea occurs. Severe diarrhea may be a sign of a serious side effect. Do not take any diarrhea medicine without first checking with your doctor. Diarrhea medicines may make your diarrhea worse or make it last longer.

For mild diarrhea, diarrhea medicine containing kaolin or attapulgite (e.g., Kaopectate tablets, Diasorb) may be taken. However, other kinds of diarrhea medicine should not be taken. They may make your diarrhea worse or make it last longer.

If you have any questions about this or if mild diarrhea continues or gets worse, check with your health care professional.

Oral contraceptives (birth control pills) containing estrogen may not work properly if you take them while you are taking ampicillin, amoxicillin, or penicillin V. Unplanned pregnancies may occur. You should use a different or additional means of birth control while you are taking any of these penicillins. If you have any questions about this, check with your health care professional.

For diabetic patients:

Penicillins may cause false test results with some urine sugar tests. Check with your doctor before changing your diet or the dosage of your diabetes medicine.

Before you have any medical tests, tell the doctor in charge that you are taking this medicine. The results of some tests may be affected by this medicine.

Amoxil 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.

Stop taking this medicine and get emergency help immediately if any of the following effects occur:

Less common

Fast or irregular breathing

fever

joint pain

lightheadedness or fainting (sudden)

puffiness or swelling around the face

red, scaly skin

shortness of breath

skin rash, hives, itching

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

Rare

Abdominal or stomach cramps and pain (severe)

abdominal tenderness

convulsions (seizures)

decreased amount of urine

diarrhea (watery and severe), which may also be bloody

mental depression

nausea and vomiting

pain at place of injection

sore throat and fever

unusual bleeding or bruising

yellow eyes or skin

Rare - For penicillin G procaine only

Agitation or combativeness

anxiety

confusion

fear of impending death

feeling, hearing, or seeing things that are not real

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

Diarrhea (mild)

headache

sore mouth or tongue

vaginal itching and discharge

white patches in the mouth and/or on the tongue

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: Amoxil side effects (in more detail)

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More Amoxil resources

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

Amoxil MedFacts Consumer Leaflet (Wolters Kluwer)

Amoxil Consumer Overview

Amoxil Prescribing Information (FDA)

Amoxicillin Professional Patient Advice (Wolters Kluwer)

Amoxicillin Prescribing Information (FDA)

Amoxicillin Monograph (AHFS DI)

Amoxicillin and Clavulanate Potassium Monograph (AHFS DI)

Biomox Prescribing Information (FDA)

DisperMox Prescribing Information (FDA)

DisperMox MedFacts Consumer Leaflet (Wolters Kluwer)

Moxatag Extended-Release Tablets MedFacts Consumer Leaflet (Wolters Kluwer)

Moxatag Consumer Overview

Moxatag Prescribing Information (FDA)

Trimox Consumer Overview

Trimox MedFacts Consumer Leaflet (Wolters Kluwer)

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Actos

Generic Name: Pioglitazone Hydrochloride
Class: Thiazolidinediones
ATC Class: A10BG03
VA Class: HS502
Chemical Name: (±)-5-[p-[2-(5-Ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione monohydrochloride
Molecular Formula: C₁₉H₂₀N₂O₃S•ClH
CAS Number: 112529-15-4

Special Alerts:

[Posted 09/17/2010] ISSUE: FDA notified healthcare professionals and patients that the Agency is reviewing data from an ongoing, ten-year epidemiological study designed to evaluate whether pioglitazone (Actos) is associated with an increased risk of bladder cancer. Findings from studies in animals and humans suggest this is a potential safety risk that needs further study. At this time, FDA has not concluded that pioglitazone increases the risk of bladder cancer. Its review is ongoing, and the Agency will update the public when it has additional information.

BACKGROUND: The drug manufacturer, Takeda, conducted a planned analysis of the study data at the five-year mark, and submitted their results to FDA. Overall, there was no statistically significant association between pioglitazone exposure and bladder cancer risk. However, further analyses were also performed looking at how long patients were on pioglitazone and the total amount of the drug they received during that time. An increased risk of bladder cancer was observed among patients with the longest exposure to pioglitazone, as well as in those exposed to the highest cumulative dose of pioglitazone.

RECOMMENDATIONS: Healthcare professionals should continue to follow the recommendations in the drug label when prescribing pioglitazone. Patients should continue taking pioglitazone unless told otherwise by their healthcare professional. Patients who are concerned about the possible risks associated with using pioglitazone should talk to their healthcare professional.

Additional Information for Patients, Information for Healthcare Professionals, and a Data Summary are provided in the Drug Safety Communication. For more information visit the FDA website at: and .

[Posted 08/14/2007] After a review of postmarketing adverse event reports, FDA determined that an updated label with a boxed warning on the risks of heart failure was needed for the entire thiazolidinedione class of antidiabetic drugs. These drugs are used in conjunction with diet and exercise to improve blood sugar control in adults with type 2 (non-insulin-dependent) diabetes. Manufacturers of certain drugs have agreed to the upgraded warning.

The strengthened warning advises healthcare professionals to observe patients carefully for the signs and symptoms of heart failure, including excessive, rapid weight gain, shortness of breath, and edema after starting drug therapy. Patients with these symptoms who then develop heart failure should receive appropriate management of the heart failure and use of the drug should be reconsidered. People who have questions should contact their healthcare providers to discuss alternative treatments. For more information visit the FDA website at: , , and .

[Posted 03/09/2007] Takeda and FDA notified healthcare professionals of recent safety data concerning pioglitazone-containing products. The results of an analysis of the manufacturer’s clinical trial database of pioglitazone showed more reports of fractures in female patients taking pioglitazone than those taking a comparator (either placebo or active). The majority of fractures observed in female patients were in the distal upper limb (forearm, hand and wrist) or distal lower limb (foot, ankle, fibula and tibia). There were more than 8100 patients in the pioglitazone-treated groups and over 7400 patients in the comparator-treated groups. The duration of pioglitazone treatment was up to 3.5 years. Healthcare professionals should consider the risk of fracture when initiating or treating female patients with type 2 diabetes mellitus with pioglitazone-containing products. For more information visit the FDA website at: and .

REMS:

FDA approved a REMS for pioglitazone to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of pioglitazone and consists of the following: medication guide. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Antidiabetic agent; thiazolidinedione (glitazone).¹ ⁸ ⁹ ¹²

Uses for Actos

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Diabetes Mellitus

Used alone or in combination with a sulfonylurea, metformin, or insulin as an adjunct to diet and exercise for the management of type 2 (noninsulin-dependent) diabetes mellitus (NIDDM).¹ ² Should be added to, not substituted for, other antidiabetic agents in patients whose NIDDM is not adequately controlled by these agents.¹³

May be added to glyburide/metformin fixed combination therapy if hyperglycemia is not adequately controlled with the fixed combination.¹⁴ May be used in combination with repaglinide if hyperglycemia is not adequately controlled with diet, exercise, and monotherapy with another oral antidiabetic agent.¹⁷

Not effective as sole therapy for type 1 diabetes mellitus or diabetic ketoacidosis; insulin is necessary.¹

Actos Dosage and Administration

Administration

Oral Administration

Administer orally once daily without regard to meals.¹

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as pioglitazone hydrochloride; dosage expressed in terms of pioglitazone.¹

Adults

Diabetes Mellitus

Monotherapy

Oral

Initially, 15 or 30 mg once daily.¹ If response is inadequate, increase dosage in increments, up to a maximum dosage of 45 mg daily.¹ If response is inadequate with monotherapy, consider combination therapy.¹

Combination with Other Antidiabetic Agents

Oral

May continue current dosage of the sulfonylurea, metformin, or insulin upon initiation of pioglitazone.¹

Combination therapy with a sulfonylurea: Initially, 15 or 30 mg once daily.¹ If hypoglycemia occurs, reduce sulfonylurea dosage.¹

Combination therapy with metformin: Initially, 15 or 30 mg once daily.¹ Adjustment of metformin dosage unlikely.¹

Combination therapy with insulin: Initially, 15 or 30 mg once daily.¹ If hypoglycemia occurs or if fasting plasma glucose (FPG) concentrations decrease to <100 mg/dL, decrease insulin dosage by 10–25%.¹ Further adjustments should be individualized based on therapeutic response.¹

Prescribing Limits

Adults

Maximum 45 mg daily (as monotherapy or in combination with a sulfonylurea, metformin, or insulin).¹

Special Populations

Renal Impairment

No dosage adjustment necessary.¹

Geriatric Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

No dosage adjustment necessary.¹

CHF

Should be initiated at the lowest approved dosage in patients with type 2 diabetes and systolic CHF (NYHA class II).¹ If subsequent dosage escalation is necessary, increase dosage gradually only after several months of treatment.¹ Monitor carefully for weight gain, edema, or other manifestations of CHF exacerbation.¹ Use not recommended in patients with more severe CHF (NYHA class III or IV).¹

Cautions for Actos

Contraindications

Known hypersensitivity to pioglitazone or any ingredient in the formulation.¹

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Effects on Fluid Balance

Risk of fluid retention; may cause or exacerbate heart failure.¹ ¹³ Weight gain reported, possibly associated with fluid retention and fat accumulation.¹

Use with caution in patients with edema.¹ Observe for manifestations of heart failure (e.g., dyspnea, rapid weight gain, edema) and discontinue therapy if any deterioration in cardiac status occurs.¹ Use not recommended in patients with New York Heart Association (NYHA) class III or IV heart failure.¹

General Precautions

Ovulatory Effects

Possible ovulation in premenopausal anovulatory women; risk of pregnancy unless contraceptive measures initiated.¹

Hematologic Effects

Possible dose-related decreases in hemoglobin and hematocrit; usually evident within 4–12 weeks of therapy.¹ May be related to plasma volume expansion.¹ Rarely associated with clinically important hematologic manifestations.¹

Hepatic Effects

No evidence of hepatotoxicity in clinical studies to date.¹ ¹² ¹³ However, hepatitis, elevations in hepatic enzymes, mixed hepatocellular-cholestatic liver injury,¹⁵ and, very rarely, hepatic failure associated with fatalities reported during postmarketing experience.¹

Monitor liver function tests prior to initiation of therapy, then periodically thereafter according to clinician judgment.¹ ¹² Monitor more frequently if used in patients with mild hepatic impairment (ALT 1–2.5 times the upper limit of normal [ULN]).¹ (See Hepatic Impairment under Cautions.)

Recheck liver function if ALT increases to >3 times the ULN or if manifestations suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, dark urine) occur.¹ Discontinue therapy if ALT remains elevated at >3 times the ULN or if jaundice develops.¹

Specific Populations

Pregnancy

Category C.¹ Most clinicians recommend that insulin be used during pregnancy.¹

Lactation

Distributed into milk in rats; not known whether distributed into human milk.¹ Use not recommended.¹

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age; use not recommended.¹ ¹³

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults.¹

Hepatic Impairment

Use with caution in patients with mild hepatic impairment (ALT 1–2.5 times the ULN).¹ ¹² Use not recommended in patients with active hepatic disease, ALT >2.5 times the ULN, or troglitazone-associated jaundice.¹ ¹²

Common Adverse Effects

Upper respiratory tract infection, headache, sinusitis, myalgia, tooth disorder, aggravation of diabetes mellitus, pharyngitis, edema.¹

Interactions for Actos

Metabolized principally by CYP2C8 and, to a lesser extent, by CYP3A4 and other isoenzymes (e.g., CYP1A1).¹ Weak inducer of CYP3A4.¹

Specific Drugs

Drug	Interaction	Comments
Antidiabetic agents	Additive effects; possible hypoglycemia¹	May need to reduce dosage of other antidiabetic agents¹
Atorvastatin	Decreased plasma concentrations and AUC for atorvastatin and pioglitazone¹
Digoxin	Pharmacokinetic interaction unlikely¹
Fexofenadine	Pharmacokinetic interaction unlikely¹
Ketoconazole	Increased serum concentrations and AUC for pioglitazone¹³
Midazolam	Decreased midazolam concentrations¹
Nifedipine, extended-release	Decreased peak nifedipine concentrations and AUC¹	Clinical importance unknown¹
Oral contraceptives, hormonal (ethinyl estradiol and norethindrone)	Decreased ethinyl estradiol concentrations¹	Clinical importance unknown¹
Ranitidine	Pharmacokinetic interaction unlikely¹
Theophylline	Pharmacokinetic interaction unlikely¹
Warfarin	Pharmacokinetic or pharmacologic interaction (e.g., effect on PT) unlikely¹

Actos Pharmacokinetics

Absorption

Bioavailability

Peak serum concentrations attained within 2 hours.¹

Absolute bioavailability is 83%.^a

Food

Food delays time to peak serum concentration to 3–4 hours but does not affect extent of absorption.¹

Special Populations

In patients with hepatic impairment (Child-Pugh class B or C), peak pioglitazone concentration is decreased by 45%.¹

In geriatric patients, AUC of pioglitazone is increased; not clinically relevant.¹

In females, peak serum concentration and AUC are increased by 20–60%.¹

Distribution

Extent

Distributed into milk in rats.¹ Not known whether the drug distributes into human milk.¹

Plasma Protein Binding

>99% (mainly albumin).¹

Elimination

Metabolism

Extensively metabolized, principally by CYP2C8 and, to a lesser extent, by CYP3A4 and other isoenzymes (e.g., CYP1A1).¹

Elimination Route

Excreted in urine (15–30%) and in feces, primarily as metabolites.¹

Half-life

3–7 hours (for pioglitazone) or 16–24 hours (for pioglitazone and metabolites).¹

Special Populations

In geriatric patients, terminal half-life is prolonged; not clinically relevant.¹

Stability

Storage

Oral

Tablets

Tight containers at 25°C (may be exposed to 15–30°C).¹ Protect from moisture and humidity.¹

Actions

Structurally and pharmacologically related to rosiglitazone and troglitazone (no longer commercially available in the US);¹ ⁸ ⁹ ¹ ¹² unrelated to other antidiabetic agents (e.g., sulfonylureas, biguanides, α-glucosidase inhibitors).¹ ¹²

A peroxisome proliferator-activated receptor_γ (PPAR_γ) agonist; increases transcription of insulin-responsive genes.¹

Increases insulin sensitivity in target tissues and decreases hepatic gluconeogenesis.¹ Ameliorates insulin resistance associated with type 2 diabetes mellitus without increasing insulin secretion from pancreatic β cells.¹ Does not lower glucose concentrations below euglycemia.¹

Ineffective in absence of insulin.¹

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Importance of adhering to diet and exercise regimen.¹ Importance of regular monitoring (preferably self-monitoring) of blood glucose and HbA_1c.¹

Importance of immediately informing clinician if potential manifestations of heart failure (e.g., rapid weight gain, edema, shortness of breath) occur.¹

Importance of informing patients that liver function tests will be performed prior to initiation of therapy and periodically thereafter.¹ (See Hepatic Effects under Cautions.) Advise patients to inform clinician if potential manifestations of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, dark urine) occur.¹

Risk of hypoglycemia in patients receiving concomitant antidiabetic agent therapy.¹ Provide instructions regarding management of hypoglycemia, including recognition of symptoms, predisposing conditions, and treatment.¹

Risk of pregnancy in premenopausal anovulatory women.¹ Advise patients to utilize effective contraception during therapy.¹

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.¹

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

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

Preparations

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

Pioglitazone Hydrochloride
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	15 mg	Actos	Takeda
		30 mg	Actos	Takeda
		45 mg	Actos	Takeda

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Actoplus Met 15-500MG Tablets (TAKEDA PHARMACEUTICALS): 30/$135.99 or 90/$385.98

Actoplus Met 15-850MG Tablets (TAKEDA PHARMACEUTICALS): 30/$135.99 or 90/$385.98

Actoplus met XR 15-1000MG 24-hr Tablets (TAKEDA PHARMACEUTICALS): 30/$145.45 or 90/$415.57

Actoplus met XR 30-1000MG 24-hr Tablets (TAKEDA PHARMACEUTICALS): 30/$280.99 or 90/$800.00

Actos 15MG Tablets (TAKEDA PHARMACEUTICALS): 30/$179.98 or 90/$515.96

Actos 30MG Tablets (TAKEDA PHARMACEUTICALS): 30/$273.98 or 90/$799.99

Actos 45MG Tablets (TAKEDA PHARMACEUTICALS): 30/$289.99 or 90/$849.97

Duetact 30-2MG Tablets (TAKEDA PHARMACEUTICALS): 30/$274.29 or 90/$796.86

Duetact 30-4MG Tablets (TAKEDA PHARMACEUTICALS): 30/$255.58 or 90/$712.75

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 October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Takeda Pharmaceuticals America. Actos (pioglitazone hydrochloride) tablets prescribing information. Lincolnshire, IL; 2004 July.

2. Kawamori R, Matsuhisa M, Kinoshita J et al. Pioglitazone enhances splanchnic glucose uptake as well as peripheral glucose uptake in non-insulin-dependent diabetes mellitus. AD-4833 Clamp-OGL Study Group. Diabetes Res Clin Pract 1998 Jul;41(1):35-43.

3. Berger J, Bailey P, Biswas C et al. Thiazolidinediones produce a conformational change in peroxisomal proliferator-activated receptor-γ: binding and activation correlate with antidiabetic actions in db/db mice. Endocrinology. 1996; 137:4189-95. [PubMed 8828476]

4. Parke-Davis. Rezulin (troglitazone) tablets prescribing information. Morris Plains, NJ; 1998 Jul.

5. Parke-Davis. Rezulin (troglitazone) tablets prescribing information. Morris Plains, NJ; 1999 Jun.

6. Sigmund WR II. Dear health professional letter regarding important prescribing information for Rezulin. Morris Plains: Parke-Davis. (undated)

7. Anon. New labeling and use changes for Rezulin. FDA Talk Paper. Rackville, MD: Food and Drug Administration; 1999 Jun 16.

8. Young PW, Buckle DR, Cantello BC et al. Identification of high-affinity binding sites for the insulin sensitizer rosiglitazone (BRL-49653) in rodent and human adipocytes using a radioiodinated ligand for peroxisonal proliferator-activated receptor gamma. J Pharmacol Exp Ther. 1998; 284:751-9. [PubMed 9454824]

9. Arakawa K, Inamasu M, Matsumoto M et al. Novel benzoxazol 2,4-thiazolidinediones as potent hypoglycemic agents. Chem Pharm Bull. 1997; 45:1984-93. [PubMed 9433768]

10. Matsuhisa M, Shiz Q, Wan C et al. The effect of pioglitazone on hepatic glucose uptake measured with indirect and direct methods in alloxan-induced diabetic dogs. Diabetes. 1997; 46:224-31. [PubMed 9000698]

11. Tanis SP, Parker TT, Colca JR et al. Synthesis and biological activity of metabolites of the antidiabetic, antihyperglycemic agent pioglitazone. J Med Chem. 1996; 39:5053-63. [PubMed 8978836]

12. Anon. Rosiglitazone for type 2 diabetes mellitus. Med Lett Drugs Ther. 1999; 41:71-3. [PubMed 10603986]

13. Takeda Pharmaceuticals North America, Indianapolis, IN: Personal communication.

14. Bristol-Myers-Squibb Company. Glucovance(glyburide and metformin hydrochloride) tablets prescribing information. Princeton, NJ; 2001 Mar.

15. May LD, Lefkowitch JH, Kram MT et al. Mixed hepatocellular-cholestatic liver injury after pioglitazone therapy. Ann Intern Med. 2002; 136:449-52. [IDIS 480334] [PubMed 11900497]

16. American Diabetes Association. Type 2 diabetes in children and adolescents. Pediatrics. 2000; 105:671-80. [IDIS 443594] [PubMed 10699131]

17. Novo Nordisk. Prandin(repaglinide) tablets prescribing information. Princeton, NJ; 2002 Oct.

18. Kipnes MS, Krosnick A, Rendell MS et al. Pioglitazone hydrochloride in combination with sulfonylurea therapy improves glycemic control in patients with type 2 diabetes mellitus: a randomized, placebo-controlled study. Am J Med. 2001; 111:10-7. [IDIS 467740] [PubMed 11448655]

19. Nesto RW, Bell D, Bonow RO et al for the American Heart Association and American Diabetes Association. AHA/ADA consensus statement: thiazolidinedione use, fluid retention, and congestive heart failure. Circulation. 2003; 108:2941-48. [IDIS 511519] [PubMed 14662691]

20. Kidd RS, Straughn AB, Meyer MC et al. Pharmacokinetics of chlorpheniramine, phenytoin, glipizide and nifedipine in an individual homozygous for the CYP2C9*3 allele. Pharmacogenetics. 1999; 9:71-80. [IDIS 424517] [PubMed 10208645]

21. Bottorf M, Hansen P. Long-term safety of hepatic hydroxymethyl glutaryl coenzyme A reductase inhibitors: the role of metabolism. Arch Intern Med. 2000; 160:2273-80. [IDIS 453535] [PubMed 10927723]

22. Nowak SN, Edwards DJ, Clarke A et al. Pioglitazone: effect on CYP3A4 activity. J Clin Pharmacol. 2002; 42:1299-1302. [IDIS 492542] [PubMed 12463723]

23. Yeates RA< Scharpf F, Laufen H et al. Screening for cytochrome P450 3a in man: studies with midazolam and nifedipine. J Pharm Pharmacol. 1996; 48:933-4. [IDIS 376297] [PubMed 8910856]

24. Ma JD, Nafziger AN, Kashuba ADM et al. Limited sampling strategy of S-warfarin concentrations, but not warfarin S/R rations accurately predicts S-warfarin AUC during basline and inhibition in CYP2C9 extensive metabolizers. J Clin Pharmacol. 2004; 44:570-6. [IDIS 516320] [PubMed 15145963]

25. Martinez C, Albet C, Agundez JAG et al. Comparative in vitor and in vivo inhibition of cytochrome P450 CYP1A2, CYP2Dg, and CYP3A4 by H₂-receptor antagonists. Clin Pharmacol Ther. 1999; 65:369-76. [PubMed 10223772]

26. Bachmann K, White D, Jauregui L et al. An evaluation of the dose-dependent inhibition of CYP1A2 by rofecoxib using theophylline as a CYP1A2 probe. J Clin Pharmacol. 2003; 43:1082-90. [IDIS 505406] [PubMed 14517190]

a. Hanefeld M. Pharmcokinetics and clinical efficacy of pioglitazone. Int J Clin Pract Suppl. 2001; 121:19-25. [PubMed 11594240]

More Actos resources

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Actos Dosage
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Drug Images
Actos Drug Interactions
Actos Support Group
26 Reviews for Actos - Add your own review/rating

Actos Prescribing Information (FDA)

Actos Advanced Consumer (Micromedex) - Includes Dosage Information

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Diabetes, Type 2
Nonalcoholic Fatty Liver Disease

altretamine

Generic Name: altretamine (all TREH tah mean)

Brand Names: Hexalen

What is altretamine?

Altretamine is a cancer (antineoplastic) medication. Altretamine interferes with the growth of cancer cells and slows their growth and spread in the body.

Altretamine is used to treat cancer of the ovaries.

Altretamine may also be used for purposes other than those listed in this medication guide.

What is the most important information I should know about altretamine?

Altretamine should only be administered under the supervision of a qualified healthcare provider experienced in the use of cancer chemotherapeutic agents.

Serious side effects have been reported with the use of altretamine including: allergic reactions (difficulty breathing; closing of the throat; swelling of the lips, tongue, or face; or hives); decreased bone marrow function and blood problems (extreme fatigue; easy bruising or bleeding; black, bloody or tarry stools; fever or chills; or signs of infection such as fever; chills, or sore throat); neurologic problems (mood disorders, altered consciousness, weakness, dizziness, vertigo); and others. Talk to your doctor about the possible side effects from treatment with altretamine.

What should I discuss with my healthcare provider before taking altretamine?

Before taking altretamine, tell your doctor if you have:

any nervous system (brain and nerves) problems; or

bone marrow problems.

You may not be able to take altretamine, or you may require a dosage adjustment or special monitoring during treatment if you have any of the conditions listed above.

Altretamine is in the FDA pregnancy category D. This means that altretamine is known to cause birth defects in an unborn baby. Do not take altretamine without first talking to your doctor if you are pregnant or could become pregnant during treatment. Contraceptive measures are recommended during treatment with altretamine. It is not known whether altretamine passes into breast milk. Do not take altretamine without first talking to your doctor if you are breast feeding a baby.

How should I take altretamine?

Take altretamine exactly as directed by your doctor. If you do not understand these instructions, as your doctor, nurse or pharmacist to explain them to you.

Your doctor will determine the correct amount and frequency of treatment with altretamine depending upon the cancer being treated and other factors. Talk to your doctor if you have any questions or concerns regarding the treatment schedule.

Altretamine is usually taken four times a day, after meals and at bedtime.

Take each oral dose with a large glass of water.

Your doctor will probably want you to have regularly scheduled blood tests and other medical evaluations during treatment with altretamine to monitor progress and side effects.

Store altretamine capsules at room temperature away from heat and moisture. Keep this product out of the reach of children.

See also: Altretamine dosage (in more detail)

What happens if I miss a dose?

Contact your doctor if you miss a dose of altretamine.

What happens if I overdose?

If for any reason an overdose of altretamine is suspected, seek emergency medical attention or contact your healthcare provider immediately.

Symptoms of an altretamine overdose tend to be similar to side effects caused by the medication, although often more severe.

What should I avoid while taking altretamine?

Altretamine can lower the activity of your immune system making you susceptible to infections. Avoid contact with people who have colds, the flu, or other contagious illnesses and do not receive vaccines that contain live strains of a virus (e.g., live oral polio vaccine) during treatment with altretamine. In addition, avoid contact with individuals who have recently been vaccinated with a live vaccine. There is a chance that the virus can be passed on to you.

Altretamine side effects

If you experience any of the following serious side effects, seek emergency medical attention or contact your doctor immediately:

an allergic reaction (shortness of breath; closing of your throat; difficulty breathing; swelling of your lips, face, or tongue; or hives);

decreased bone marrow function and blood problems (extreme fatigue; easy bruising or bleeding; black, bloody or tarry stools; or fever, chills, or signs of infection);

pain, tremors, tingling, burning, or prickling in hands or feet;

mood changes;

severe drowsiness or loss of consciousness;

loss of coordination, weakness, dizziness, unsteadiness or falling; or

severe nausea or vomiting.

Other less serious side effects may be more likely to occur. Talk to your doctor if you experience:

temporary hair loss;

itching or rash; or

mild to moderate nausea or vomiting.

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome. You may report side effects to FDA at 1-800-FDA-1088.

Altretamine Dosing Information

Usual Adult Dose for Ovarian Cancer:

260 mg/m2/day administered either for 14 or 21 consecutive days in a 28 day cycle. The total daily dose should be given as 4 divided oral doses after meals and at bedtime.

Altretamine should be temporarily discontinued (for 14 days or longer) and subsequently restarted at 200 mg/m2/day for any of the following situations:

Gastrointestinal intolerance unresponsive to symptomatic measures;
White blood count Platelet count Progressive neurotoxicity.

If neurologic symptoms fail to stabilize on the reduced dose schedule, altretamine should be discontinued indefinitely.

What other drugs will affect altretamine?

Before taking altretamine, tell your doctor if you are taking a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), phenelzine (Nardil), or tranylcypromine (Parnate). You may require a dosage adjustment or special monitoring during treatment if you are taking one of these medicines.

Before taking altretamine, tell your doctor if you are taking cimetidine (Tagamet, Tagamet HB). You may require a dosage adjustment or special monitoring during treatment.

Do not receive "live" vaccines during treatment with altretamine. Administration of a live vaccine may be dangerous during treatment with altretamine.

Drugs other than those listed here may also interact with altretamine. Talk to your doctor and pharmacist before taking any other prescription or over-the-counter medicines, including herbal products, during treatment with altretamine.

More altretamine resources

Altretamine Side Effects (in more detail)
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Altretamine Drug Interactions
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0 Reviews for Altretamine - Add your own review/rating

altretamine Advanced Consumer (Micromedex) - Includes Dosage Information

Altretamine Professional Patient Advice (Wolters Kluwer)

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Altretamine MedFacts Consumer Leaflet (Wolters Kluwer)

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Compare altretamine with other medications

Ovarian Cancer

Where can I get more information?

Your pharmacist has additional information about altretamine written for health professionals that you may read.

See also: altretamine side effects (in more detail)

Adriamycin

doxorubicin hydrochloride

Dosage Form: injection, solution
Adriamycin (DOXOrubicin HCl) for Injection, USP

Adriamycin (DOXOrubicin HCl) Injection, USP

For Intravenous Use Only

Rx ONLY

Warning

Severe local tissue necrosis will occur if there is extravasation during administration (see DOSAGE AND ADMINISTRATION). Doxorubicin must not be given by the intramuscular or subcutaneous route.

Myocardial toxicity manifested in its most severe form by potentially fatal congestive heart failure (CHF) may occur either during therapy or months to years after termination of therapy. The probability of developing impaired myocardial function based on a combined index of signs, symptoms and decline in left ventricular ejection fraction (LVEF) is estimated to be 1 to 2% at a total cumulative dose of 300 mg/m2 of doxorubicin, 3 to 5% at a dose of 400 mg/m2, 5 to 8% at 450 mg/m2 and 6 to 20% at 500 mg/m2. The risk of developing CHF increases rapidly with increasing total cumulative doses of doxorubicin in excess of 400 mg/m2. Risk factors (active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, concomitant use of other cardiotoxic drugs) may increase the risk of cardiac toxicity. Cardiac toxicity with doxorubicin may occur at lower cumulative doses whether or not cardiac risk factors are present. Pediatric patients are at increased risk for developing delayed cardiotoxicity.

Secondary acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) have been reported in patients treated with anthracyclines, including doxorubicin (see ADVERSE REACTIONS). The occurrence of refractory secondary AML or MDS is more common when anthracyclines are given in combination with DNA-damaging anti-neoplastic agents or radiotherapy, when patients have been heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have been escalated. The rate of developing secondary AML or MDS has been estimated in an analysis of 8563 patients with early breast cancer treated in 6 studies conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP), including NSABP B-15. Patients in these studies received standard doses of doxorubicin and standard or escalated doses of cyclophosphamide (AC) adjuvant chemotherapy and were followed for 61,810 patient years. Among 4483 such patients who received conventional doses of AC, 11 cases of AML or MDS were identified, for an incidence of 0.32 cases per 1000 patient years (95% CI, 0.16 to 0.57) and a cumulative incidence at 5 years of 0.21% (95% CI, 0.11 to 0.41%). In another analysis of 1474 patients with breast cancer who received adjuvant treatment with doxorubicin-containing regimens in clinical trials conducted at University of Texas M.D. Anderson Cancer Center,the incidence was estimated at 1.5% at 10 years. In both experiences, patients who received regimens with higher cyclophosphamide dosages, who received radiotherapy, or who were aged 50 or older had an increased risk of secondary AML or MDS. Pediatric patients are also at risk of developing secondary AML.

Dosage should be reduced in patients with impaired hepatic function.

Severe myelosuppression may occur.

Doxorubicin should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agent.

Adriamycin Description

Doxorubicin is a cytotoxic anthracycline antibiotic isolated from cultures of Streptomyces peucetius var. caesius. Doxorubicin consists of a naphthacenequinone nucleus linked through a glycosidic bond at ring atom 7 to an amino sugar, daunosamine. Chemically, doxorubicin hydrochloride is (8S,10S) - 10 - [(3 - Amino - 2,3,6 - trideoxy - a - L - lyxo - hexopyranosyl) - oxy] - 8 - glycoloyl - 7,8,9,10 - tetrahydro - 6,8,11 - trihydroxy - 1 - methoxy - 5,12 - naphthacenedione hydrochloride. The structural formula is as follows:

C27H29NO11•HCl

M.W.=579.99

Doxorubicin binds to nucleic acids, presumably by specific intercalation of the planar anthracycline nucleus with the DNA double helix. The anthracycline ring is lipophilic, but the saturated end of the ring system contains abundant hydroxyl groups adjacent to the amino sugar, producing a hydrophilic center. The molecule is amphoteric, containing acidic functions in the ring phenolic groups and a basic function in the sugar amino group. It binds to cell membranes as well as plasma proteins. It is supplied in the hydrochloride form as a sterile red-orange lyophilized powder containing lactose and as a sterile parenteral, isotonic solution with sodium chloride for intravenous use only.

It is supplied in the hydrochloride form as a sterile red-orange lyophilized powder containing lactose and as a sterile parenteral, isotonic solution with sodium chloride for intravenous use only.

Adriamycin (DOXOrubicin HCl) for Injection, USP:

Each 10 mg lyophilized vial contains 10 mg of Doxorubicin Hydrochloride, USP and 50 mg of Lactose Monohydrate, NF.

Each 20 mg lyophilized vial contains 20 mg of Doxorubicin Hydrochloride, USP and 100 mg of Lactose Monohydrate, NF.

Each 50 mg lyophilized vial contains 50 mg of Doxorubicin Hydrochloride, USP and 250 mg of Lactose Monohydrate, NF.

Adriamycin (DOXOrubicin HCI) Injection, USP:

Each 2 mg/mL, 5 mL (10 mg) vial contains 10 mg Doxorubicin Hydrochloride, USP; Sodium Chloride 0.9% (to adjust tonicity) and Water for Injection q.s.; pH adjusted to 3 using Hydrochloric Acid.

Each 2 mg/mL, 10 mL (20 mg) vial contains 20 mg Doxorubicin Hydrochloride, USP; Sodium Chloride 0.9% (to adjust tonicity) and Water for Injection q.s.; pH adjusted to 3 using Hydrochloric Acid.

Each 2 mg/mL, 25 mL (50 mg) vial contains 50 mg Doxorubicin Hydrochloride, USP; Sodium Chloride 0.9% (to adjust tonicity) and Water for Injection q.s.; pH adjusted to 3 using Hydrochloric Acid.

Each 2 mg/mL, 100 mL (200 mg) multiple dose vial contains 200 mg Doxorubicin Hydrochloride, USP; Sodium Chloride 0.9% (to adjust tonicity) and Water for Injection q.s.; pH adjusted to 3 using Hydrochloric Acid.

Adriamycin - Clinical Pharmacology

The cytotoxic effect of doxorubicin on malignant cells and its toxic effects on various organs are thought to be related to nucleotide base intercalation and cell membrane lipid binding activities of doxorubicin. Intercalation inhibits nucleotide replication and action of DNA and RNA polymerases. The interaction of doxorubicin with topoisomerase II to form DNA-cleavable complexes appears to be an important mechanism of doxorubicin cytocidal activity.

Doxorubicin cellular membrane binding may affect a variety of cellular functions. Enzymatic electron reduction of doxorubicin by a variety of oxidases, reductases and dehydrogenases generates highly reactive species including the hydroxyl free radical OH•. Free radical formation has been implicated in doxorubicin cardiotoxicity by means of Cu (II) and Fe (III) reduction at the cellular level.

Cells treated with doxorubicin have been shown to manifest the characteristic morphologic changes associated with apoptosis or programmed cell death. Doxorubicin-induced apoptosis may be an integral component of the cellular mechanism of action relating to therapeutic effects, toxicities, or both.

Animal studies have shown activity in a spectrum of experimental tumors, immunosuppression, carcinogenic properties in rodents, and induction of a variety of toxic effects, including delayed and progressive cardiac toxicity, myelosuppression in all species, and atrophy to testes in rats and dogs.

Pharmacokinetics

Pharmacokinetic studies, determined in patients with various types of tumors undergoing either single or multi-agent therapy have shown that doxorubicin follows a multiphasic disposition after intravenous injection. In four patients, doxorubicin has demonstrated dose-independent pharmacokinetics in the dose range of 30 to 70 mg/m2.

Distribution.

The initial distributive half-life of approximately 5 minutes suggests rapid tissue uptake of doxorubicin, while its slow elimination from tissues is reflected by a terminal half-life of 20 to 48 hours. Steady-state distribution volume ranges from 809 to 1214 L/m2 and is indicative of extensive drug uptake into tissues. Binding of doxorubicin and its major metabolite, doxorubicinol, to plasma proteins is about 74 to 76% and is independent of plasma concentration of doxorubicin up to 1.1 mcg/mL.

Doxorubicin was excreted in the milk of one lactating patient, with peak milk concentration at 24 hours after treatment being approximately 4.4 -fold greater than the corresponding plasma concentration. Doxorubicin was detectable in the milk up to 72 hours after therapy with 70 mg/m2 of doxorubicin given as a 15-minute intravenous infusion and 100 mg/m2 of cisplatin as a 26-hour intravenous infusion. The peak concentration of doxorubicinol in milk at 24 hours was 0.11 mcg/mL and AUC up to 24 hours was 9 mcg.h/mL while the AUC for doxorubicin was 5.4 mcg.h/mL.

Doxorubicin does not cross the blood brain barrier.

Metabolism.

Enzymatic reduction at the 7 position and cleavage of the daunosamine sugar yields aglycones which are accompanied by free radical formation, the local production of which may contribute to the cardiotoxic activity of doxorubicin. Disposition of doxorubicinol (DOX-OL) in patients is formation rate limited, with the terminal half-life of DOX-OL being similar to doxorubicin. The relative exposure of DOX-OL, i.e., the ratio between the AUC of DOX-OL and the AUC of doxorubicin, compared to doxorubicin ranges between 0.4 and 0.6.

Excretion.

Plasma clearance is in the range of 324 to 809 mL/min/m2 and is predominately by metabolism and biliary excretion. Approximately 40% of the dose appears in the bile in 5 days, while only 5 to 12% of the drug and its metabolites appear in the urine during the same time period. In urine, <3% of the dose was recovered as DOX-OL over 7 days.

Systemic clearance of doxorubicin is significantly reduced in obese women with ideal body weight greater than 130%. There was a significant reduction in clearance without any change in volume of distribution in obese patients when compared with normal patients with less than 115% ideal body weight.

Pharmacokinetics in Special Populations

Pediatric.

Following administration of 10 to 75-mg/m2 doses of doxorubicin to 60 children and adolescents ranging from 2 months to 20 years of age, doxorubicin clearance averaged 1443 +/- 114 mL/min/m2. Further analysis demonstrated that clearance in 52 children greater than 2 years of age (1540 mL/min/m2) was increased compared with adults. However, clearance in infants younger than 2 years of age (813 mL/min/m2) was decreased compared with older children and approached the range of clearance values determined in adults.

Geriatric.

While the pharmacokinetics of elderly subjects (≥65 years of age) have been evaluated, no dosage adjustment is recommended based on age. (See PRECAUTIONS, Geriatric use )

Gender.

A published clinical study involving 6 men and 21 women with no prior anthracycline therapy reported a significantly higher median doxorubicin clearance in the men compared to the women (1088 mL/min/m2 versus 433 mL/min/m2). However, the terminal half-life of doxorubicin was longer in men compared to the women (54 versus 35 hrs).

Race.

The influence of race on the pharmacokinetics of doxorubicin has not been evaluated.

Hepatic Impairment.

The clearance of doxorubicin and doxorubicinol was reduced in patients with impaired hepatic function (see DOSAGE AND ADMINISTRATION).

Renal Impairment.

The influence of renal function on the pharmacokinetics of doxorubicin has not been evaluated.

Clinical Studies

The effectiveness of doxorubicin-containing regimens in the adjuvant therapy of early breast cancer has primarily been established based on data collected in a meta-analysis published in 1998 by the Early Breast Cancer Trialists Collaborative Group (EBCTCG). The EBCTCG obtains primary data on all relevant studies, both published and unpublished, for early stage breast cancer and regularly updates these analyses. The principal endpoints for the adjuvant chemotherapy trials were disease-free survival (DFS) and overall survival (OS). The meta-analyses allowed comparisons of cyclophosphamide, methotrexate, and 5- fluorouracil (CMF) to no chemotherapy (19 trials including 7523 patients) and comparisons of doxorubicin-containing regimens with CMF as an active control (6 trials including 3510 patients). The pooled estimates of DFS and OS from these trials were used to calculate the effect of CMF relative to no therapy. The hazard ratio for DFS for CMF compared to no chemotherapy was 0.76 (95% CI 0.71 to 0.82) and for OS was 0.86 (95% CI 0.80 to 0.93). Based on a conservative estimate of CMF effect (lower 2-sided 95% confidence limit of hazard ratio) and 75% retention of CMF effect on DFS, it was determined that the doxorubicin containing regimens would be considered as non-inferior to CMF if the upper 2-sided 95% confidence limit of the hazard ratio was less than 1.06, i.e., not more than 6% worse than CMF. A similar calculation for OS would require a non-inferiority margin of 1.02.

Six randomized trials in the EBCTCG meta-analysis compared doxorubicin-containing regimens to CMF. A total of 3510 women with early breast cancer involving axillary lymph nodes were evaluated; approximately 70% were premenopausal and 30% were postmenopausal. At the time of the meta-analysis, 1745 first recurrences and 1348 deaths had occurred. Analyses demonstrated that doxorubicin-containing regimens retained at least 75% of the historical CMF adjuvant effect on DFS and are effective. The hazard ratio for DFS (dox:CMF) was 0.91 (95% CI 0.82 to 1.01) and for OS was 0.91 (95% CI 0.81 to 1.03). Results of these analyses for both DFS and OS are provided in Table 1 and Figures 1 and 2.

Table 1. Summary of Randomized Trials Comparing Doxorubicin-Containing Regimens Versus CMF in EBCTCG Meta-Analysis
Abbreviations: DFS = disease free survival; OS = overall survival; AC = doxorubicin, cyclophosphamide; AVbCMF = doxorubicin, vinblastine, cyclophosphamide, methotrexate, 5-fluorouracil; CMF = cyclophosphamide, methotrexate, 5-fluorouracil; CMFVA = cyclophosphamide, methotrexate, 5-fluorouracil , vincristine, doxorubicin; FAC = 5-fluorouracil, doxorubicin, cyclophosphamide; FACV = 5-fluorouracil, doxorubicin, cyclophosphamide, vincristine; HR = hazard ratio; CI = confidence interval
* Includes pooled data from patients who received either AC alone for 4 cycles, or who were treated with AC for 4 cycles followed by 3 cycles of CMF. † Patients received alternating cycles of AVb and CMF.
Study (starting year)	Regimens	No. of Cycles	No. of Patients	Doxorubicin-Containing Regimens vs CMF HR (95% CI)
Study (starting year)	Regimens	No. of Cycles	No. of Patients	DFS	OS
NSABP B-15 (1984)	AC	4	1562*
				0.93 (0.82-1.06)	0.97 (0.83-1.12)
	CMF	6	776
SECSG 2 (1976)	FAC	6	260
				0.86 (0.66-1.13)	0.93 (0.69-1.26)
	CMF	6	268
ONCOFRANCE (1978)	FACV	12	138
				0.71 (0.49-1.03)	0.65 (0.44-0.96)
	CMF	12	113
SE Sweden BCG A (1980)	AC	6	21
				0.59 (0.22-1.61)	0.53 (0.21-1.37)
	CMF	6	22
NSABC Israel Br0283 (1983)	AVB†CMF	4	55
		6		0.91 (0.5.3-1.57)	0.88 (0.47-1.63)
	CMF	8	50
Austrian BCSG 3 (1984)	CMFVA	6	121
				1.07 (0.73-1.55)	0.93 (0.64-1.35)
	CMF	8	124
Combined Studies	Doxorubicin-Containing Regimens CMF		2157
				0.91 (0.82-1.01)	0.91 (0.81-1.03)
			1353

With respect to DFS, 2 of 6 studies (NSABP B-15 and ONCOFRANCE) met the non-inferiority standard individually and with respect to OS, 1 study met the non-inferiority margin individually (ONCOFRANCE). The largest of the 6 studies in the EBCTCG meta-analysis, a randomized, open-label, multicenter trial (NSABP B-15) was conducted in approximately 2300 women (80% premenopausal; 20% postmenopausal) with early breast cancer involving axillary lymph nodes. In this trial, 6 cycles of conventional CMF was compared to 4 cycles of doxorubicin and cyclophosphamide (AC) and 4 cycles of AC followed by 3 cycles of CMF. No statistically significant differences in terms of DFS or OS were observed. (See Table 1.)

Indications and Usage for Adriamycin

Adriamycin (DOXOrubicin HCl) Injection, USP and Adriamycin (DOXOrubicin HCl) for Injection, USP have been used successfully to produce regression in disseminated neoplastic conditions such as acute lymphoblastic leukemia, acute myeloblastic leukemia, Wilms’ tumor, neuroblastoma, soft tissue and bone sarcomas, breast carcinoma, ovarian carcinoma, transitional cell bladder carcinoma, thyroid carcinoma, gastric carcinoma, Hodgkin’s disease, malignant lymphoma and bronchogenic carcinoma in which the small cell histologic type is the most responsive compared to other cell types.

Doxorubicin is also indicated for use as a component of adjuvant therapy in women with evidence of axillary lymph node involvement following resection of primary breast cancer.

Contraindications

Patients should not be treated with doxorubicin if they have any of the following conditions: baseline neutrophil count <1500 cells/mm3; severe hepatic impairment; recent myocardial infarction; severe myocardial insufficiency; severe arrhythmias; previous treatment with complete cumulative doses of doxorubicin, daunorubicin, idarubicin, and/or other anthracyclines and anthracenediones; or hypersensitivity to doxorubicin, any of its excipients, or other anthracyclines or anthracenediones. (See WARNINGS and DOSAGE AND ADMINISTRATION)

Warnings

General

Doxorubicin should be administered only under the supervision of qualified physicians experienced in the use of cytotoxic therapy. Patients should recover from acute toxicities of prior cytotoxic treatment (such as stomatitis, neutropenia, thrombocytopenia, and generalized infections) before beginning treatment with doxorubicin. Also, initial treatment with doxorubicin should be preceded by a careful baseline assessment of blood counts; serum levels of total bilirubin, AST, and creatinine; and cardiac function as measured by left ventricular ejection function (LVEF). Patients should be carefully monitored during treatment for possible clinical complications due to myelosuppression. Supportive care may be necessary for the treatment of severe neutropenia and severe infectious complications. Monitoring for potential cardiotoxicity is also important, especially with greater cumulative exposure to doxorubicin. Doxorubicin may potentiate the toxicity of other anticancer therapies (see PRECAUTIONS, Drug interactions).

Cardiac Function

Cardiotoxicity is a known risk of anthracycline treatment. Anthracycline-induced cardiotoxicity may be manifested by early (or acute) or late (delayed) events. Early cardiotoxity of doxorubicin consists mainly of sinus tachycardia and/or electrocardiogram (ECG) abnormalities such as non-specific ST-T wave changes. Tachyarrhythmias, including premature ventricular contractions and ventricular tachycardia, bradycardia, as well as atrioventricular and bundle-branch block have also been reported. These effects do not usually predict subsequent development of delayed cardiotoxicity, are rarely of clinical importance, and are generally not considered an indication for the suspension of doxorubicin treatment.

Delayed cardiotoxicity usually develops late in the course of therapy with doxorubicin or within 2 to 3 months after treatment termination, but later events, several months to years after completion of treatment, have also been reported. Delayed cardiomyopathy is manifested by a reduction in LVEF and/or signs and symptoms of congestive heart failure (CHF) such as tachycardia, dyspnea, pulmonary edema, dependent edema, cardiomegaly and hepatomegaly, oliguria, ascites, pleural effusion, and gallop rhythm. Subacute effects such as pericarditis/myocarditis have also been reported. Life-threatening CHF is the most severe form of anthracycline-induced cardiomyopathy and represents the cumulative doselimiting toxicity of the drug.

The probability of developing impaired myocardial function, based on a combined index of signs, symptoms and decline in left ventricular ejection fraction (LVEF) is estimated to be 1 to 2% at a total cumulative dose of 300 mg/m2 of doxorubicin, 3 to 5% at a dose of 400 mg/m2, 5 to 8% at a dose of 450 mg/m2 and 6 to 20% at a dose of 500 mg/m2 given in a schedule of a bolus injection once every 3 weeks. In a retrospective review, the probability of developing congestive heart failure was reported to be 5/168 (3%) at a cumulative dose of 430 mg/m2 of doxorubicin, 8/110 (7%) at 575 mg/m2 and 3/14 (21%) at 728 mg/m2. In a prospective study of doxorubicin in combination with cyclophosphamide, fluorouracil and/or vincristine in patients with breast cancer or small cell lung cancer, the probability of CHF at various cumulative doses of doxorubicin was 1.5% at 300 mg/m2, 4.9% at 400 mg/m2, 7.7% at 450 mg/m2 and 20.5% at 500 mg/m2. The risk of developing CHF increases rapidly with increasing total cumulative doses of doxorubicin in excess of 400 mg/m2.

Cardiotoxicity may occur at lower doses in patients with prior mediastinal/pericardial irradiation, concomitant use of other cardiotoxic drugs, doxorubicin exposure at an early age, and advanced age. Data also suggest that pre-existing heart disease is a co-factor for increased risk of doxorubicin cardiotoxicity. In such cases, cardiac toxicity may occur at doses lower than the recommended cumulative dose of doxorubicin. Studies have suggested that concomitant administration of doxorubicin and calcium channel entry blockers or cardiotoxic drugs, especially those with long half-lives, e.g., trastuzumab, may increase the risk of doxorubicin cardiotoxicity (see PRECAUTIONS, General; DOSAGE AND ADMINISTRATION). The total dose of doxorubicin administered to the individual patient should also take into account previous or concomitant therapy with related compounds such as daunorubicin, idarubicin and mitoxantrone. Although not formally tested, it is probable that the toxicity of doxorubicin and other anthracyclines or anthracenediones is additive. Cardiomyopathy and/or congestive heart failure may be encountered several months or years after discontinuation of doxorubicin therapy.

The risk of acute manifestations of doxorubicin cardiotoxicity in pediatric patients may be as much or lower than in adults. Pediatric patients appear to be at particular risk for developing delayed cardiac toxicity in that doxorubicin-induced cardiomyopathy impairs myocardial growth as pediatric patients mature, subsequently leading to possible development of congestive heart failure during early adulthood. As many as 40% of pediatric patients may have subclinical cardiac dysfunction and 5 to 10% of pediatric patients may develop congestive heart failure on long term follow-up. This late cardiac toxicity may be related to the dose of doxorubicin. The longer the length of follow-up, the greater the increase in the detection rate. Treatment of doxorubicin-induced congestive heart failure includes the use of digitalis, diuretics, after load reducers such as angiotensin I converting enzyme (ACE) inhibitors, low salt diet, and bed rest. Such intervention may relieve symptoms and improve the functional status of the patient.

Monitoring Cardiac Function

The risk of serious cardiac impairment may be decreased through regular monitoring of LVEF during the course of treatment with prompt discontinuation of doxorubicin at the first sign of impaired function. The preferred method for assessment of cardiac function is evaluation of LVEF measured by multi-gated radionuclide angiography (MUGA) or echocardiography (ECHO). An ECG may also be done. A baseline cardiac evaluation with a MUGA scan or an ECHO is recommended, especially in patients with risk factors for increased cardiac toxicity. Repeated MUGA or ECHO determinations of LVEF should be performed, particularly with higher, cumulative anthracycline doses. The technique used for assessment should be consistent through follow-up. In patients with risk factors, particularly prior anthracycline or anthracenedione use, the monitoring of cardiac function must be particularly strict and the risk-benefit of continuing treatment with doxorubicin in patients with impaired cardiac function must be carefully evaluated.

Endomyocardial biopsy is recognized as the most sensitive diagnostic tool to detect anthracycline-induced cardiomyopathy; however, this invasive examination is not practically performed on a routine basis. ECG changes such as dysrhythmias, a reduction of the QRS voltage, or a prolongation beyond normal limits of the systolic time interval may be indicative of anthracycline-induced cardiomyopathy, but ECG is not a sensitive or specific method for following anthracycline-related cardiotoxicity.

Pediatric patients are at increased risk for developing delayed cardiotoxicity following doxorubicin administration and therefore a follow-up cardiac evaluation is recommended periodically to monitor for this delayed cardiotoxicity.

In adults, a 10% decline in LVEF to below the lower limit of normal or an absolute LVEF of 45%, or a 20% decline in LVEF at any level is indicative of deterioration in cardiac function. In pediatric patients, deterioration in cardiac function during or after the completion of therapy with doxorubicin is indicated by a drop in fractional shortening (FS) by an absolute value of ≥10 percentile units or below 29%, and a decline in LVEF of 10 percentile units or an LVEF below 55%. In general, if test results indicate deterioration in cardiac function associated with doxorubicin, the benefit of continued therapy should be carefully evaluated against the risk of producing irreversible cardiac damage. Acute life-threatening arrhythmias have been reported to occur during or within a few hours after doxorubicin administration.

Hematologic Toxicity

As with other cytotoxic agents, doxorubicin may produce myelosuppression. Myelosuppression requires careful monitoring. Total and differential WBC, red blood cell (RBC), and platelet counts should be assessed before and during each cycle of therapy with doxorubicin. A dose-dependent, reversible leukopenia and/or granulocytopenia (neutropenia) are the predominant manifestations of doxorubicin hematologic toxicity and are the most common acute dose-limiting toxicities of this drug. With the recommended dose schedule, leukopenia is usually transient, reaching its nadir 10 to 14 days after treatment with recovery usually occurring by the 21st day. Thrombocytopenia and anemia may also occur. Clinical consequences of severe myelosuppression include fever, infections, sepsis/septicemia, septic shock, hemorrhage, tissue hypoxia, or death.

Secondary Leukemia

The occurrence of secondary AML or MDS has been reported most commonly in patients treated with chemotherapy regimens containing anthracyclines (including doxorubicin) and DNA-damaging antineoplastic agents, in combination with radiotherapy, when patients have been heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have been escalated. Such cases generally have a 1 to 3 year latency period. The rate of developing secondary AML or MDS has been estimated in an analysis of 8563 patients with early breast cancer treated in 6 studies conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP), including NSABP B-15. Patients in these studies received standard doses of doxorubicin and standard or escalated doses of cyclophosphamide (AC) adjuvant chemotherapy and were followed for 61,810 patient years. Among 4483 such patients who received conventional doses of AC, 11 cases of AML or MDS were identified, for an incidence of 0.32 cases per 1000 patient years (95% CI, 0.16 to 0.57) and a cumulative incidence at 5 years of 0.21% (95% CI, 0.11 to 0.41%). In another analysis of 1474 patients with breast cancer who received adjuvant treatment with doxorubicin-containing regimens in clinical trials conducted at University of Texas M.D. Anderson Cancer Center, the incidence was estimated at 1.5% at 10 years. In both experiences, patients who received regimens with higher cyclophosphamide dosages, who received radiotherapy, or who were aged 50 or older had an increased risk of secondary AML or MDS.

Pediatric patients are also at risk of developing secondary AML.

Effects at Site of Injection

Phlebosclerosis may result from an injection into a small vessel or from repeated injections into the same vein. Following the recommended administration procedures may minimize the risk of phlebitis/thrombophlebitis at the injection site (see DOSAGE AND ADMINISTRATION, Instruction for Use/Handling).

Extravasation

On intravenous administration of doxorubicin, extravasation may occur with or without an accompanying stinging or burning sensation, even if blood returns well on aspiration of the infusion needle. If any signs or symptoms of extravasation have occurred, the injection or infusion should be immediately terminated and restarted in another vein (see DOSAGE AND ADMINISTRATION)

Hepatic Impairment

Since metabolism and excretion of doxorubicin occurs predominantly by the hepatobiliary route, toxicity of recommended doses of doxorubicin can be enhanced by hepatic impairment; therefore, prior to individual dosing, evaluation of hepatic function is recommended using conventional laboratory tests such as SGOT, SGPT, alkaline phosphatase, and bilirubin (see DOSAGE AND ADMINISTRATION).

Immunosuppressant Effects/Increased Susceptibility to Infections

Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including doxorubicin, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving doxorubicin. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

Pregnancy Category D

Doxorubicin can cause fetal harm when administered to a pregnant woman. Doxorubicin was teratogenic and embryotoxic at doses of 0.8 mg/kg/day (about 1/13 the recommended human dose on a body surface area basis) when administered during the period of organogenesis in rats. Teratogenicity and embryotoxicity were also seen using discrete periods of treatment. The most susceptible was the 6- to 9-day gestation period at doses of 1.25 mg/kg/day and greater. Characteristic malformations included esophageal and intestinal atresia, tracheo-esophageal fistula, hypoplasia of the urinary bladder and cardiovascular anomalies. Doxorubicin was embryotoxic (increase in embryofetal deaths) and abortifacient at 0.4 mg/kg/day (about 1/14 the recommended human dose on a body

There are no adequate and well-controlled studies in pregnant women. If doxorubicin is to be used during pregnancy, or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus. Women of childbearing age should be advised to avoid becoming pregnant.

Precautions

General

Doxorubicin is not an anti-microbial agent. Doxorubicin is emetigenic. Antiemetics may reduce nausea and vomiting; prophylactic use of antiemetics should be considered before administration of doxorubicin, particularly when given in conjunction with other emetigenic drugs. Doxorubicin should not be administered in combination with other cardiotoxic agents unless the patient’s cardiac function is closely monitored. Patients receiving doxorubicin after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, may also be at an increased risk of developing cardiotoxicity. Physicians should avoid doxorubicin-based therapy for up to 24 weeks after stopping trastuzumab when possible. If doxorubicin used before this time, careful monitoring of cardiac function is recommended (See WARNINGS, DOSAGE AND ADMINISTRATION).

Information for patients

Patients should be informed of the expected adverse effects of doxorubicin, including gastrointestinal symptoms (nausea, vomiting, diarrhea, and stomatitis) and potential neutropenic complications. Patients should consult their physician if vomiting, dehydration, fever, evidence of infection, symptoms of CHF, or injection-site pain occurs following therapy with doxorubicin. Patients should be informed that they will almost certainly develop alopecia. Patients should be advised that their urine may appear red for 1 to 2 days after administration of doxorubicin and that they should not be alarmed. Patients should understand that there is a risk of irreversible myocardial damage associated with treatment with doxorubicin, as well as a risk of treatment-related leukemia. Because doxorubicin may induce chromosomal damage in sperm, men undergoing treatment with doxorubicin should use effective contraceptive methods. Women treated with doxorubicin may develop irreversible amenorrhea, or premature menopause.

Drug interactions

Doxorubicin is extensively metabolized by the liver. Changes in hepatic function induced by concomitant therapies may affect doxorubicin metabolism, pharmacokinetics, therapeutic efficacy, and/or toxicity. Toxicities associated with doxorubicin, especially hematologic and gastrointestinal events, may be increased when doxorubicin is used in combination with other cytotoxic drugs.

Paclitaxel: There have been a number of reports in the literature that describe an increase in cardiotoxicity when doxorubicin is co-administered with paclitaxel. Two published studies report that initial administration of paclitaxel infused over 24 hours followed by doxorubicin administered over 48 hours resulted in a significant decrease in doxorubicin clearance with more profound neutropenic and stomatitis episodes than the reverse sequence of administration.

Progesterone: In a published study, progesterone was given intravenously to patients with advanced malignancies (ECOG PS < 2) at high doses (up to 10 g over 24 hours) concomitantly with a fixed doxorubicin dose (60 mg/m2) via bolus injection. Enhanced doxorubicininduced neutropenia and thrombocytopenia were observed

Verapamil: A study of the effects of verapamil on the acute toxicity of doxorubicin in mice revealed higher intial peak concentrations of doxorubicin in the heart with a higher incidence and severity of degenerative changes in cardiac tissue resulting in a shorter survival.

Cyclosporine: The addition of cyclosporine to doxorubicin may result in increases in AUC for both doxorubicin and doxorubicinol possibly due to a decrease in clearance of parent drug and a decrease in metabolism of doxorubicinol. Literature reports suggest that adding cyclosporine to doxorubicin results in more profound and prolonged hematologic toxicitythan doxorubicin alone. Coma and/or seizures have also been described.

Dexrazoxane: In a clinical study of women with metastatic breast cancer, the concurrent use of the cardioprotectant, dexrazoxane, with the initiation of a regimen of fluorouracil, doxorubicin, and cyclophosphamide (FAC) was associated with a lower tumor response rate. Later initiation of dexrazoxane (after administration of a cumulative doxorubicin dose of 300 mg/m2 of doxorubicin had been given as a component of FAC) was not associated with a reduction in chemotherapy activity. Dexrazoxane is only indicated for use in women with metastatic breast cancer who have received a cumulative doxorubicin dose of 300 mg/m2 and are continuing with doxorubicin therapy.

Cytarabine: Necrotizing colitis manifested by typhlitis (cecal inflammation), bloody stools and severe and sometimes fatal infections have been associated with a combination of doxorubicin given by intravenous push daily for 3 days and cytarabine given by continuous infusion daily for 7 or more days.

Sorafenib: In clinical studies, both an increase of 21% and 47%, and no change in the AUC of doxorubicin were observed with concomitant treatment with sorafenib 400 mg twice daily. The clinical significance of these findings is unknown.

Cyclophosphamide: The addition of cyclophosphamide to doxorubicin treatment does not affect exposure to doxorubicin, but may result in an increase in exposure to doxorubicinol, a metabolite. Doxorubicinol only has 5% of the cytotoxic activity of doxorubicin. Concurrent treatment with doxorubicin has been reported to exacerbate cyclophosphamide-induced hemorrhagic cystitis. Acute myeloid leukemia has been reported as a second malignancy after treatment with doxorubicin and cyclophosphamide.

Literature reports have also described the following drug interactions: Phenobarbital increases the elimination of doxorubicin; phenytoin levels may be decreased by doxorubicin; streptozocin (Zanosar®) may inhibit hepatic metabolism of doxorubicin; saquinavir in combination with cyclophosphamide, doxorubicin, and etoposide increased mucosal toxicity in patients with HIV-associated non-Hodgkin’s lymphoma; and administration of live vaccines to immunosuppressed patients including those undergoing cytotoxic chemotherapy may be hazardous (see WARNINGS).

Laboratory Tests

Initial treatment with doxorubicin requires observation of the patient and periodic monitoring of complete blood counts, hepatic function tests, and left ventricular ejection fraction (see WARNINGS). Abnormalities of hepatic function tests may occur. Like other cytotoxic drugs, doxorubicin may induce “tumor lysis syndrome” and hyperuricemia in patients with rapidly growing tumors. Blood uric acid levels, potassium, calcium, phosphate, and creatinine s

Thursday, October 6, 2016

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