Megace ES

Before taking megestrol,

• tell your doctor and pharmacist if you are allergic to megestrol, any other medications, or any of the inactive ingredients in megestrol tablets, suspension, or concentrated suspension. Ask your doctor or pharmacist for a list of the inactive ingredients.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention antibiotics and indinavir (Crixivan). Your doctor may need to adjust the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you have or have ever had a blood clot anywhere in the body, a stroke, diabetes, or kidney or liver disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking megestrol, call your doctor immediately. Megestrol may harm the fetus. Do not breast-feed while you are taking megestrol.
• you should know that megestrol may interfere with the normal menstrual cycle (period) in women. However, you should not assume that you cannot become pregnant. Use a reliable method of birth control to prevent pregnancy.
• if you are having surgery, including dental surgery, during or shortly after your treatment, tell the doctor or dentist that you are taking megestrol.

Megestrol may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• impotence
• decreased sexual desire
• unexpected vaginal bleeding
• difficulty falling asleep or staying asleep
• gas
• rash

Some side effects can be serious. If you experience any of these symptoms, call your doctor immediately:

• nausea
• vomiting
• dizziness
• weakness
• blurred vision
• extreme thirst
• frequent urination
• extreme hunger
• leg pain
• difficulty breathing
• sharp, crushing chest pain or heaviness in chest
• slow or difficult speech
• weakness or numbness of an arm or leg

Megestrol may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

Dosage Forms And Strengths

Megace® ES is a milky white, lemon-lime flavored oral suspension containing 125 mg of megestrol acetate per mL. Megace® ES does not contain the same amount of megestrol acetate as Megace® oral suspension or any of the other megestrol acetate oral suspensions.

Storage And Handling

Megace ES® oral suspension is a milky white, lemon-lime flavored oral suspension containing 125 mg of megestrol acetate per mL. Available in bottles of 150 mL (5 fl oz) NDC 49884 -94969.

Store Megace® ES oral suspension between 15° to 25° C (59° to 77° F) and dispense in a tight container. Protect from heat.

Health Hazard Data

There is no threshold limit value established by OSHA, NIOSH, or ACGIH. Exposure or overdose at levels approaching recommended dosing levels could result in side effects described above [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS]. Women at risk of pregnancy should avoid such exposure.

Manufactured by: PAR PHARMACEUTICAL COMPANIES, INC., Spring Valley, New York 10977. Revised: Mar 2014.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Megestrol can harm an unborn baby or cause birth defects. Do not use megestrol if you are pregnant. Use birth control to prevent pregnancy.

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

Although there is no specific information comparing use of progestins in children or teenagers with use in other age groups, this medicine is not expected to cause different side effects or problems in children or teenagers than it does in adults.

Geriatric

This medicine has been tested and has not been shown to cause different side effects or problems in older people than it does in younger adults.

Pregnancy

Progesterone, a natural hormone that the body makes during pregnancy, has not caused problems. In fact, it is sometimes used in women to treat a certain type of infertility and to aid in egg donor or infertility procedures.

Other progestins have not been studied in pregnant women. Be sure to tell your doctor if you become pregnant while using any of the progestins. It is best to use some kind of birth control method while you are receiving progestins in high doses. High doses of progestins are not recommended for use during pregnancy since there have been some reports that they may cause birth defects in the genitals (sex organs) of a male fetus. Also, some of these progestins may cause male-like changes in a female fetus and female-like changes in a male fetus, but these problems usually can be reversed. Low doses of progestins, such as those doses used for contraception, have not caused major problems when used accidentally during pregnancy.

Breast Feeding

Although progestins pass into the breast milk, they have not been shown to cause problems in nursing babies. However, progestins may change the quality or amount (increase or decrease) of the mother's breast milk. It may be necessary for you to take another medicine or to stop breast-feeding during treatment. Be sure you have discussed the risks and benefits of the medicine with your doctor.

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 not recommended. Your doctor may decide not to treat you with a medication in this class or change some of the other medicines you take.

• Boceprevir
• Dofetilide
• Tranexamic Acid

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.

• Amobarbital
• Aprepitant
• Aprobarbital
• Bosentan
• Butabarbital
• Butalbital
• Carbamazepine
• Ceritinib
• Conivaptan
• Dabrafenib
• Darunavir
• Dexamethasone
• Efavirenz
• Eliglustat
• Enzalutamide
• Eslicarbazepine Acetate
• Eterobarb
• Etravirine
• Felbamate
• Fosphenytoin
• Griseofulvin
• Heptabarbital
• Hexobarbital
• Idelalisib
• Isotretinoin
• Lesinurad
• Lixisenatide
• Lumacaftor
• Mephobarbital
• Methohexital
• Mitotane
• Modafinil
• Nafcillin
• Netupitant
• Nevirapine
• Oxcarbazepine
• Pentobarbital
• Phenobarbital
• Phenytoin
• Pitolisant
• Prednisone
• Primidone
• Rifabutin
• Rifampin
• St John's Wort
• Sugammadex
• Theophylline
• Thiopental
• Tizanidine
• Topiramate
• Ulipristal

Interactions with Food/Tobacco/Alcohol

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

Other Medical Problems

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

• Asthma or
• Epilepsy (or history of) or
• Heart or circulation problems or
• Kidney disease (severe) or
• Migraine headaches—Progestins may cause fluid retention which may cause these conditions to become worse.

• Bleeding problems, undiagnosed, such as blood in the urine or changes in vaginal bleeding—May make diagnosis of these problems more difficult.

• Blood clots, or history of or
• Breast cancer, or history of or
• Deep vein thrombosis (blood clot in the leg), active or history of or
• Heart attack, active or history of or
• Liver disease, including jaundice, or history of or
• Pulmonary embolism (clot in the lung), active or history of or
• Stroke , active or history of or
• Venous thromboembolism (clot in the veins), or history of—Progestins should not be used in patients with these conditions.

• Breast disease (such as breast lumps or cysts), history of—May make this condition worse for diseases that do not react in a positive way to progestins.

• Diabetes mellitus—May cause an increase in your blood sugar and a change in the amount of medicine you take for diabetes; progestins in high doses are more likely to cause this problem.

• Memory loss (dementia)—May make this condition worse.

• Vision changes—This medicine may cause changes in vision; your medicine may need to be stopped if these conditions become worse.

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

To make the use of a progestin as safe and reliable as possible, you should understand how and when to take it and what effects may be expected. Progestins usually come with patient directions. Read them carefully before taking or using this medicine.

Take this medicine only as directed by your doctor. Do not take more of it and do not take it for a longer time than your doctor ordered. To do so may increase the chance of side effects. Try to take the medicine at the same time each day to reduce the possibility of side effects and to allow it to work better.

Progestins are often given together with certain medicines. If you are using a combination of medicines, make sure that you take each one at the proper time and do not mix them. Ask your health care professional to help you plan a way to remember to take your medicines at the right times.

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.

For medroxyprogesterone
• For oral dosage form (tablets):
  • For controlling unusual and heavy bleeding of the uterus (dysfunctional uterine bleeding) or treating unusual stopping of menstrual periods (amenorrhea):
    • Adults and teenagers—5 to 10 milligrams (mg) per day for five to ten days as directed by your doctor.
  • For preparing the uterus for the menstrual period:
    • Adults and teenagers—10 milligrams (mg) per day for five or ten days as directed by your doctor.
  • For preventing estrogen from thickening the lining of the uterus (endometrial hyperplasia) when taking estrogen for ovarian hormone therapy in postmenopausal women:
    • Adults—When taking estrogen each day on Days 1 through 25: Oral, 5 to 10 milligrams (mg) of medroxyprogesterone per day for ten to fourteen or more days each month as directed by your doctor. Or, your doctor may want you to take 2.5 or 5 mg per day without stopping. Your doctor will help decide the number of tablets that is best for you and when to take them.
• For intramuscular injection dosage form:
  • For treating cancer of the kidneys or uterus:
    • Adults and teenagers—At first, 400 to 1000 milligrams (mg) injected into a muscle as a single dose once a week. Then, your doctor may lower your dose to 400 mg or more once a month.
• For subcutaneous injection dosage form:
  • For treating pain related to endometriosis:
    • Adults and teenagers—104 milligrams (mg) injected under the skin of the anterior thigh or abdomen every three months (12 to 14 weeks) for not more than 2 years.

For megestrol
• For oral dosage form (suspension):
  • For treating loss of appetite (anorexia), muscles (cachexia), or weight caused by acquired immunodeficiency syndrome (AIDS):
    • Adults and teenagers—800 milligrams (mg) a day for the first month. Then your doctor may want you to take 400 or 800 mg a day for three more months.
• For oral dosage form (tablets):
  • For treating cancer of the breast:
    • Adults and teenagers—160 milligrams (mg) a day as a single dose or in divided doses for two or more months.
  • For treating cancer of the uterus:
    • Adults and teenagers—40 to 320 milligrams (mg) a day for two or more months.
  • For treating loss of appetite (anorexia), muscles (cachexia), or weight caused by cancer:
    • Adults and teenagers—400 to 800 milligrams (mg) a day.

For norethindrone
• For oral dosage form (tablets):
  • For controlling unusual and heavy bleeding of the uterus (dysfunctional uterine bleeding) or treating unusual stopping of menstrual periods (amenorrhea):
    • Adults and teenagers—2.5 to 10 milligrams (mg) a day from Day 5 through Day 25 (counting from the first day of the last menstrual cycle). Or, your doctor may want you to take the medicine only for five to ten days as directed.
  • For treating endometriosis:
    • Adults and teenagers—At first, 5 milligrams (mg) a day for two weeks. Then, your doctor may increase your dose slowly up to 15 mg a day for six to nine months. Let your doctor know if your menstrual period starts. Your doctor may want you to take more of the medicine or may want you to stop taking the medicine for a short period of time.

For progesterone
• For oral dosage form (capsules):
  • For preventing estrogen from thickening the lining of the uterus (endometrial hyperplasia) when taking estrogen for ovarian hormone therapy in postmenopausal women:
    • Adults—200 milligrams (mg) per day at bedtime for 12 continuous days per 28-day cycle of estrogen treatment each month.
  • For treating unusual stopping of menstrual periods (amenorrhea):
    • Adults—400 milligrams (mg) per day at bedtime for ten days.
• For vaginal dosage form (gel):
  • For treating unusual stopping of menstrual periods (amenorrhea):
    • Adults and teenagers—45 milligrams (mg) (one applicatorful of 4% gel) once every other day for up to six doses. Dose may be increased to 90 mg (one applicatorful of 8% gel) once every other day for up to six doses if needed.
  • For use with infertility procedures:
    • Adults and teenagers—90 milligrams (mg) (one applicatorful of 8% gel) one or two times a day. If pregnancy occurs, treatment can continue for up to ten to twelve weeks.
• For injection dosage form:
  • For controlling unusual and heavy bleeding of the uterus (dysfunctional uterine bleeding) or treating unusual stopping of menstrual periods (amenorrhea):
    • Adults and teenagers—5 to 10 milligrams (mg) a day injected into a muscle for six to ten days. Or, your doctor may want you to receive 100 or 150 mg injected into a muscle as a single dose. Sometimes your doctor may want you first to take another hormone called estrogen. If your menstrual period starts, your doctor will want you to stop taking the medicine.
• For vaginal dosage form (suppositories):
  • For maintaining a pregnancy (at ovulation and at the beginning of pregnancy):
    • Adults and teenagers—25 mg to 100 milligrams (mg) (one suppository) inserted into the vagina one or two times a day beginning near the time of ovulation. Your doctor may want you to receive the medicine for up to eleven weeks.

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.

For all progestins, except for progesterone capsules for postmenopausal women: If you miss a dose of this medicine, take the missed dose 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.

For progesterone capsules for postmenopausal women: If you miss a dose of 200 mg of progesterone capsules at bedtime, take 100 mg in the morning then go back to your regular dosing schedule. If you take 300 mg of progesterone a day and you miss your morning and evening doses, you should not take the missed dose. Return to your regular dosing schedule.

Storage

Keep out of the reach of children.

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

Do not keep outdated medicine or medicine no longer needed.

Hypersensitivity Reaction

History of hypersensitivity to megestrol acetate or any component of the formulation.

Pregnancy

Known or suspected pregnancy.

Indinavir

Due to the significant decrease in the exposure of indinavir by megestrol acetate, administration of a higher dose of indinavir should be considered when coadministering with megestrol acetate [See Clinical Pharmacology (12.3)].

Zidovudine and Rifabutin

No dosage adjustment for zidovudine and rifabutin is needed when megestrol acetate is coadministered with these drugs [See Clinical Pharmacology (12.3)].

Mechanism of Action

Several investigators have reported on the appetite enhancing property of megestrol acetate and its possible use in cachexia. The precise mechanism by which megestrol acetate produces effects in anorexia and cachexia is unknown at the present time.

Pharmacokinetics

Absorption and Distribution

Mean plasma concentrations of megestrol acetate after administration of 625 mg (125 mg/mL) of Megace® ES oral suspension are equivalent under fed conditions to 800 mg (40 mg/mL) of megestrol acetate oral suspension in healthy volunteers.

In order to characterize the dose proportionality of Megace® ES, pharmacokinetic studies across a range of doses were conducted when administered under fasting and fed conditions. Pharmacokinetics of megestrol acetate was linear in the dosing range between 150 mg and 675 mg after Megace® ES administration regardless of meal condition. The mean peak plasma concentration (Cmax) and the mean area under the concentration time-curve (AUC) after a high fat meal were increased by 48% and 36%, respectively, compared to those under the fasting condition after 625 mg Megace® ES administration. This food effect is less than that seen for the original formulation, megestrol acetate 800 mg/20 mL, where a high fat meal significantly increased AUC and Cmax of megestrol acetate to 2-fold and 7-fold, respectively, compared to those under the fasting condition. There was no difference in safety following administration in the fed state, therefore Megace® ES could be taken without regard to meals.

Plasma steady state pharmacokinetics of megestrol acetate was evaluated in 10 adult, cachectic male adult patients with acquired immunodeficiency syndrome (AIDS) and an involuntary weight loss greater than 10% of baseline who received single oral doses of 800 mg/day of megestrol acetate oral suspension for 21 days. The Mean (±1SD) Cmax of megestrol acetate was 753 (±539) ng/mL. The mean AUC was 10476 (±7788) ng x hr/mL. Median Tmax value was five hours.

In another study, 24 asymptomatic HIV seropositive male adult subjects were dosed once daily with 750 mg of megestrol acetate oral suspension for 14 days. Mean Cmax and AUC values were 490 (±238) ng/mL and 6779 (±3048) hr x ng/mL, respectively. The median Tmax value was three hours. The mean Cmin value was 202 (±101) ng/mL. The mean % of fluctuation value was 107 (±40).

Metabolism and Excretion

The major route of drug elimination in humans is urine. When radio-labeled megestrol acetate was administered to humans in doses of 4 to 90 mg, the urinary excretion within 10 days ranged from 56.5% to 78.4% (mean 66.4%) and fecal excretion ranged from 7.7% to 30.3% (mean 19.8%). The total recovered radioactivity varied between 83.1% and 94.7% (mean 86.2%).

Megestrol acetate metabolites which were identified in urine constituted 5% to 8% of the dose administered. Respiratory excretion as labeled carbon dioxide and fat storage may have accounted for at least part of the radioactivity not found in urine and feces.

The mean elimination half-life of megestrol ranged from 20 to 50 hours in healthy subjects.

Specific Populations

The pharmacokinetics of megestrol acetate has not been studied in specific population, for example, pediatric, renal impairment, and hepatic impairment.

Drug Interactions

The effects of indinavir, zidovudine or rifabutin on the pharmacokinetics of megestrol acetate were not studied.

Zidovudine

Pharmacokinetic studies show that there are no significant alterations in exposure of zidovudine when megestrol acetate is administered with this drug.

Rifabutin

Pharmacokinetic studies show that there are no significant alterations in exposure of rifabutin when megestrol acetate is administered with this drug.

Indinavir

A pharmacokinetic study in healthy male subjects demonstrated that coadministration of megestrol acetate (675 mg for 14 days) and indinavir (single dose 800 mg) results in a significant decrease in the pharmacokinetic parameters (~32% for Cmax and ~21% for AUC) of indinavir.

How Supplied

Megace ES® oral suspension is a milky white, lemon-lime flavored oral suspension containing 125 mg of megestrol acetate per mL. Available in bottles of 150 mL (5 fl oz) NDC 63481-160-38.

Storage

Store Megace® ES oral suspension between 15° to 25° C (59° to 77° F) and dispense in a tight container. Protect from heat.

Safe Handling

Health Hazard Data

There is no threshold limit value established by OSHA, NIOSH, or ACGIH. Exposure or overdose at levels approaching recommended dosing levels could result in side effects described above [see Warnings and Precautions (5) and Adverse Reactions (6)]. Women at risk of pregnancy should avoid such exposure.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.