Impavido

Black Box Warnings

Do not administer to pregnant women; may cause fetal harm

Fetal death and teratogenicity occurred in animals administered at doses lower than the recommended human dose

Obtain a serum or urine pregnancy test in females of reproductive potential prior to prescribing

Advise females of reproductive potential to use effective contraception during therapy and for 5 months after therapy

Contraindications

Pregnancy (see Black Box Warnings)

Sjögren-Larsson syndrome

Hypersensitivity

Cautions

May cause fetal harm; do not use during pregnancy or become pregnancy within 5 months following therapy completion (see Black Box Warnings)

Causes impaired fertility in rats and reversible follicular atresia and diestrus in dogs; reduced viable sperm counts and impaired fertility in rats; effects on human fertility have not been studied

Vomiting and/or diarrhea commonly occur; encourage fluid intake to avoid volume depletion

Vomiting and/or diarrhea occurring during therapy may affect oral contraceptive absorption and thereby compromise their efficacy; advise females to use additional nonhormonal or alternative method(s) of effective contraception

Increased serum creatinine, ALT, AST, bilirubin reported; monitor

Thrombocytopenia reported; monitor platelets

Stevens-Johnson syndrome reported; discontinue if an exfoliative or bullous rash occurs

Impavido comes in 50 milligram (mg) tablets.

Your dose will depend on your body weight. If you weigh between 30 and 44 kg (66 to 96.8 pounds), the usual dose is one50 mg tablet, twice a day for 28 days.

If you weigh more than 96.8 pounds, your doctor may prescribe one 50 mg tablet, three times a day for 28 days.

You should always take Impavido with food.

Impavido Overdose

If you suspect an overdose, you should contact a poison control center or emergency room immediately.

You can get in touch with a poison control center at (800) 222-1222.

Missed Dose of Impavido

If you miss a dose of Impavido, try to take it as soon as you remember.

If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of the medication at the same time.

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

Contraindications

• Pregnant women.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

• Hypersensitivity to miltefosine or any ingredient in the formulation.1

• Sjögren-Larsson syndrome.1

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 Embryofetal toxicity, including death and teratogenicity, observed in animals that received miltefosine prior to mating, during early pregnancy, and during organogenesis at doses lower than the maximum recommended human dose.1

Do not use in pregnant women.1

Prior to prescribing for women of reproductive potential, obtain urine or serum pregnancy test.1 Advise women of reproductive potential to use effective contraception during and for 5 months after completion of treatment.1 If adverse GI effects occur in such patients receiving oral contraceptives, additional nonhormonal or alternative methods of effective contraception should be used.1

Sensitivity Reactions

Stevens-Johnson syndrome reported.1

Discontinue if an exfoliative or bullous rash occurs.1

General Precautions

Reproductive Effects

Impaired fertility observed in female rats; 1 reversible follicular atresia and diestrus observed in female dogs.1 Effects on fertility not adequately studied in female patients.1

Reduced viable sperm counts, impaired fertility, and testicular atrophy observed in male rats;1 these effects not fully reversed 10 weeks after miltefosine discontinued.1

Scrotal pain and decreased or absent ejaculation reported in male patients receiving miltefosine.1 Effects on fertility not adequately studied in male patients.1

Advise patients of animal fertility findings;1 advise patients that potential for impaired fertility in humans receiving miltefosine not adequately evaluated.1

GI Effects

Vomiting and/or diarrhea commonly occur during miltefosine therapy;1 vomiting reported in up to 48% of patients.1 2 3 5

Because vomiting and/or diarrhea may result in volume depletion, encourage fluid intake.1

Since GI absorption and efficacy of oral contraceptives may be affected by vomiting and/or diarrhea, women of reproductive potential should use additional nonhormonal or alternative methods of effective contraception if these adverse GI effects occur.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Hepatic Effects

Elevated hepatic aminotransferase (ALT, AST) and bilirubin concentrations observed in clinical trials evaluating miltefosine for treatment of visceral leishmaniasis.1

Monitor liver aminotransferases (ALT, AST) and bilirubin in patients receiving miltefosine.1

Renal Effects

Elevated Scr observed in clinical trials evaluating miltefosine for treatment of cutaneous, mucocutaneous, and visceral leishmaniasis.1

Monitor renal function weekly during and for 4 weeks after completion of miltefosine treatment.1

Hematologic Effects

Thrombocytopenia reported in patients receiving miltefosine for treatment of visceral leishmaniasis.1 Monitor platelet counts in patients being treated for visceral leishmaniasis.1

Specific Populations

Pregnancy

Category D.1

Do not use in pregnant women.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Embryofetal toxicity, including death and teratogenicity, observed in rats and rabbits receiving miltefosine during organogenesis;1 numerous visceral and skeletal fetal malformations observed in rats receiving miltefosine prior to mating through day 7 of pregnancy.1

Lactation

Not known if miltefosine distributed into human milk.1

Discontinue nursing or the drug.1

Avoid breast-feeding for 5 months after completion of miltefosine treatment.1

Pediatric Use

Safety and efficacy not established in children <12 years of age.1

Animal studies indicate juvenile rats are more sensitive to miltefosine-induced adverse effects, especially retinal degeneration and kidney effects, than adult rats.1

Geriatric Use

Clinical studies did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently than younger adults.1

Hepatic Impairment

Pharmacokinetics not studied in patients with hepatic impairment.1 Patients with ALT or AST concentrations ≥3 times ULN and bilirubin levels ≥2 times ULN were excluded from clinical studies.1

Renal Impairment

Pharmacokinetics not studied in patients with renal impairment.1 Patients with Scr or BUN levels ≥1.5 times ULN were excluded from clinical studies.1

Common Adverse Effects

Adverse GI effects (e.g., diarrhea, nausea, vomiting, abdominal pain, epigastralgia, decreased appetite),1 2 3 5 6 CNS effects (dizziness,1 5 6 headache,1 3 6 somnolence),1 motion sickness,1 3 asthenia,1 malaise,1 pyrexia,1 pruritus,1 5 lymphangitis,1 increased Scr,1 2 3 increased BUN,2 increased hepatic aminotransferases (ALT, AST).1 2 3

Does not markedly induce or inhibit activity of CYP isoenzymes in vitro or in animal studies.1

Potential for interaction with drug transporters not established.1

In the U.S.

• Impavido

Available Dosage Forms:

• Capsule

Therapeutic Class: Anti-Infective Agent

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

Allergies

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

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of miltefosine in children younger than 12 years of age. Safety and efficacy have not been established.

Geriatric

Although appropriate studies on the relationship of age to the effects of miltefosine have not been performed in the geriatric population, no geriatric-specific problems have been documented to date.

Pregnancy

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

Breast Feeding

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

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

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

Other Medical Problems

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

• Diarrhea or
• Kidney disease or
• Liver disease—Use with caution. May make these conditions worse.

• Sjögren-Larsson-Syndrome (a rare disease)—Should not be used in patients with this condition.

• It is used to treat a certain type of infection (leishmaniasis).

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take with food.
• Swallow whole. Do not chew, break, open, or melt.
• To gain the most benefit, do not miss doses.
• Keep taking Impavido as you have been told by your doctor or other health care provider, even if you feel well.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

Impavido® (Im-PA-vee-do)
(miltefosine)
Capsules

Read this Medication Guide before you receive Impavido. This information does not take the place of talking to your healthcare provider about you medical condition or treatment.

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

Impavido may cause serious risks to pregnancy:

• Do not take Impavido if you are pregnant. If you take Impavido during pregnancy, your baby is at risk for death or serious birth defects. • Women who can become pregnant should use effective birth control (contraception) during Impavido treatment and for 5 months after stopping Impavido treatment. Discuss with your healthcare provider which birth control method is right for you. • If you become pregnant while taking Impavido, tell your healthcare provider right away. Talk to your healthcare provider about taking part in the Impavido Pregnancy Registry. This is a study to learn how Impavido affects pregnancy and babies. You can enroll in this registry by calling 1-866-588-5405.

What is Impavido?

Impavido is prescription medicine used to treat certain types of leishmaniasis:

• visceral leishmaniasis (affecting your internal organs) • cutaneous leishmaniasis (affecting the skin) • mucosal leishmaniasis (affecting the nose, mouth and throat)

It is not known if Impavido is safe and effective in children under 12 years of age.

Who should not take Impavido? Do not take Impavido if you:

• are pregnant • have Sjögren-Larsson-Syndrome • are allergic to miltefosine or any of the ingredients in Impavido. See the end of this leaflet for a list of the ingredients in Impavido. • are a woman who can become pregnant and have not had a pregnancy test. Women who can get pregnant must have a urine or blood pregnancy test before taking Impavido. • are a woman who can become pregnant and you are not willing to use effective birth control during Impavido treatment and for 5 months after treatment

Before you take Impavido, tell your healthcare provider about all of your medical conditions, including if you:

• have kidney or liver problems. Your healthcare provider should do blood tests to check your kidneys and liver before you start, during and after your treatment with Impavido. • are pregnant or planning to become pregnant. Impavido may harm your unborn baby. • are breastfeeding or plan to breastfeed. It is not known if Impavido passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take Impavido. You should avoid breastfeeding while you take Impavido and for 5 months after you stop taking Impavido.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

How should I take Impavido?

• Take Impavido exactly as your healthcare provider tells you to. • Complete your full 28 day Impavido treatment. • Take Impavido capsules whole. Do not break, crush, dissolve, or chew Impavido before swallowing. • Take Impavido with food to help reduce stomach problems.

What are the possible side effects of Impavido?

Impavido may cause serious side effects, including:

See “What is the most important information I should know about Impavido?”

• Fertility problems in male and female rats and abnormal menstrual cycle in female dogs. It is not known if Impavido causes fertility problems in men or women • Testicular pain and absent or decreased ejaculation • Kidney and liver problems • Stomach problems. Impavido can cause vomiting, diarrhea, and dehydration. Call your healthcare provider right away if you have severe vomiting and diarrhea that does not go away. Drink a lot of water to help prevent dehydration while you are having vomiting and diarrhea. • Decreased effectiveness of oral contraceptive pills. Vomiting and diarrhea may cause your birth control pills to be less effective at preventing pregnancy. Use an extra method of birth control, such as male condoms with spermicide, until you are no longer having vomiting and diarrhea. • Decrease in platelets (which are blood cells that help blood clot). • Serious Skin Problems. Impavido can cause a serious skin problem called Stevens-Johnson Syndrome. If you develop a skin rash with blisters while taking Impavido, stop taking Impavido right away and call your healthcare provider.

The most common side effects of Impavido include: nausea, vomiting and diarrhea. Other side effects include abdominal pain, decreased appetite, dizziness, headache, sleepiness, skin itching, and abnormalities in liver or kidney tests.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Impavido. For more information, ask your healthcare provider.

You may report side effects to FDA at 1-800-FDA-1088.

How should I store Impavido?

• Store Impavido at room temperature between 68°F to 77°F (20°C to 25°C). • Protect Impavido from moisture.

Keep Impavido and all medicines out of the reach of children.

General information about the safe and effective use of Impavido.

Medicines are sometimes prescribed for purposes other than those listed in this Medication Guide. Do not use Impavido for a condition for which it was not prescribed. This Medication Guide summarizes the most important information about Impavido. If you would like more information, talk to your healthcare provider or pharmacist. You can ask your healthcare or pharmacist for information about Impavido that is written for health professionals. Do not give Impavido to other people, even if they have the same symptoms that you have. For more information, go to www.Impavido.com or www.dailymed.nlm.nih.gov, or call 1-866-588-5405.

What are the ingredients in Impavido?

Active ingredient: miltefosine

Inactive ingredients: colloidal silicon dioxide, microcrystalline cellulose, lactose monohydrate, talc, and magnesium stearate. The capsule shell contains gelatin, titanium dioxide, ferric oxide, and purified water.

Distributed by: Profounda, Inc.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Issued: Oct 2015

PR034

In animal studies, Impavido has caused birth defects and death of unborn offspring. It is not known whether these effects would occur in people. You should not use miltefosine you are pregnant.

You may need to have a negative pregnancy test before starting this treatment. Use effective birth control while you are taking Impavido and for at least 5 months after your treatment ends.

Take Impavido exactly as prescribed by your doctor. Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Take with food to lessen upset stomach.

Do not crush, chew, break, or dissolve a Impavido tablet. Swallow it whole.

Tell your doctor if you have any changes in weight. Miltefosine doses are based on weight (especially in children and teenagers), and any changes may affect the dose.

Vomiting or diarrhea can cause you to become dehydrated. This can lead to kidney failure while you are taking this medicine. Drink plenty of water each day while you are taking this medicine.

While using Impavido, you may need frequent blood tests. Your kidney function will need to be checked during treatment and for 4 weeks after you stop using this medicine.

Impavido is usually taken for 28 days in a row. Use this medicine for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared.

Store at room temperature away from moisture and heat. Keep each tablet in its blister pack until you are ready to take it.

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

Common side effects of Impavido include: nausea, diarrhea, increased serum creatinine, and vomiting. See below for a comprehensive list of adverse effects.

Applies to miltefosine: oral capsule

Along with its needed effects, miltefosine (the active ingredient contained in Impavido) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

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

Incidence not known

• Abdominal or stomach pain
• bloating or swelling of the face, arms, hands, lower legs, or feet
• bloody, black, or tarry stools
• chills or fever
• dizziness
• itching or rash
• pain in the scrotum
• pinpoint red spots on the skin
• smaller amount of semen ejaculated than usual
• severe diarrhea or vomiting
• unusual bleeding or bruising
• unusual tiredness or weakness
• yellow eyes or skin

Some side effects of miltefosine 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

• Decreased appetite
• diarrhea
• fever
• lack or loss of strength
• vomiting

Less common

• General feeling of discomfort or illness
• itching skin
• sleepiness or unusual drowsiness