Pronunciation:

sir-OH-li-mus

Brand Names:

• Rapamune

Dosage Forms:

• Tablet
• Solution

Warnings:

• Increased susceptibility to infection and the possible development of lymphoma and other malignancies may result from immunosuppression
  • Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression. Only physicians experienced in immunosuppressive therapy and management of renal transplant patients should use sirolimus. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.
• Liver Transplantation – Excess Mortality, Graft Loss, and Hepatic Artery Thrombosis (HAT)
  • The use of sirolimus in combination with tacrolimus was associated with excess mortality and graft loss in a study in de novo liver transplant patients. Many of these patients had evidence of infection at or near the time of death.
  • In this and another study in de novo liver transplant recipients, the use of sirolimus in combination with cyclosporine or tacrolimus was associated with an increase in HAT; most cases of HAT occurred within 30 days post-transplantation and most led to graft loss or death.
• Lung Transplantation – Bronchial Anastomotic Dehiscence
  • Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung transplant patients when sirolimus has been used as part of an immunosuppressive regimen.
• The safety and efficacy of sirolimus as immunosuppressive therapy have not been established in liver or lung transplant patients, and therefore, such use is not recommended .

Increased susceptibility to infection and the possible development of lymphoma and other malignancies may result from immunosuppression. Only physicians experienced in immunosuppressive therapy and management of renal transplant patients should prescribe sirolimus and they should have complete information requisite for the follow-up of the patient. The use of sirolimus in combination with cyclosporine or tacrolimus was associated with excess mortality, graft loss, and hepatic artery thrombosis in studies in de novo liver transplant patients. Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung transplant patients when sirolimus has been used as part of an immunosuppressive regimen. The safety and efficacy of sirolimus as immunosuppressive therapy have not been established in liver or lung transplant patients, and therefore, such use is not recommended .

Classifications:

Therapeutic—

Immune Suppressant

Uses of This Medicine:

Sirolimus belongs to a group of medicines known as immunosuppressive agents. It is used to lower the body's natural immunity in patients who receive kidney transplants.

When a patient receives an organ transplant, the body's white blood cells will try to get rid of (reject) the transplanted organ. Sirolimus works by preventing the white blood cells from getting rid of the transplanted organ.

Sirolimus is a very strong medicine. It can cause side effects that can be very serious, such as kidney problems. It may also reduce the body's ability to fight infections. You and your doctor should talk about the good this medicine will do as well as the risks of using it.

Sirolimus is available only with your doctor's prescription.

Before Using This Medicine:

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.

Children—

Appropriate studies have not been performed on the relationship of age to the effects of sirolimus in children below 13 years of age or in children considered to be at high immunologic risk. Safety and efficacy have not been established .

Older adults—

Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of sirolimus in the elderly. However, elderly patients are more likely to have liver and heart problems which may require caution in patients receiving sirolimus .

Pregnancy—

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

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.

Other medicines—

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Posaconazole
• Voriconazole

Other interactions—

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:

• Cancer or
• Hyperlipidemia (high amount of cholesterol and fats in the blood) or
• Lung disease (e.g., pneumonitis or pulmonary fibrosis)—Sirolimus can make these conditions worse.

• Chickenpox (including recent exposure) or
• Herpes zoster (shingles)—Risk of severe disease affecting other parts of the body.

• Infection—Sirolimus decreases the body's ability to fight infection.

• Liver transplantation—or
• Lung transplantation—Sirolimus is not recommended in liver or lung transplant patients.

Proper Use of This Medicine:

This medicine usually comes with patient information or directions. Read them carefully and make sure you understand them before taking this medicine. If you have any questions, ask your doctor .

Take this medicine only as directed by your doctor. Do not use more or less of it, and do not use it more often than your doctor ordered. The exact amount of medicine you need has been carefully worked out. Using too much will increase the risk of side effects, while using too little may lead to rejection of your transplanted kidney.

To help you remember to take your medicine, try to get into the habit of taking it at the same time each day. This will help sirolimus work better by keeping a constant amount in the blood.

Absorption of this medicine may be changed if you change your diet. This medicine should be taken consistently with respect to meals. You should not change the type or amount of food you eat unless you discuss it with your doctor .

Grapefruits and grapefruit juice may increase the effects of sirolimus by increasing the amount of this medicine in your body. You should not eat grapefruit or drink grapefruit juice while you are taking this medicine.

Do not stop taking this medicine without first checking with your doctor. You may have to take this medicine for the rest of your life to prevent your body from rejecting the transplant.

Sirolimus usually is used along with a corticosteroid (cortisone-like medicine) and cyclosporine (another immunosuppressive agent). Sirolimus should be taken 4 hours after cyclosporine modified oral solution (Neoral®) or cyclosporine modified capsules (Neoral®). If you have any questions about this, ask your doctor .

If you have been taking sirolimus together with cyclosporine for 2 to 4 months after your transplant, your doctor may want you to stop using cyclosporine and increase the dose of sirolimus. However, some patients (e.g., black patients or those with transplant rejection in the past) may need to continue using cyclosporine for up to one year after the transplant. Your doctor will tell you if you need to keep taking cyclosporine .

Sirolimus tablets should not be crushed, chewed, or split. If you are unable to take the tablet form, your doctor will give you an oral solution of sirolimus and be given instructions on how to take it .

Mix sirolimus oral solution with at least 2 ounces (¼ cup, 60 milliliters [mL]) of water or orange juice in a glass or plastic container. Stir the mixture well and drink it immediately. Then, rinse the container with at least 4 ounces (½ cup, 120 mL) of additional water or orange juice, stir it well, and drink it to make sure that all of the medicine is taken.

Dosing—

The dose of this medicine 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 this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

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

• For oral dosage form (oral solution or tablets):
  • To prevent kidney transplant rejection:
    • Adults and children 13 years of age and older weighing 88 pounds (40 kilograms) or more—The usual dose is 2 milligrams (mg) a day after an initial one-time dose of 6 mg. Some patients may require a dose of up to 5 mg a day after an initial one-time dose of 15 mg.
    • For children 13 years of age and older who weigh less than 88 pounds (40 kilograms)—The dose is based on body size. It is usually 1 mg per square meter of body surface area once a day after an initial one-time dose of 3 mg per square meter of body surface area.
    • For children up to 13 years of age—Use and dose must be determined by your doctor .

Storage—

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

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

Store tablets at room temperature. Store the oral liquid form in the refrigerator.

Precautions While Using This Medicine:

It is very important that your doctor check your progress at regular visits to make sure that this medicine is working properly and to check for unwanted effects.

While you are taking sirolimus, it is important to maintain good dental hygiene and see a dentist regularly for teeth cleaning.

Raw oysters or other shellfish may contain bacteria that can cause serious illness and possibly death. This is more likely to be a problem if these foods are eaten by patients with certain medical conditions. Even eating oysters from “clean” water or good restaurants does not guarantee that the oysters do not contain the bacteria. Eating raw shellfish is not a problem for most healthy people; however, patients with the following conditions may be at greater risk: cancer, immune disorders, organ transplantation, long-term corticosteroid use (as for asthma, arthritis, or organ transplantation), liver disease (including viral hepatitis), excess alcohol intake (2 to 3 drinks or more per day), diabetes, stomach problems (including stomach surgery and low stomach acid), and hemochromatosis (an iron disorder). Do not eat raw oysters or other shellfish while you are taking sirolimus. Be sure oysters and shellfish are fully cooked.

While you are being treated with sirolimus, and after you stop treatment with it, it is important to see your doctor about the immunizations (vaccinations) you should receive. Do not get any immunizations without your doctor's approval. Sirolimus may lower your body's resistance and there is a chance you might get the infection the immunization is meant to prevent. In addition, other persons living in your household should not take oral polio vaccine since there is a chance they could pass the polio virus on to you. Also, avoid other persons who have taken the oral polio vaccine. Do not get close to them, and do not stay in the same room with them for very long. If you cannot take these precautions, you should consider wearing a protective face mask that covers the nose and mouth.

Treatment with sirolimus may increase the chance of getting other infections. If you can, avoid people with colds or other infections. If you think you are getting a cold or other infection, check with your doctor .

This medicine may also increase your risk of bleeding. Check with your doctor immediately if you notice any unusual bleeding or bruising; black, tarry stools; blood in urine or stools; or pinpoint red spots on your skin .

Sirolimus may cause serious types of allergic reactions, especially when used with certain medicines. Tell your doctor right away if you have a rash; itching; large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs; trouble with breathing; or chest tightness while you are using this medicine .

Sirolimus may cause you to have a greater risk for getting cancer, especially skin cancer. When you begin taking this medicine:

• Stay out of direct sunlight, especially between the hours of 10:00 a.m. and 3:00 p.m., if possible.
• Wear protective clothing, including a hat. Also, wear sunglasses.
• Apply a sun block product that has a skin protection factor (SPF) of at least 15. Some patients may require a product with a higher SPF number, especially if they have a fair complexion. If you have any questions about this, check with your doctor.
• Apply a sun block lipstick that has an SPF of at least 15 to protect your lips.
• Do not use a sunlamp or tanning bed or booth .

Check with your doctor right away if you notice a new mole; a change in size, shape or color of an existing mole; or a mole that leaks fluid or bleeds.

Side Effects of This Medicine:

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

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

More common

Abdominal cramps or pain

accumulation of pus

anxiousness, unexplained

backache

black or red, tarry stools

bleeding from gums or nose

blindness

bloody or cloudy urine

blue lips and fingernails

blurred vision

body aches or pain

bone pain

bruising

burning or stinging of skin

burning while urinating

burning, dry, or itching eyes

burning, tingling, numbness, or pain in the hands, arms, feet, or legs

change in mental status

changes in skin color

chest pain

chills

cold hands and feet

cold sweats

confusion

convulsions (seizures)

cough; cough producing mucus; cough that sometimes produces a pink frothy sputum

coughing up blood

dark or bloody urine

deafness

decreased urge to urinate

decreased urine output

decreased vision

difficult, fast, noisy breathing sometimes with wheezing

difficulty in breathing or swallowing

difficulty speaking

dilated neck veins

discharge from eye

dizziness

drowsiness

dry mouth

ear congestion

earache

excessive tearing

extreme fatigue

eye pain

facial hair growth in females

fainting

faintness or lightheadedness when getting up from lying or sitting position

fast, slow, or irregular heartbeat

fatigue

feeling faint

feeling of warmth or heat

fever

flushed, dry skin

flushing or redness of skin, especially on face and neck

fractures

frequent urge to urinate

fruit-like breath odor

full or round face, neck, or trunk

general feeling of discomfort or illness

increased hunger

increased menstrual flow or vaginal bleeding

increased sweating

increased thirst

increased urination

irregular breathing

irritability

itching, pain, redness, swelling, tenderness, or warmth on skin

lab results that show problems with liver

lack or loss of appetite

large, flat, blue or purplish patches in the skin

lightheadedness

loss of consciousness

loss of sexual ability, desire, drive, or performance

loss of voice

lower back or side pain

lump in abdomen

menstrual irregularities

mood changes

muscle cramps in hands, arms, feet, legs, or face

muscle pain

muscle wasting

nasal congestion

nausea or vomiting

noisy breathing

numbness or tingling around lips, hands, or feet

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

pain, tenderness, swelling of foot or leg

painful blisters on trunk of body

painful cold sores or blisters on lips, nose, eyes, or genitals

painful or difficult urination

pale skin

paralysis

pinpoint red spots on skin

pounding or racing heartbeat or pulse

prolonged bleeding from cuts

pus in urine

rapid heartbeat

rapid, shallow breathing

rash

red or dark brown urine

redness or swelling in ear

redness, pain, swelling of eye, eyelid, or inner lining of eyelid

ringing in the ears

runny nose

sensation of pins and needles

severe constipation

severe vomiting

severe, sudden headache

shortness of breath

slurred speech

sneezing

sore mouth or tongue

sore throat

sores or white spots on lips or in mouth

stabbing pain

stomach pain or upset

stomachache

sudden decrease in amount of urine

sudden loss of coordination

sudden, severe weakness or numbness in arm or leg

sudden, unexplained shortness of breath

sweating

swelling of face, fingers, hands, ankles, feet, or lower legs

swollen glands

swollen, painful or tender lymph glands in neck, armpit, or groin

swollen, red, tender area of infection

tenderness, pain, swelling, warmth, skin discoloration, and prominent superficial veins over affected area

tightness in chest

tiredness

tremor

trouble breathing

ulcers on lips or in mouth

unusual bleeding or bruising

unusual tiredness or weakness

vision changes

weakness or heaviness of legs

weight gain, unusual

weight loss, unusual

wheezing

white patches in mouth and/or on tongue

yellow skin and eyes

Less common

Bloating

change is size, shape, or color of existing mole

darkened urine

hoarseness

mole that leaks fluid or bleeds

new mole

pains in stomach, side or abdomen, possibly radiating to the back

skin ulcer or sores

Incidence not known

Abnormal wound healing

hives

itching

large, hive-like swelling on face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs

nails loose or detached

puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue

swelling of arms or legs

yellow nails lacking a cuticle

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

Abdomen enlarged

abnormal vision

acne

belching

blistering, crusting, irritation, itching, or reddening of skin

burning feeling in chest or stomach

burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feeling

constipation

continuing ringing or buzzing or other unexplained noise in ears

cracked, dry, or scaly skin

crying

decrease in frequency of urination

decrease in height

decreased interest in sexual intercourse

degenerative disease of the joint

depersonalization

diarrhea

difficulty in moving

difficulty in passing urine (dribbling)

discouragement

dysphoria

ear pain

euphoria

excess air or gas in stomach or intestines

excessive muscle tone, muscle tension or tightness

fear

feeling sad or empty

headache

hearing loss

heartburn

inability to have or keep an erection

increase in heart rate

increased hair growth, especially on the face

increased urge to urinate during the night

indigestion

irritation in mouth

itching skin

joint pain or swelling

kidney pain

leg cramps

loss of bladder control

loss of energy or weakness

loss of interest or pleasure

loss of strength

lower abdominal pain

mental depression

muscle aches, pain, stiffness, or weakness

nervousness

pain

pain in back, ribs, arms, or legs

pain or burning in throat

pain or tenderness around eyes and cheekbones

paranoia

passing gas

pelvic pain

quick to react or overreact emotionally

rapid breathing

rapidly changing moods

inflammation, redness, or swelling of gums or mouth

shaking or trembling

shivering

sleepiness

sunken eyes

swelling

swelling of the scrotum

tender or enlarged gums

tenderness in stomach area

thickening of the skin

trouble concentrating

trouble in sleeping

waking to urinate at night

wrinkled skin

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.