Sirolimus – Uses, Dosage, Side Effects, Interaction

Sirolimus is macrocyclic antibiotic with potent immunosuppressive activity that is used alone or in combination with calcineurin inhibitors and corticosteroids to prevent cellular rejection after renal transplantation. Sirolimus therapy can be associated with mild serum enzyme elevations and it has been linked to rare instances of clinically apparent cholestatic liver injury.

Sirolimus is a natural macrocyclic lactone produced by the bacterium Streptomyces hygroscopicus, with immunosuppressant properties. In cells, sirolimus binds to the immunophilin FK Binding Protein-12 (FKBP-12) to generate an immunosuppressive complex that binds to and inhibits the activation of the mammalian Target Of Rapamycin (mTOR), a key regulatory kinase. This results in the inhibition of T lymphocyte activation and proliferation that occurs in response to antigenic and cytokine (IL-2, IL-4, and IL-15) stimulation and inhibition of antibody production. (NCI04)

Sirolimus is a macrolide lactam isolated from Streptomyces hygroscopicus consisting of a 29-membered ring containing 4 trans double bonds, three of which are conjugated. It is an antibiotic, immunosuppressive, and antineoplastic agent. It has a role as an immunosuppressive agent, an antineoplastic agent, an antibacterial drug, an mTOR inhibitor, a bacterial metabolite, an anticoronaviral agent, and a geroprotector. It is a cyclic acetal, a cyclic ketone, an ether, a secondary alcohol, an organic heterotricyclic compound, an antibiotic antifungal drug, and a macrolide lactam.

Mechanism of Action

Sirolimus works by inhibiting T-lymphocyte activation and proliferation stimulated by antigens and cytokines such as interleukin (IL)-2, IL-4, and IL-15. In target cells, sirolimus binds to the cytoplasmic receptor FK506-binding protein-12 (FKBP12), an immunophilin, to form an immunosuppressive complex. FKBP12-sirolimus complex binds to and inhibits the activation of the mammalian target of rapamycin (mTOR), which is a serine/threonine-specific protein kinase that regulates cell growth, proliferation, survival, mobility, and angiogenesis. mTOR regulates the downstream signalling pathways involved in cell survival, such as the phosphatidylinositol-3 kinase (PI3K)/Akt signalling pathway. Inhibition of mTOR leads to the suppression of cytokine-driven T-cell proliferation, thus the progression from the G1 to the S phase of the cell cycle is inhibited. Sirolimus also inhibits antibody production. _In vitro_, sirolimus and other mTOR inhibitors inhibit the production of certain growth factors that may affect angiogenesis, fibroblast proliferation, and vascular permeability. Lymphangioleiomyomatosis is a disorder that primarily affects the lungs. It is characterized by lung tissue infiltration, unregulated alveolar smooth muscle proliferation, and cystic destruction of parenchyma. Although infrequent, it occurs as a symptomatic pulmonary complication in tuberous sclerosis complex (TSC), which is an inherited disorder caused by mutations in TSC genes. Loss of functional TSC gene leads to the aberrant activation of the mTOR signalling pathway, resulting in cellular proliferation and release of lymphangiogenic growth factors. Sirolimus inhibits the activated mTOR pathway and proliferation of alveolar smooth muscle cell proliferation.

or

Sirolimus inhibits cytokine (Interleukin (IL)-2, IL-4, and IL-15) — stimulated T lymphocyte activation and proliferation; it also inhibits antibody production. This may occur through the formation of an immunosuppressive complex with FK Binding Protein-12 (FKBP-12). Although the sirolimus-(FKBP-12) complex is inactive against calcineurin activity, the complex binds to and inhibits activation of a key regulatory kinase, the mammalian Target of Rapamycin (mTOR). This is believed to suppress cytokine-driven T-cell proliferation, inhibiting cell cycle progression from the G, to S phase.

Sirolimus is an immunosuppressant drug with antifungal and antitumor effects. In animal models, sirolimus prolonged allograft survival following various organ transplants and reversed an acute rejection of heart and kidney allografts in rats. Upon oral administration of 2 mg/day and 5 mg/day, sirolimus significantly reduced the incidence of organ rejection in low- to moderate-immunologic risk renal transplant patients at six months following transplantation compared with either azathioprine or placebo. In some studies, the immunosuppressive effect of sirolimus lasted up to six months after discontinuation of therapy: this tolerization effect is alloantigen-specific. Sirolimus potently inhibits antigen-induced proliferation of T cells, B cells, and antibody production. In rodent models of autoimmune disease, sirolimus suppressed immune-mediated events associated with systemic lupus erythematosus, collagen-induced arthritis, autoimmune type I diabetes, autoimmune myocarditis, experimental allergic encephalomyelitis, graft-versus-host disease, and autoimmune uveoretinitis.

Indications

  • Sirolimus is indicated for the prophylaxis of organ rejection in patients aged 13 years or older receiving renal transplants. In patients at low-to moderate-immunologic risk, it is recommended that sirolimus be used initially in a regimen with [cyclosporine] and corticosteroids; cyclosporine should be withdrawn two to four months after transplantation. In patients at high-immunologic risk (defined as Black recipients and/or repeat renal transplant recipients who lost a previous allograft for immunologic reasons and/or patients with high panel-reactive antibodies [PRA; peak PRA level > 80%]), it is recommended that sirolimus be used in combination with cyclosporine and corticosteroids for the first year following transplantation. It is also used to treat lymphangioleiomyomatosis. In the US, albumin-bound sirolimus for intravenous injection is indicated for the treatment of adult patients with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor (PEComa). In Europe, it is recommended that sirolimus for the prophylaxis of organ rejection in renal transplants is used in combination with cyclosporin microemulsion and corticosteroids for two to three months. Sirolimus may be continued as maintenance therapy with corticosteroids only if cyclosporin microemulsion can be progressively discontinued.
  • Sirolimus is a macrocyclic antibiotic with potent immunosuppressive activity that is used alone or in combination with calcineurin inhibitors and corticosteroids to prevent cellular rejection after renal transplantation.
  • Sirolimus protein-bound particles are approved to treat adults with:  Perivascular epithelioid cell tumors that are metastatic or cannot be removed by surgery. Sirolimus protein-bound particles are a form of sirolimus contained in nanoparticles (very tiny particles of protein). The drug is also called nanoparticle albumin-bound rapamycin. This form may work better than other forms of sirolimus and have fewer side effects. Sirolimus protein-bound particles are also being studied in the treatment of other types of cancer.
  • Rapamune is indicated for the prophylaxis of organ rejection in adult patients at low to the moderate immunological risk of receiving a renal transplant. It is recommended that Rapamune be used initially in combination with ciclosporin microemulsion and corticosteroids for 2 to 3 months. Rapamune may be continued as maintenance therapy with corticosteroids only if ciclosporin microemulsion can be progressively discontinued.
  • Rapamune is indicated for the treatment of patients with sporadic lymphangioleiomyomatosis with moderate lung disease or declining lung function.
  • Prevention of arteriovenous access dysfunction
  • Treatment of chronic non-infectious uveitis
  • Sirolimus is indicated for the prevention of rejection of transplanted kidney allografts. It is recommended that sirolimus be used in a regimen with cyclosporine and corticosteroids.
  • Angiofibromas of the face
  • Chordomas
  • Graft Versus Host Disease (cGvHD)
  • Heart Transplant Rejection
  • Liver Transplant Rejection
  • Lung Transplant Rejection
  • Lymphangioleiomyomatosis (LAM)
  • Renal Angiomyolipomas
  • Transplanted Organ Rejection
  • Metastatic malignant Perivascular Epithelioid Cell Neoplasms
  • Unresectable, locally advanced malignant Perivascular Epithelioid Cell Neoplasms

Use in Cancer

Sirolimus protein-bound particles are approved to treat adults with:

Sirolimus protein-bound particles are a form of sirolimus contained in nanoparticles (very tiny particles of protein). The drug is also called nanoparticle albumin-bound rapamycin. This form may work better than other forms of sirolimus and have fewer side effects.

Sirolimus protein-bound particles are also being studied in the treatment of other types of cancer.

Contraindications

  • an unusual viral infection called cytomegalovirus infection
  • pneumonia with a fungus called Pneumocystis jirovecii
  • a bad infection
  • cancer or malignancy
  • high cholesterol
  • high amount of triglyceride in the blood
  • excessive fat in the blood
  • high blood pressure
  • fluid in the covering of the heart or pericardium
  • escape of fluid into the lungs
  • liver problems
  • decreased kidney function
  • male infertility
  • visible water retention
  • fluid retention in the legs, feet, arms or hands
  • ascites
  • elevation of proteins in the urine
  • impaired wound healing
  • pregnancy
  • a patient who is producing milk and breastfeeding
  • malignant lymphoma
  • liver transplant
  • lung transplant
  • a blood clot in the liver after a liver transplant
  • a bronchial anastomotic dehiscence where the transplanted lung surgical connection comes apart
  • lung tissue problem
  • progressive multifocal leukoencephalopathy, a type of brain infection
  • lymphedema, or swelling due to blockage of lymph nodes
  • skin cancer
  • kidney problems due to BK polyomavirus
  • Ascites (fluid in the stomach) or
  • Blood clotting problems (eg, thrombotic microangiopathy, thrombotic thrombocytopenic purpura) or
  • Heart disease (eg, pericardial effusion) or
  • Hyperlipidemia (high amount of cholesterol and fats in the blood) or
  • Infection (eg, bacteria, fungus, virus) or
  • Lung disease (eg, bronchiolitis obliterans organizing pneumonia [BOOP], pleural effusion, pneumonitis, pulmonary fibrosis) or
  • Lymphoma (cancer of the lymph glands) or
  • Peripheral edema (swelling of the hands, ankles, or feet) or
  • Proteinuria (protein in the urine) or
  • Skin cancer, history of—Use with caution. This may make these conditions worse.
  • Liver disease—Use with caution. You may require a smaller dose.
  • Liver transplantation or
  • Lung transplantation—Use is not recommended in patients with these conditions.

Dosage

Strengths: 1 mg/mL; 1 mg; 2 mg; 0.5 mg

Organ Transplant – Rejection Prophylaxis

FOR PATIENTS AT LOW TO MODERATE IMMUNOLOGIC RISK:
Dosing by body weight:

  • Less than 40 kg:
  • Loading dose: 3 mg/m2 on day 1
  • Maintenance: 1 mg/m2 once daily
  • Greater than or equal to 40 kg:
  • Loading dose: 6 mg orally on day 1
  • Maintenance: 2 mg orally once daily

IN PATIENTS AT HIGH IMMUNOLOGIC RISK (defined as Black transplant recipients and/or repeat renal transplant recipients who lost a previous allograft for immunologic reason and/or patients with high-panel reactive antibodies [PRA; peak PRA level greater than 80%]):

  • For patients receiving sirolimus with cyclosporine: Loading Dose: Up to 15 mg on day one post-transplantation
  • Maintenance Dose: Beginning on day 2, an initial maintenance dose of 5 mg/day should be given. A trough level should be obtained between days 5 and 7, and the daily dose of sirolimus should be adjusted thereafter.
  • Antibody induction therapy may be used.
  • It is recommended that this sirolimus be used in a regimen with cyclosporine and corticosteroids.
  • Sirolimus should be taken consistently with or without food.
  • Once the sirolimus maintenance dose is adjusted, patients should continue on the new maintenance dose for at least 7 to 14 days before further dosage adjustment with concentration monitoring.

MAINTENANCE THERAPY AFTER WITHDRAWAL OF CYCLOSPORINE:

  • Cyclosporine withdrawal is not recommended in high-immunological risk patients. Following 2 to 4 months of combined therapy, withdrawal of cyclosporine may be considered in low-to-moderate-risk patients. Cyclosporine should be discontinued over 4 to 8 weeks, and a necessary increase in the dosage of sirolimus (up to 4-fold) should be anticipated due to the removal of metabolic inhibition by cyclosporine and to maintain of adequate immunosuppressive effects. -Dose-adjusted trough target concentrations are typically 16 to 24 ng/mL for the first year post-transplant and 12 to 20 ng/mL thereafter (measured by chromatographic methodology).

Pulmonary Lymphangioleiomyomatosis

  • Initial dose: 2 mg/day
  • Sirolimus whole blood trough concentrations should be measured in 10 to 20 days, with dosage adjustment to maintain concentrations between 5 and 15 ng/mL.
  • This drug should be taken consistently with or without food.

Pediatric Dose for Organ Transplant – Rejection Prophylaxis

FOR PATIENTS AT LOW TO MODERATE IMMUNOLOGIC RISK:
Greater than or equal to 13 years of age: Dosing by body weight:

  • Less than 40 kg:
  • Loading dose: 3 mg/m2 on day 1
  • Maintenance: 1 mg/m2 once daily
  • Greater than or equal to 40 kg:
  • Loading dose: 6 mg orally on day 1
  • Maintenance: 2 mg orally once daily

Dose Adjustments

  • Sirolimus dosages should be adjusted to maintain trough concentrations within the desired range based on risk and concomitant therapy. Maximum daily dose: 40 mg. The dosage should be adjusted at intervals of 7 to 14 days to account for the long half-life of sirolimus. In general, dose proportionality may be assumed. The new sirolimus dose equals the current dose multiplied by (target concentration/current concentration).
  • If a large dose increase is required, consider the loading dose calculated as: Loading dose equals (new maintenance dose minus current maintenance dose) multiplied by 3.
  • The maximum dose in one day: is 40 mg
  • If the required dose is greater than 40 mg (due to the loading dose), then the dose should be divided over 2 days. Serum concentrations should not be used as the sole basis for dosage adjustment. Clinical signs/symptoms, tissue biopsy, and laboratory parameters should also be monitored.

Administration advice:

  • This drug should be administered as soon as possible after transplantation.
  • Tablets should be swallowed whole and not crushed, chewed, or split.
  • This drug should be taken consistently with or without food. Patients unable to take oral tablets should be prescribed the oral solution.
  • It is recommended that this drug be taken 4 hours after administration of cyclosporine.
  • This drug should not be taken with grapefruit juice.

Side Effects

The Most Common

  • stomach pain
  • headache
  • constipation
  • diarrhea
  • nausea
  • joint pain
  • unusual bleeding or bruising
  • cough
  • swollen, red, cracked, scaly skin
  • hives
  • rash
  • itching
  • difficulty breathing or swallowing
  • swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs
  • hoarseness

More common

  • Accumulation of pus
  • anxiousness, unexplained
  • backache
  • black or red, tarry stools
  • bleeding from the gums or nose
  • blurred vision
  • body aches or pain
  • bone pain
  • bruising
  • burning or stinging of the 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
  • confusion
  • cough
  • dark or bloody urine
  • deafness
  • decreased urine output
  • decreased vision
  • difficulty with breathing or swallowing
  • dilated neck veins
  • discharge from the eyes
  • dizziness
  • drowsiness
  • dry mouth
  • earache
  • excessive tearing
  • eye pain
  • facial hair growth in females
  • faintness or lightheadedness when getting up from lying or sitting position
  • fast, slow, or irregular heartbeat
  • fever
  • flushing or redness of the skin, especially on the face and neck
  • general feeling of discomfort or illness
  • increased hunger
  • increased menstrual flow or vaginal bleeding
  • itching, pain, redness, swelling, tenderness, or warmth on the skin
  • lack or loss of appetite
  • large, flat, blue, or purplish patches in the skin
  • loss of sexual ability, desire, drive, or performance
  • loss of voice
  • muscle pain
  • nasal congestion
  • nausea or vomiting
  • numbness or tingling around the lips, hands, or feet
  • pain in the chest, groin, or legs, especially the calves
  • painful cold sores or blisters on the lips, nose, eyes, or genitals
  • pale skin
  • prolonged bleeding from cuts
  • rapid heartbeat
  • rash
  • red or dark brown urine
  • redness or swelling in the ear
  • redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid
  • ringing in the ears
  • runny nose
  • seizures
  • sensation of pins and needles
  • severe constipation
  • severe vomiting
  • severe, sudden headache
  • slurred speech
  • sore throat
  • sores or white spots on the lips or in the mouth
  • stomach cramps, pain, or upset
  • sudden decrease in the amount of urine
  • sudden loss of coordination
  • sudden, severe weakness or numbness in the arm or leg
  • sweating
  • swollen, painful, or tender lymph glands in the neck, armpit, or groin
  • tenderness, pain, swelling, warmth, skin discoloration, and prominent superficial veins over the affected area
  • tremor
  • ulcers on the lips or in the mouth
  • unusual tiredness or weakness
  • vision changes
  • weakness or heaviness of the legs
  • white patches in the mouth or on the tongue
  • yellow skin and eyes

Rare

  • Bloating
  • change in size, shape, or color of an existing mole
  • hoarseness
  • a mole that leaks fluid or bleeds
  • new mole
  • pains in the stomach, side or abdomen, possibly radiating to the back
  • skin ulcer or sores
  • Abnormal wound healing
  • headache
  • hives or itching
  • large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
  • nails lose or detached
  • puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
  • swelling of the arms or legs
  • yellow nails lacking a cuticle
  • Abnormal vision
  • acne
  • belching
  • blistering, crusting, irritation, itching, or reddening of the skin
  • burning feeling in the chest or stomach
  • burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling feeling
  • constipation
  • continuing ringing or buzzing or other unexplained noise in the ears
  • cracked, dry, or scaly skin
  • crying
  • decrease in frequency of urination
  • degenerative disease of the joint
  • depersonalization
  • diarrhea
  • difficulty with moving
  • difficulty with passing urine (dribbling)
  • dysphoria
  • ear pain
  • enlarged abdomen or stomach
  • euphoria
  • excess air or gas in the stomach or intestines
  • excessive muscle tone, muscle tension or tightness
  • fear
  • feeling sad or empty
  • 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

Drug interaction

Pregnancy and Lactation

AU TGA pregnancy category: C
US FDA pregnancy category: C

Pregnancy

Based on animal studies and the mechanism of action, FYARRO can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. Although there are no data on the use of FYARRO in pregnant women, there are limited data on the use of sirolimus during pregnancy. In animal studies, oral sirolimus was embryo/fetotoxic in rats [see Data] at sub-therapeutic doses. Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Lactation

There are no data on the presence of FYARRO in human milk or its effects on the breastfed child or on milk production. It is not known whether sirolimus is present in human milk. There are no data on its effects on the breastfed infant or milk production. The pharmacokinetic and safety profiles of sirolimus in infants are not known. Sirolimus is present in the milk of lactating rats. There is potential for serious adverse effects from sirolimus in breastfed infants based on the mechanism of action [see Clinical Pharmacology. Because of the potential for serious adverse reactions in breastfed infants from FYARRO, advise women not to breastfeed during treatment with FYARRO and for 2 weeks after the last dose.

To use the bottles of solution, follow these steps:

  • Open the solution bottle. On first use, insert the plastic tube with stopper tightly into the bottle until it is even with the top of the bottle. Do not remove from the bottle once inserted.
  • For each use, tightly insert one of the amber syringes, with the plunger fully pushed in, into the opening in the plastic tube.
  • Draw up the amount of solution your doctor has prescribed by gently pulling out the plunger of the syringe until the bottom of the black line of the plunger is even with the correct mark on the syringe. Keep the bottle upright. If bubbles form in the syringe, empty the syringe into the bottle and repeat this step.
  • Empty the syringe into a glass or plastic cup containing at least 2 ounces (60 milliliters [1/4 cup]) of water or orange juice. Do not use apple juice, grapefruit juice, or other liquids. Stir vigorously for 1 minute and drink immediately.
  • Refill the cup with at least 4 ounces (120 milliliters [1/2 cup]) of water or orange juice. Stir vigorously and drink the rinse solution.
  • Dispose of the used syringe.

If you need to carry a filled syringe with you, snap a cap onto the syringe and put the syringe in the carrying case. Use the medication in the syringe within 24 hours.

Precautions

It is very important that your doctor check your or your child’s progress at regular visits to make sure that this medicine is working properly. Blood and urine tests may be needed to check for unwanted effects.

Using this medicine while you are pregnant can harm your unborn baby. Use an effective form of birth control to keep from getting pregnant, and keep using it for at least 12 weeks after you stop taking sirolimus. If you think you have become pregnant while using the medicine, tell your doctor right away.

If you are planning to have children, talk with your doctor before using this medicine. Some men and women using this medicine have become infertile (unable to have children).

Using this medicine may increase your risk of getting skin cancer or cancer of the lymph system (lymphoma). Talk to your doctor if you have concerns about this risk.

This medicine may increase your risk of developing infections. Avoid being near people who are sick while you are using this medicine. Wash your hands often. Tell your doctor if you have any kind of infection before you start using this medicine. Tell your doctor if you have ever had an infection that would not go away or an infection that kept coming back.

Sirolimus may cause serious types of allergic reactions, including anaphylaxis,, which can be life-threatening and require immediate medical attention. Call your doctor right away if you or your child has a rash, itching, red, swollen skin, trouble breathing, trouble swallowing, or chest tightness while you are using this medicine.

Sirolimus may cause a serious type of allergic reaction called angioedema. This may occur more often when it is used with certain heart and blood pressure medicines called ACE inhibitors (eg, captopril [Capoten®], enalapril [Vasotec®], fosinopril [Monopril®], quinapril [Accupril®], ramipril [Altace®]). Check with your doctor right away if you have a rash, itching, a large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or genitals, trouble breathing, or chest tightness while you are using this medicine.

This medicine may also increase your risk of bleeding and cause delay in wound healing. Stay away from rough sports or other situations where you could be bruised, cut, or injured. Brush and floss your teeth gently. Be careful when using sharp objects, including razors and fingernail clippers. Check with your doctor immediately if you or your child notice any unusual bleeding or bruising, black, tarry stools, blood in the urine or stools, or pinpoint red spots on your skin.

This medicine may increase your cholesterol and fats in the blood. If this condition occurs, your doctor may give you or your child some medicines that can lower the amount of cholesterol and fats in the blood.

This medicine may increase your risk of developing a rare and serious virus infection called BK virus-associated nephropathy (BKVAN). The BK virus may affect how your kidneys work and cause a transplanted kidney to fail. Check with your doctor right away if you or your child has bloody urine, a decreased frequency or amount of urine, increased thirst, loss of appetite, lower back or side pain, nausea, swelling of the face, fingers, or lower legs, trouble breathing, unusual tiredness or weakness, vomiting, or weight gain.

This medicine may cause a serious lung problem called interstitial lung disease or non-infectious pneumonitis. Check with your doctor right away if you have chest pain, chills, cough, fever, or trouble breathing.

This medicine may increase your risk of developing a serious and rare brain infection called progressive multifocal leukoencephalopathy (PML). Check with your doctor right away if you or your child has vision changes, loss of coordination, clumsiness, confusion, memory loss, difficulty speaking or understanding what others say, and weakness in the legs.

This medicine may make your skin more sensitive to sunlight and can increase your risk of having skin cancer. Use a sunscreen when you are outdoors and avoid sunlamps and tanning beds.

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 (vaccines) without your doctor’s approval. Sirolimus may lower your body’s resistance and there is a chance you might get the infection the vaccine is meant to prevent. In addition, you should not be around other persons living in your household who receive live virus vaccines because there is a chance they could pass the virus on to you. Some examples of live vaccines include measles, mumps, influenza (nasal flu vaccine), poliovirus (oral form), rotavirus, and rubella. Do not get close to them and do not stay in the same room with them for very long. If you have questions about this, talk to your doctor.

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.

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.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal (eg, St. John’s wort) or vitamin supplements.

What special precautions should I follow?

Before taking sirolimus,

  • tell your doctor and pharmacist if you are allergic to sirolimus, any other medications, or any of the ingredients in sirolimus tablets or solution. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, and nutritional supplements you are taking. Be sure to mention any of the following: aminoglycoside antibiotics such as amikacin, gentamicin, kanamycin, neomycin (Neo-Fradin, Neo-Rx), streptomycin, and tobramycin (Tobi); amphotericin B (Abelcet, AmBisome, Amphocin, Fungizone); angiotensin-converting enzyme (ACE) inhibitors such as benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altace), and trandolapril (Mavik); antifungals such as clotrimazole (Lotrimin), fluconazole (Diflucan), itraconazole (Sporanox), ketoconazole (Nizoral), and voriconazole (Vfend); bromocriptine (Cycloset, Parlodel); cimetidine (Tagamet); cisapride (Propulsid) (not available in the U.S.); clarithromycin (Biaxin); danazol (Danocrine); diltiazem (Cardizem, Dilacor, Tiazac); erythromycin (E.E.S., E-Mycin, Erythrocin); HIV protease inhibitors such as indinavir (Crixivan) and ritonavir (Norvir, in Kaletra); certain medications for cholesterol; medications for seizures such as carbamazepine (Tegretol), phenobarbital (Luminal), and phenytoin (Dilantin); metoclopramide (Reglan); nicardipine (Cardene); rifabutin (Mycobutin); rifampin (Rifadin, Rimactane); rifapentine (Priftin); telithromycin (Ketek); troleandomycin (TAO) (not available in the U.S.); and verapamil (Calan, Covera, Isoptin, Verelan). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • if you are taking cyclosporine (Neoral) soft gelatin capsules or solution, take them 4 hours before sirolimus.
  • tell your doctor what herbal products you are taking, especially St. John’s wort.
  • tell your doctor if you have or have ever had high cholesterol or triglycerides or liver disease.
  • tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. You should use an effective method of birth control before starting to take sirolimus, while taking sirolimus, and for 12 weeks after stopping sirolimus. If you become pregnant while taking sirolimus, call your doctor.
  • if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking sirolimus.
  • do not have any vaccinations without talking to your doctor.

References

  1. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021083s059,021110s076lbl.pdf
  2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021110s058lbl.pdf
  3. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021083s067,021110s085lbl.pdf
  4. https://pubchem.ncbi.nlm.nih.gov/compound/Sirolimus#section=Information-Sources
  5. https://www.cancer.gov/about-cancer/treatment/drugs/sirolimus-protein-bound-particles
  6. https://medlineplus.gov/druginfo/meds/a602026.html
  7. https://go.drugbank.com/drugs/DB00877
  8. https://www.drugs.com/pregnancy/sirolimus.html
  9. https://en.wikipedia.org/wiki/Sirolimus
  10. https://www.mayoclinic.org/drugs-supplements/sirolimus-oral-route/side-effects/drg-20068199?
  11. https://www.webmd.com/drugs/2/drug-17701-5301/sirolimus-oral/sirolimus-oral/details/list-contraindications
  12. ChEMBL
    http://www.ebi.ac.uk/Information/termsofuse.html
    https://www.ebi.ac.uk/chembl/compound_report_card/CHEMBL413/
    ChEMBL Protein Target Tree
    https://www.ebi.ac.uk/chembl/g/#browse/targets
  13. Chemical Probes Portal
    Rapamycin
    https://www.chemicalprobes.org/rapamycin
  14. Drug Gene Interaction database (DGIdb)
    http://www.dgidb.org/downloads
    SIROLIMUS
    https://www.dgidb.org/drugs/SIROLIMUS
  15. DrugBank
    https://www.drugbank.ca/legal/terms_of_use
    Sirolimus
    https://www.drugbank.ca/drugs/DB00877
  16. IUPHAR/BPS Guide to PHARMACOLOGY
    https://www.guidetopharmacology.org/about.jsp#license
    sirolimus
    https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6031
    https://www.guidetopharmacology.org/targets.jsp
  17. Therapeutic Target Database (TTD)
    Sirolimus
    http://idrblab.net/ttd/data/drug/details/D03LJR
  18. CAS Common Chemistry
    https://creativecommons.org/licenses/by-nc/4.0/
    Rapamycin
    https://commonchemistry.cas.org/detail?cas_rn=53123-88-9
  19. ChemIDplus
    LICENSE
    https://www.nlm.nih.gov/copyright.html
    Sirolimus [USAN:INN:BAN]
    https://chem.nlm.nih.gov/chemidplus/sid/0053123889
    https://chem.nlm.nih.gov/chemidplus/
  20. EPA DSSTox
    LICENSE
    https://www.epa.gov/privacy/privacy-act-laws-policies-and-resources
    Sirolimus
    https://comptox.epa.gov/dashboard/DTXSID5023582
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  21. European Chemicals Agency (ECHA)
    https://echa.europa.eu/web/guest/legal-notice
    https://echa.europa.eu/substance-information/-/substanceinfo/100.107.147
    Rapamycin
    https://echa.europa.eu/information-on-chemicals/cl-inventory-database/-/discli/details/4633
  22. FDA Global Substance Registration System (GSRS)
    https://www.fda.gov/about-fda/about-website/website-policies#linking
    SIROLIMUS
    https://gsrs.ncats.nih.gov/ginas/app/beta/substances/W36ZG6FT64
  23. Hazardous Substances Data Bank (HSDB)
    SIROLIMUS
    https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7284
  24. Human Metabolome Database (HMDB)
    http://www.hmdb.ca/citing
    Sirolimus
    http://www.hmdb.ca/metabolites/HMDB0015015
  25. CCSbase
    https://ccsbase.net/
  26. ChEBI
    Sirolimus
    http://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:9168
    ChEBI Ontology
    http://www.ebi.ac.uk/chebi/userManualForward.do#ChEBI%20Ontology
  27. FDA Pharm Classes
    https://www.fda.gov/about-fda/about-website/website-policies#linking
    SIROLIMUS
    https://dailymed.nlm.nih.gov/dailymed/browse-drug-classes.cfm
    FDA Pharmacological Classification
    https://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/ucm162549.htm
  28. LiverTox
    LICENSE
    https://www.nlm.nih.gov/copyright.html
    Sirolimus
    https://www.ncbi.nlm.nih.gov/books/n/livertox/Sirolimus/
  29. LOTUS – the natural products occurrence database
    https://lotus.nprod.net/
    sirolimus
    https://www.wikidata.org/wiki/Q32089
    LOTUS Tree
    https://lotus.naturalproducts.net/
  30. NCI Thesaurus (NCIt)
    https://www.cancer.gov/policies/copyright-reuse
    https://ncithesaurus.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&ns=ncit&code=C1212
    NCI Thesaurus Tree
    https://ncit.nci.nih.gov
  31. NORMAN Suspect List Exchange
    https://creativecommons.org/licenses/by/4.0/
    https://www.norman-network.com/nds/SLE/
  32. ClinicalTrials.gov
    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
    https://clinicaltrials.gov/
  33. DailyMed
    LICENSE
    https://www.nlm.nih.gov/copyright.html
    SIROLIMUS
    https://dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=SIROLIMUS
  34. Nature Chemical Biology
    https://pubchem.ncbi.nlm.nih.gov/substance/7982025
    https://pubchem.ncbi.nlm.nih.gov/substance/24430811
    https://pubchem.ncbi.nlm.nih.gov/substance/26701762
    https://pubchem.ncbi.nlm.nih.gov/substance/49635682
    https://pubchem.ncbi.nlm.nih.gov/substance/49815675
    https://pubchem.ncbi.nlm.nih.gov/substance/441325678
    https://pubchem.ncbi.nlm.nih.gov/substance/445470554
  35. The Natural Products Atlas
    https://www.npatlas.org/terms
    Rapamycin
    https://www.npatlas.org/explore/compounds/NPA000414
    The Natural Products Atlas Classification
    https://www.npatlas.org/
  36. European Medicines Agency (EMA)
    https://www.ema.europa.eu/en/about-us/legal-notice
    Rapamune (EMEA/H/C/000273)
    https://www.ema.europa.eu/en/medicines/human/EPAR/rapamune
    Sirolimus (P/0395/2017)
    https://www.ema.europa.eu/en/medicines/human/paediatric-investigation-plans/emea-002213-pip01-17
    Sirolimus (P/0336/2021)
    https://www.ema.europa.eu/en/medicines/human/paediatric-investigation-plans/emea-001416-pip01-12-m03
  37. EU Clinical Trials Register
    https://www.clinicaltrialsregister.eu/
  38. FDA Orange Book
    https://www.fda.gov/about-fda/about-website/website-policies#linking
    https://www.fda.gov/drugs/drug-approvals-and-databases/approved-drug-products-therapeutic-equivalence-evaluations-orange-book
  39. LIPID MAPS
    Sirolimus
    https://lipidmaps.org/databases/lmsd/LMPK06000003
    Lipid Classification
    https://www.lipidmaps.org/
  40. WHO Anatomical Therapeutic Chemical (ATC) Classification
    https://www.whocc.no/copyright_disclaimer/
    https://www.whocc.no/atc/
    ATC Code
    https://www.whocc.no/atc_ddd_index/
  41. FDA Medication Guides
    https://www.fda.gov/about-fda/about-website/website-policies#linking
    Rapamune
    https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=medguide.page
  42. National Drug Code (NDC) Directory
    https://www.fda.gov/about-fda/about-website/website-policies#linking
    SIROLIMUS
    https://www.fda.gov/drugs/drug-approvals-and-databases/national-drug-code-directory
  43. Haz-Map, Information on Hazardous Chemicals and Occupational Diseases
    https://haz-map.com/About
    Sirolimus
    https://haz-map.com/Agents/7046
  44. NCI Cancer Drugs
    LICENSE
    https://www.cancer.gov/policies/copyright-reuse
    Fyarro (Sirolimus Protein-Bound Particles)
    https://www.cancer.gov/about-cancer/treatment/drugs/sirolimus-protein-bound-particles
  45. NIPH Clinical Trials Search of Japan
    https://rctportal.niph.go.jp/en/
  46. NLM RxNorm Terminology
    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
    sirolimus
    https://rxnav.nlm.nih.gov/id/rxnorm/35302
  47. Protein Data Bank in Europe (PDBe)
    http://www.ebi.ac.uk/pdbe-srv/pdbechem/chemicalCompound/show/RAP
  48. PubChem
    https://pubchem.ncbi.nlm.nih.gov
  49. RCSB Protein Data Bank (RCSB PDB)
    https://www.rcsb.org/pages/policies
    https://www.rcsb.org/
  50. SpectraBase
    RAPAMYCIN
    https://spectrabase.com/spectrum/BVHjlBzTHPp
    RAPA;RAPAMYCIN
    https://spectrabase.com/spectrum/CbAW6qd556R
  51. Springer Nature
    https://pubchem.ncbi.nlm.nih.gov/substance/?source=15745&sourceid=65063664-384305690
    https://pubchem.ncbi.nlm.nih.gov/substance/?source=15745&sourceid=65063664-384374043
  52. The Cambridge Structural Database
    https://www.ccdc.cam.ac.uk/structures/Search?Ccdcid=838233
  53. Thieme Chemistry
    https://creativecommons.org/licenses/by-nc-nd/4.0/
    https://pubchem.ncbi.nlm.nih.gov/substance/?source=22163&sourceid=65063664-384306109
    https://pubchem.ncbi.nlm.nih.gov/substance/?source=22163&sourceid=65063664-384378232
  54. Wikidata
    https://creativecommons.org/publicdomain/zero/1.0/
    Sirolimus
    https://www.wikidata.org/wiki/Q32089
  55. Wiley
    https://pubchem.ncbi.nlm.nih.gov/substance/?source=wiley&sourceid=118681
  56. Medical Subject Headings (MeSH)
    https://www.nlm.nih.gov/copyright.html
    Sirolimus
    https://www.ncbi.nlm.nih.gov/mesh/68020123
    MeSH Tree
    http://www.nlm.nih.gov/mesh/meshhome.html
    Antibiotics, Antineoplastic
    https://www.ncbi.nlm.nih.gov/mesh/68000903
    Anti-Bacterial Agents
    https://www.ncbi.nlm.nih.gov/mesh/68000900
    Antifungal Agents
    https://www.ncbi.nlm.nih.gov/mesh/68000935
    Immunosuppressive Agents
    https://www.ncbi.nlm.nih.gov/mesh/68007166
  57. UN Globally Harmonized System of Classification and Labelling of Chemicals (GHS)
    GHS Classification Tree
    http://www.unece.org/trans/danger/publi/ghs/ghs_welcome_e.html
  58. PATENTSCOPE (WIPO)
    SID 388369079
    https://pubchem.ncbi.nlm.nih.gov/substance/388369079
    SID 426926627
    https://pubchem.ncbi.nlm.nih.gov/substance/426926627
  59. NCBI
    https://www.ncbi.nlm.nih.gov/projects/linkout