Sirolimus – Uses, Dosage, Side Effects, Interaction

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that sirolimus be used initially in a regimen with [cyclosporine] and corticosteroids; cyclosporine should be withdrawn two to four months after transplantation.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

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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. CompTox Chemicals Dashboard Chemical Lists
  13. NCI Thesaurus Tree
  14. The Natural Products Atlas Classification
  15. Lipid Classification
  16. PubChem
  17. Antibiotics, Antineoplastic
  18. NCBI