Sirolimus drug interactions: the full safety rundown

Last updated 2026-07-27

What is sirolimus and why does it interact with so many drugs?

Sirolimus (also sold as rapamycin, and marketed as Rapamune, Fyarro, and the topical Hyftor) is an mTOR inhibitor the FDA approved in 1999 to prevent organ rejection after kidney transplant ^[1]. Fyarro treats a rare soft tissue sarcoma (malignant PEComa) and Hyftor treats facial angiofibromas from tuberous sclerosis ^[1]. None of these approvals cover aging, lifespan extension, or general longevity use. That use is entirely off-label, and it matters for interactions because almost everything we know about how sirolimus behaves with other drugs comes from transplant patients taking daily doses, not from people taking small intermittent doses once a week for longevity purposes. The reason sirolimus interacts with so many drugs comes down to one enzyme system: cytochrome P450 3A4 (CYP3A4), plus a transporter protein called P-glycoprotein (P-gp). Sirolimus is broken down almost entirely by CYP3A4 in the liver and gut wall, and P-gp controls how much of the drug gets absorbed into the bloodstream in the first place. Anything that blocks or speeds up either of those systems changes how much sirolimus ends up in your blood, sometimes by a huge margin. The FDA label states plainly that sirolimus is 'a substrate for both CYP3A4 and P-glycoprotein (P-gp)' ^[2], which is the mechanistic root of nearly every interaction on this page.

Which drugs and supplements raise sirolimus blood levels dangerously?

Strong CYP3A4 or P-gp inhibitors are the biggest concern because they can push sirolimus levels high enough to cause toxicity: excess immunosuppression, kidney effects, high cholesterol, and worse mouth ulcers. The Rapamune label explicitly names ketoconazole, voriconazole, itraconazole, telithromycin, and clarithromycin as strong inhibitors that significantly increase sirolimus concentrations, and it advises avoiding concomitant use or adjusting the dose and monitoring levels closely if it can't be avoided ^[2]. Grapefruit and grapefruit juice deserve their own callout because people don't think of food as a drug interaction. Grapefruit contains furanocoumarins that irreversibly inhibit intestinal CYP3A4, and the FDA label says sirolimus 'should not be administered with grapefruit juice' for this reason ^[2]. This isn't a mild effect; grapefruit can meaningfully raise blood levels of many CYP3A4 substrates, and the interaction can last for days because the enzyme has to regenerate. Other notable inhibitors include diltiazem, verapamil, erythromycin, fluconazole, and protease inhibitors used for HIV. If you're on any of these long-term, sirolimus dosing needs real adjustment, not guesswork, which is one more reason this drug should never be self-managed without lab monitoring. | Interaction type | Example drugs/substances | Effect on sirolimus | Source |

Which drugs lower sirolimus levels and risk under-dosing?

The opposite problem is just as real. Strong CYP3A4/P-gp inducers speed up sirolimus metabolism and can drop blood levels low enough that the drug stops working as intended (in a transplant patient that means rejection risk; in an off-label longevity user it likely just means wasted money and no measurable effect). Rifampin and rifabutin, the antibiotics used for tuberculosis and some other infections, are the classic strong inducers named in the FDA label, and coadministration is generally discouraged ^[2]. St. John's Wort is the supplement version of this problem. It's a potent CYP3A4 inducer, and it shows up on nearly every major interaction list for immunosuppressants, sirolimus included. If you're taking St. John's Wort for mood and also taking sirolimus, you may effectively be taking a lower dose than you think without any warning sign until levels are checked. Anticonvulsants like carbamazepine and phenytoin are also known CYP3A4 inducers and appear in sirolimus interaction data from general drug interaction references, though the core FDA trials focused mainly on rifampin. If you're on a seizure medication and considering sirolimus, this is a conversation for a prescriber with lab monitoring capability, not a forum thread.

Does sirolimus interact with cyclosporine or other immunosuppressants?

Yes, and this is one of the best-studied interactions because sirolimus was originally approved specifically for combination use with cyclosporine. The FDA label notes that concomitant cyclosporine increases sirolimus exposure, and long-term combined use is associated with increased risk of kidney toxicity, which is why many transplant regimens now separate dosing times or withdraw cyclosporine after an induction period ^[2]. Tacrolimus, another calcineurin inhibitor, has documented interactions with sirolimus as well, generally in the direction of altered exposure for both drugs. This category matters most to actual transplant patients rather than longevity users, but it's worth knowing that sirolimus's interaction profile was built inside combination immunosuppressive regimens, which is a very different clinical context from a healthy adult taking it alone once a week.

Can you get vaccines while taking sirolimus?

Live vaccines are the specific concern. Because sirolimus is an immunosuppressant, the FDA label states that 'the use of live vaccines should be avoided' during treatment, and gives measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and intranasal flu vaccines as examples of live vaccines to avoid ^[2]. Non-live (inactivated) vaccines, including the standard flu shot and COVID-19 vaccines, don't carry this same theoretical mechanism of harm, though the immune response to any vaccine may be blunted while on an immunosuppressant. This matters more than people expect for off-label longevity users because intermittent, low-dose protocols still suppress immune signaling through mTOR, even if the degree is less than continuous transplant dosing. If you're due for a yellow fever vaccine before travel, or your kid needs an MMR booster and you're the one administering doses in the household (not a direct risk to you, but worth knowing the general rule), plan around your sirolimus schedule and talk to a prescriber, not a travel clinic that doesn't know your dosing history.

What about NSAIDs, ACE inhibitors, and blood pressure drugs?

The Rapamune label discusses ACE inhibitors (like lisinopril or enalapril) in the context of a specific reported adverse reaction: angioedema, a swelling reaction, seen more often when ACE inhibitors were used concomitantly with sirolimus, particularly in patients also on mTOR inhibitor-based regimens ^[2]. If you're on an ACE inhibitor for blood pressure and start sirolimus, tell your prescriber; this isn't a reason to avoid the combination automatically, but it is a reason for both drugs to be on your prescriber's radar simultaneously. NSAIDs (ibuprofen, naproxen) don't have a dramatic sirolimus-specific interaction documented in the core label, but the combination of an immunosuppressant with a drug class known to affect kidney function deserves caution, especially in anyone with existing kidney concerns, since sirolimus itself carries kidney-related monitoring requirements in transplant use.

Does sirolimus cause mouth ulcers, and do other drugs make that worse?

Mouth ulcers (stomatitis) are one of the most commonly reported side effects of sirolimus across dosing contexts, including the low, intermittent protocols used off-label for longevity. Clinical trial data in the FDA label lists stomatitis and mouth ulceration among the more frequent adverse reactions in sirolimus-treated patients ^[2], and it's a recurring theme in real-world reports from off-label users as well. There's no strong drug-drug interaction specifically proven to worsen sirolimus mouth ulcers, but concomitant drugs that dry out the mouth, or other medications that independently cause oral mucositis (some chemotherapy agents, for example), could plausibly compound the problem. Practically, most people manage sirolimus-related mouth sores with alcohol-free mouth rinses and by avoiding acidic or abrasive foods around the days blood levels peak. If ulcers are severe or persistent, that's a dosing conversation, not something to just push through. Anyone building out a dosing schedule should factor this side effect into which day of the week they choose to dose.

How does sirolimus affect blood sugar, cholesterol, and metabolic drugs?

Sirolimus has known metabolic effects independent of any other drug: it commonly raises triglycerides and cholesterol, and can worsen insulin resistance in some patients, effects documented in the FDA label's list of adverse reactions including hyperlipidemia and hyperglycemia ^[2]. If you're already on a statin, a fibrate, or a diabetes medication, sirolimus can push those numbers around, which means your baseline labs and follow-up labs matter more than usual. This is a case where the interaction isn't so much drug-versus-drug at the enzyme level, it's drug-versus-drug at the level of the same lab values moving in the same bad direction. Someone with borderline high cholesterol who starts sirolimus without monitoring may not notice anything until a routine panel comes back abnormal months later. Baseline lipid panel, fasting glucose or HbA1c, and a follow-up at 8 to 12 weeks is the minimum sane monitoring plan for anyone taking this off-label, and it's worth building that into whatever cycle length you land on.

Is rapamycin the same as sirolimus for interaction purposes?

Yes, completely. Rapamycin is the original name for the compound (isolated from soil bacteria found on Easter Island), and sirolimus is the pharmaceutical name for the same molecule ^[1]. Every interaction, side effect, and monitoring consideration on this page applies identically whether the bottle says rapamycin or sirolimus, whether it's the brand Rapamune or a compounded version. There is no chemical difference that would change how it interacts with CYP3A4, grapefruit, or anything else. If a source treats them as different drugs with different interaction profiles, that source is wrong.

Why is there no human longevity trial to confirm these interactions at low doses?

This is the central gap in the whole longevity conversation, and it applies directly to interactions too. Every number above, the grapefruit warning, the rifampin warning, the ACE inhibitor angioedema signal, comes from transplant-dose sirolimus given daily to organ transplant patients, a population that's older, sicker, and on many more concomitant drugs than the average person taking low-dose intermittent sirolimus for longevity. The strongest lifespan evidence for rapamycin comes from mice, specifically the National Institute on Aging's Interventions Testing Program (ITP), which found that rapamycin extended median lifespan in genetically heterogeneous mice, with effects seen even when treatment started relatively late in life ^[3][4]. That's a real, replicated, multi-site finding, one of the most solid results in the entire aging-intervention literature. But a mouse trial is not a human trial. As of now, there is no completed human study measuring whether low-dose, intermittent sirolimus extends lifespan or healthspan in humans, and there is essentially no dedicated interaction study for the specific intermittent, low-dose protocols (e.g., 1-6 mg once weekly) that longevity users actually follow. The interaction data we do have (this whole article) is extrapolated from a different dosing pattern in a different patient population. That extrapolation is reasonable pharmacology, CYP3A4 and P-gp don't change their behavior based on why someone's taking the drug, but the magnitude of risk at low intermittent doses is genuinely less well characterized than at continuous transplant doses. Anyone telling you the interaction risk is fully mapped out for off-label longevity dosing is overstating the evidence.

What should you actually tell your prescriber before starting sirolimus?

Bring a full list, more than the drugs you take daily. That means prescription medications, over-the-counter drugs, and supplements, since St. John's Wort and grapefruit both fall outside what people usually think to mention. Specifically flag: any antifungal (ketoconazole, fluconazole, itraconazole, voriconazole), any macrolide antibiotic (clarithromycin, erythromycin), rifampin or rifabutin if you've had TB exposure, any calcium channel blocker (diltiazem, verapamil), any ACE inhibitor, cyclosporine or tacrolimus, and any HIV protease inhibitor. A responsible prescriber will also want baseline labs (kidney function, lipid panel, blood glucose or HbA1c, complete blood count) before the first dose and periodic follow-up after that, not because it's bureaucratic box-checking, but because sirolimus blood levels and its metabolic side effects are genuinely variable person to person and the drug's therapeutic window in transplant medicine is narrow enough that levels get checked routinely in that population. This is also where a dosage calculator becomes useful for thinking through starting points, but it doesn't replace a prescriber who knows your full medication list and can order labs. If you're evaluating options, the provider-reviewed route through Sirolimus Rx connects you with a prescriber who screens for exactly these interactions before anything ships, with product fulfilled through a licensed pharmacy partner rather than any unregulated source.

Frequently asked questions

Can I drink grapefruit juice while taking sirolimus?

No. The FDA label for sirolimus (Rapamune) specifically states it should not be taken with grapefruit juice, because grapefruit inhibits intestinal CYP3A4 and can raise sirolimus blood levels unpredictably. This applies at any dose, including low, intermittent longevity protocols, since the enzyme inhibition doesn't depend on dose size.

Does sirolimus interact with alcohol?

There's no specific FDA-labeled interaction between sirolimus and alcohol, but heavy alcohol use can independently affect liver metabolism and worsen sirolimus's known effects on triglycerides and glucose. Moderate use is generally not flagged as dangerous, but it's a reasonable question to raise with your prescriber given the metabolic side effect overlap.

Can I take ibuprofen or Tylenol with sirolimus?

Occasional acetaminophen or ibuprofen use isn't specifically contraindicated in the FDA label, but sirolimus can affect kidney function in transplant-dose contexts, and NSAIDs carry their own kidney risk. Regular NSAID use alongside sirolimus is worth flagging to a prescriber rather than assuming it's automatically fine long-term.

Is it safe to take sirolimus with statins?

There's no absolute contraindication, but sirolimus itself commonly raises cholesterol and triglycerides, per adverse reaction data in the FDA label, so combining it with a statin means both drugs are influencing the same lab values. Baseline and follow-up lipid panels are the sensible way to manage this, not avoidance.

Why can't I get an MMR or yellow fever vaccine on sirolimus?

These are live vaccines, and the FDA label advises avoiding live vaccines during sirolimus treatment because immunosuppression can theoretically allow a live vaccine strain to cause infection instead of just triggering immunity. Inactivated vaccines like the standard flu shot don't carry this same specific concern.

Does rapamycin interact differently than sirolimus?

No. Rapamycin and sirolimus are the same molecule; rapamycin is the original compound name and sirolimus is the pharmaceutical name used on FDA labeling. Every interaction described for one applies identically to the other, regardless of brand name or compounding source.

Can I take antibiotics while on sirolimus?

It depends on the antibiotic. Macrolides like clarithromycin and erythromycin are strong CYP3A4 inhibitors that raise sirolimus levels significantly per the FDA label, while rifampin is a strong inducer that lowers levels. Many other antibiotic classes don't have major documented interactions, but always disclose sirolimus use before starting any antibiotic.

Does St. John's Wort interact with sirolimus?

Yes. St. John's Wort is a potent CYP3A4 inducer and can significantly lower sirolimus blood levels, potentially making the drug less effective without any obvious warning sign. This combination is generally discouraged, and it's exactly the kind of supplement interaction people forget to mention to a prescriber.

What are the biggest immunosuppression risks from sirolimus at longevity doses?

Even low, intermittent dosing suppresses mTOR signaling involved in immune cell proliferation, so increased infection susceptibility is a real, biologically plausible risk, though it's less studied at longevity doses than at continuous transplant doses. Avoiding live vaccines and monitoring for unusual or prolonged infections are the practical precautions.

Has any human study proven sirolimus extends lifespan?

No completed human trial has measured whether sirolimus extends lifespan or healthspan. The strongest evidence is from the NIA's Interventions Testing Program in mice, which found lifespan extension across multiple sites and both sexes. Extrapolating that to humans, including interaction safety at low doses, remains an open question, not settled science.

Can sirolimus cause mouth ulcers, and is that a drug interaction?

Mouth ulcers (stomatitis) are a well-documented direct side effect of sirolimus itself, listed among common adverse reactions in the FDA label, rather than a drug interaction per se. Other medications that independently irritate the mouth could theoretically compound it, but there's no specific proven drug-drug interaction driving this effect.

Should I stop sirolimus before surgery or a new prescription?

That decision belongs to your prescriber and surgical team, since sirolimus's immunosuppressive effects and interaction profile (especially with antibiotics commonly used peri-surgically) matter for wound healing and infection risk. Never stop or start a new medication around a planned procedure without disclosing your sirolimus use first.

Sources

1. FDA, Drugs@FDA database entry for Rapamune (sirolimus): Sirolimus (Rapamune) FDA approval for kidney transplant rejection prophylaxis, original approval 1999
2. FDA, Rapamune (sirolimus) full prescribing information, NDA 021083, label PDF: CYP3A4/P-gp substrate status, grapefruit juice warning, strong inhibitor/inducer lists, live vaccine avoidance, ACE inhibitor angioedema signal, cyclosporine interaction and nephrotoxicity, stomatitis and metabolic adverse reactions
3. National Institute on Aging, Interventions Testing Program: NIA's ITP is the multi-site program testing compounds including rapamycin for lifespan effects in genetically heterogeneous mice
4. Harrison DE, et al. 'Rapamycin fed late in life extends lifespan in genetically heterogeneous mice.' Nature. 2009;460(7253):392-395. PMID 19587680: Rapamycin extended median lifespan in mice even when started late in life, in the founding NIA ITP study
5. Miller RA, et al. 'Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice.' J Gerontol A Biol Sci Med Sci. 2011;66(2):191-201. PMID 20974732: Independent ITP cohort confirming rapamycin's lifespan extension effect in mice, replicating the original 2009 finding