Tacrolimus

What it is

Tacrolimus is a macrolide molecule originally isolated from the soil bacterium Streptomyces tsukubaensis, used as an immunosuppressant. It works by silencing a signalling enzyme called calcineurin inside T lymphocytes, which is why it belongs to the drug class “calcineurin inhibitors”. It exists in two quite different worlds of use: swallowed capsules or intravenous infusions for stopping organ transplant rejection, where it circulates throughout the body and is dosed by blood level; and a 0.03% or 0.1% ointment rubbed on the skin for eczema, where systemic absorption is normally minimal. Both carry a boxed warning, but they are different warnings about different risks.

What the research says

For transplantation, the evidence is strong: a meta-analysis of 30 randomised trials in 4,102 kidney transplant recipients found tacrolimus better than ciclosporin at preventing graft loss and acute rejection, at the price of substantially more insulin-dependent diabetes. For eczema, a Cochrane review of 20 trials in 5,885 people found tacrolimus ointment better than weak topical steroids and better than pimecrolimus, but no better than mid-to-high-potency topical steroids, and more likely to cause burning skin. The long-running question of whether the ointment causes lymphoma or skin cancer remains unresolved: a very large European cohort found an association with lymphoma in children in its first analysis, and then, with ten years of follow-up, concluded there was “little evidence” of a link overall – although that same extension still recorded a raised rate of cutaneous T-cell lymphoma in adults using tacrolimus (1.80, 95% CI 1.25-2.58) and of melanoma and nonmelanoma skin cancer in adults using pimecrolimus, with the authors flagging confounding by indication, surveillance bias and reverse causation as possible explanations. The ointment's boxed warning reflects exactly that unresolved state.

Evidence grade: Well established.

How it works

Drug class: Calcineurin inhibitor immunosuppressant (macrolide)

Tacrolimus gets inside T lymphocytes and sticks to a protein called FKBP-12. That pair then jams calcineurin, an enzyme the cell needs to switch on its inflammatory genes. With calcineurin blocked, the T cell cannot produce interleukin-2 and the other signals that recruit an immune attack – which is what stops a transplanted organ being rejected, and what calms the T-cell-driven inflammation of eczema. The label is candid that the exact mechanism is still not fully known. (Source 1)

Boxed warning

BOXED WARNING - MALIGNANCIES AND SERIOUS INFECTIONS • Increased risk of development of lymphoma and other malignancies, particularly of the skin, due to immunosuppression [see Warnings and Precautions ( 5.2 )] . • Increased susceptibility to bacterial, viral, fungal, and protozoal infections, including opportunistic infections [see Warnings and Precautions ( 5.3 , 5.4 , 5.5 )] . • Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe Prograf. 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 [see Warnings and Precautions ( 5.1 )].

(Source 2)

What it is used for

• A meta-analysis of 30 randomised trials found tacrolimus reduced graft loss and acute rejection compared with ciclosporin, but caused more insulin-dependent diabetes. Treating 100 people with tacrolimus rather than ciclosporin for the first year avoids 12 acute rejections and 2 graft losses while causing 5 extra cases of insulin-dependent diabetes. Evidence: established. (Source 3)
• Approved for liver and heart transplantation as well, with its own dosing and target trough ranges. The systematic-review evidence we reached compared tacrolimus with ciclosporin in kidney transplantation; we did not retrieve equivalent pooled outcome data for liver or heart transplantation, so the strength of evidence for those uses is not established here. Evidence: limited. (Source 4)
• A Cochrane review of 20 trials in 5,885 people found tacrolimus ointment better than low-potency topical steroids and better than pimecrolimus 1%, but equivalent to moderate-to-potent topical steroids, with more burning at the application site. Evidence: established. (Source 5)
• Widely used but thinly evidenced. A 2023 systematic review found only four controlled trials with 101 patients in total, and the pooled result for sequential topical-steroid/calcineurin-inhibitor therapy versus monotherapy or emollients was not statistically significant. Evidence: limited. (Source 6)

Interactions

• Grapefruit and grapefruit juice (label): Grapefruit blocks CYP3A enzymes, which pushes tacrolimus blood levels up. For a drug dosed to a narrow target range, that can tip someone into kidney toxicity or tremor, so the label simply says avoid it. (Source 7)
• St John's wort (Hypericum perforatum) (label): St John's wort revs up the CYP3A enzymes that destroy tacrolimus, so blood levels can fall – which in a transplant recipient means a risk of rejection. The label requires monitoring and dose adjustment if the two are combined. (Source 8)
• Potassium-sparing diuretics, ACE inhibitors and angiotensin receptor blockers (and by extension potassium supplements) (label): Tacrolimus itself raises blood potassium. Combining it with anything else that does the same can push potassium to dangerous levels, so potassium is monitored. Potassium supplements are not named in the label but fall under the same mechanism. (Source 9)
• Azole antifungals (voriconazole, posaconazole, itraconazole, ketoconazole, fluconazole, clotrimazole) (label): These block the enzyme that clears tacrolimus, raising its blood level sharply. The label instructs cutting the tacrolimus dose to a third when starting voriconazole or posaconazole. (Source 10)
• Food in general (meals taken with capsules) (label): Food reduces how much tacrolimus is absorbed, which is why the instruction is to take it the same way every day rather than sometimes with and sometimes without a meal. (Source 11)
• Alcohol, while using tacrolimus ointment (label): A distinctive and well-recognised effect of the ointment: drinking alcohol can make the treated skin or the face flush, redden and feel hot. It is listed as alcohol intolerance in the trial adverse-event tables. (Source 12)
• Phenytoin, carbamazepine and phenobarbital (label): These anticonvulsants induce CYP3A and lower tacrolimus levels; phenytoin levels can also rise in the other direction, so both drugs need monitoring. (Source 8)

Stopping it

• For the ointment, the boxed warning itself is an instruction about long-term use: avoid continuous application and treat only affected skin, which in practice means intermittent courses rather than indefinite daily use. (Source 13)
• The intermittent and sequential regimens people use instead of continuous application have not been shown to work better than simpler treatment, so there is no strong evidence base for a particular “step-down” schedule. The same review nonetheless describes the approach as effective, a conclusion its own non-significant pooled result does not support. (Source 6)
• Systemic tacrolimus is not a drug to stop on one's own: its whole purpose is preventing rejection, and the boxed warning is explicit that maintenance therapy belongs with a clinician who has the full follow-up picture. There is no withdrawal syndrome in the sense of dependence; the risk of stopping is graft rejection. (Source 2)
• Where systemic tacrolimus is causing progressive kidney damage, the label's own stopping advice is to switch rather than to persist with dose reductions. (Source 14)

What goes wrong

Tacrolimus caused nearly twice as much insulin-requiring diabetes as ciclosporin, and the excess grew with higher tacrolimus blood levels. (Source 3)

• Systematic review, Moderate certainty.
• Size: 30 randomised trials, 4,102 patients.
• Who: Kidney transplant recipients.
• How long: 1 year.
• Result: Diabetes mellitus requiring insulin RR 1.86 (95% CI 1.11 to 3.09); the relative excess increased with higher tacrolimus concentrations (P = 0.003). Tremor, headache, diarrhoea, dyspepsia and vomiting were also more common.
• Funding: not stated.

but more diabetes mellitus requiring insulin (RR = 1.86, 1.11 to 3.09), tremor, headache, diarrhoea, dyspepsia, and vomiting

Burning skin was roughly two and a half times more common with topical calcineurin inhibitors than with topical steroids, though it was mild and short-lived. (Source 15)

• Systematic review, High certainty.
• Size: 5 studies, 1,883 participants.
• Who: Children and adults with moderate to severe atopic dermatitis.
• How long: variable across trials.
• Result: RR 2.48 (95% CI 1.96 to 3.14) for burning; no difference in skin infections; symptoms described as mild and transient.
• Funding: not stated.

Burning was more frequent in those using calcineurin inhibitors than those using corticosteroid tacrolimus 0.03% (RR 2.48, 95% CI 1.96 to 3.14, 5 studies, 1883 participants, high-quality evidence), but no difference was found for skin infections.

A very large European cohort study found topical tacrolimus use associated with an increased rate of lymphoma, most strikingly in children, though the absolute rates were tiny and confounding could not be excluded. (Source 16)

• Cohort study, Low certainty.
• Size: 19,948 children and 66,127 adults starting tacrolimus; 584,121 topical corticosteroid users; 257,074 untreated subjects.
• Who: Population databases in the Netherlands, Denmark, Sweden and the UK, frequency-matched by propensity-score strata.
• How long: cohort follow-up in four national databases.
• Result: Lymphoma incidence 10.4 per 100,000 person-years in children and 41.0 in adults on tacrolimus. IRR versus topical corticosteroids 3.74 (95% CI 1.00–14.06) in children and 1.27 (0.94–1.71) in adults; highest subtype IRR 3.17 (0.58–17.23) for Hodgkin lymphoma in children.
• Funding: not stated.

The IRR (95% confidence interval [CI]) for lymphoma, tacrolimus versus TCSs, was 3.74 (1.00-14.06) in children and 1.27 (0.94-1.71) in adults.

In that cohort, adults using topical tacrolimus had a higher recorded rate of cutaneous T-cell lymphoma than adults using topical corticosteroids, and adults using pimecrolimus a higher rate of melanoma and nonmelanoma skin cancer. (Source 17)

• Cohort study, Low certainty.
• Size: 126,908 adults and 32,605 children starting tacrolimus; 61,841 adults and 27,961 children starting pimecrolimus.
• Who: Adults and children in Denmark, Sweden, the UK and the Netherlands starting a topical calcineurin inhibitor, compared with users of moderate/high-potency topical corticosteroids.
• How long: ≥10 years of follow-up for 19% of adults and 32% of children.
• Result: Tacrolimus versus topical corticosteroid in adults: incidence rate ratio 1.80 (95% CI 1.25-2.58) for cutaneous T-cell lymphoma, and below 1 for melanoma, non-Hodgkin lymphoma and Hodgkin lymphoma. Pimecrolimus in adults: 1.21 (1.03-1.41) for melanoma and 1.28 (1.20-1.35) for nonmelanoma skin cancer. Results in children were inconclusive because of few events.
• Funding: not stated.

Limit of this finding: These are rates observed in routine care, not the result of an experiment, so they cannot show that the ointments caused the cancers. The study's own authors say confounding by indication, surveillance bias and reverse causation may explain the higher figures: people prescribed a calcineurin inhibitor have more severe eczema, are watched more closely, and early skin lymphoma can itself look like eczema. Read the raised ratios as a signal that has not been explained rather than as a measured risk of treatment.

Incidence rate ratios and (95% confidence intervals) for tacrolimus versus corticosteroid users in adults were <1 for melanoma, non-Hodgkin lymphoma, and Hodgkin lymphoma; and 1.80 (1.25-2.58) for cutaneous T-cell lymphoma.

Systemic tacrolimus carries a boxed warning for lymphoma, other cancers – especially skin cancer – and serious opportunistic infections. (Source 2)

• Official position, Certainty not rated.
• Size: Not applicable; regulatory position.
• Who: Transplant recipients taking systemic tacrolimus.
• How long: ongoing therapy.
• Result: No rates given in the boxed warning itself.
• Funding: industry-funded (manufacturer's label)

Increased risk of development of lymphoma and other malignancies, particularly of the skin, due to immunosuppression [see Warnings and Precautions ( 5.2 )] .

The ointment carries a separate boxed warning that the long-term safety of topical calcineurin inhibitors has not been established and that continuous long-term use should be avoided. (Source 13)

• Official position, Certainty not rated.
• Size: Not applicable; regulatory position.
• Who: People of any age using tacrolimus ointment for atopic dermatitis; not indicated under 2 years of age.
• How long: Not applicable.
• Result: No rates given; the warning explicitly states a causal relationship has not been established.
• Funding: industry-funded (manufacturer's label)

Although a causal relationship has not been established, rare cases of malignancy (e.g., skin and lymphoma) have been reported in patients treated with topical calcineurin inhibitors, including PROTOPIC Ointment.

Kidney damage is the characteristic harm of systemic tacrolimus, reported in about half of kidney transplant recipients in the registration trials. (Source 14)

• Official position, Certainty not rated.
• Size: Adverse-reaction reporting from the US and European randomised registration trials.
• Who: Kidney, liver and heart transplant recipients on systemic tacrolimus.
• How long: trial duration.
• Result: Nephrotoxicity reported in approximately 52% of kidney transplant patients, 40% and 36% of liver transplant patients in the US and European trials, and 59% of heart transplant patients.
• Funding: industry-funded (manufacturer's label)

nephrotoxicity was reported in approximately 52% of kidney transplantation patients and in 40% and 36% of liver transplantation patients receiving Prograf in the U.S. and European randomized trials, respectively, and in 59% of heart transplantation patients in a European randomized trial

Burning, stinging or itching at the application site is the commonest complaint with tacrolimus ointment, usually lasting minutes rather than hours. (Source 18)

• Official position, Certainty not rated.
• Size: Pooled from the 12-week randomised trials summarised in the label.
• Who: Adults and children using tacrolimus ointment for atopic dermatitis.
• How long: most common in the first few days of use.
• Result: With 0.1% ointment, 90% of skin-burning events lasted between 2 minutes and 3 hours (median 15 minutes); 90% of pruritus events lasted 3 minutes to 10 hours (median 20 minutes)
• Funding: industry-funded (manufacturer's label)

With PROTOPIC Ointment 0.1%, 90% of the skin burning events had a duration between 2 minutes and 3 hours (median 15 minutes).

What the evidence supports

In kidney transplantation, tacrolimus prevented graft loss and acute rejection better than ciclosporin. (Source 3)

• Systematic review, Moderate certainty.
• Size: 123 reports from 30 randomised trials, 4,102 patients.
• Who: Kidney transplant recipients receiving tacrolimus or ciclosporin as initial immunosuppression.
• How long: 6 months to 3 years.
• Result: Graft loss at 6 months RR 0.56 (95% CI 0.36 to 0.86), persisting to 3 years; acute rejection at 1 year RR 0.69 (0.60 to 0.79); steroid-resistant rejection RR 0.49 (0.37 to 0.64)
• Funding: not stated.

At six months, graft loss was significantly reduced in tacrolimus treated recipients (RR = 0.56, 95% confidence interval 0.36 to 0.86), and this effect persisted up to three years.

Tacrolimus ointment 0.1% worked better than low-potency topical steroids and better than pimecrolimus 1% for atopic dermatitis. (Source 5)

• Systematic review, Moderate certainty.
• Size: 20 studies, 5,885 participants in total; individual comparisons 371 to 1,640 participants.
• Who: Children and adults with moderate to severe atopic dermatitis.
• How long: variable across trials; the review notes variability in dose, outcomes and follow-up made meta-analysis difficult.
• Result: Versus low-potency topical corticosteroid RR 3.09 (95% CI 2.14 to 4.45, n = 371, moderate quality); versus pimecrolimus 1% RR 1.80 (1.34 to 2.42, n = 506, moderate quality); 0.1% versus 0.03% RR 0.82 (0.72 to 0.92, n = 1,640, high quality)
• Funding: not stated.

A single trial showed that tacrolimus 0.1% was better than low-potency TCS by the physician's assessment (risk ratio (RR) 3.09, 95% confidence interval (CI) 2.14 to 4.45, 1 study, n = 371, moderate-quality evidence).

What the evidence does not support

Within the first few years of these trials, tacrolimus and ciclosporin did not differ in infection or cancer rates. (Source 3)

• Systematic review, Low certainty.
• Size: 30 randomised trials, 4,102 patients.
• Who: Kidney transplant recipients.
• How long: up to 3 years.
• Result: No significant difference in infection or malignancy between the two calcineurin inhibitors (point estimates not reported in the abstract)
• Funding: not stated.

No differences were seen in infection or malignancy.ConclusionsTreating 100 recipients with tacrolimus instead of ciclosporin

Tacrolimus ointment was not better than moderate-to-potent topical corticosteroids – on some measures the steroid was marginally ahead. (Source 19)

• Systematic review, Low certainty.
• Size: 377 participants for the 0.1% physician assessment comparison; two further studies for the 0.03% comparison.
• Who: Children and adults with moderate to severe atopic dermatitis.
• How long: variable across trials.
• Result: Tacrolimus 0.1% versus moderate-to-potent topical corticosteroid: no difference on physician's assessment (1 study, 377 participants); a marginal benefit for tacrolimus on participant's assessment (RR 1.21, 95% CI 1.13 to 1.29, low quality). For 0.03%, no difference in most outcomes and a marginal benefit favouring the corticosteroid on EASI and BSA.
• Funding: not stated.

Tacrolimus 0.1% compared with moderate-to-potent TCS showed no difference by the physician's assessment, and 2 secondary outcomes (1 study, 377 participants)

No lymphoma occurred in any of the randomised trials in the Cochrane review; the cancer signal comes entirely from spontaneous reports and observational studies. (Source 15)

• Systematic review, Low certainty.
• Size: 20 randomised trials with 5,885 participants, plus non-comparative studies.
• Who: Children and adults with atopic dermatitis using tacrolimus ointment.
• How long: trial durations only; the review notes the lack of long-term data as a limitation.
• Result: Zero lymphoma cases in included trials; systemic absorption rarely detectable and only at low levels, decreasing over time; no evidence of skin atrophy.
• Funding: not stated.

No cases of lymphoma were noted in the included studies nor in the non-comparative studies. Cases were only noted in spontaneous reports, cohorts, and case-control studies.

The Cochrane authors concluded that no evidence supported an increased malignancy risk from tacrolimus ointment, while warning that the evidence base was thin. (Source 20)

• Systematic review, Low certainty.
• Size: 20 studies, 5,885 participants.
• Who: Children and adults with moderate to severe atopic dermatitis.
• How long: variable across trials.
• Result: No quantitative estimate; the review reports absence of evidence rather than evidence of absence and says findings should be interpreted with caution.
• Funding: not stated.

Both tacrolimus formulations seemed to be safe, and no evidence was found to support the possible increased risk of malignancies or skin atrophy with their use. The reliability and strength of the evidence was limited by the lack of data

With up to ten years of follow-up the same cohort programme concluded there was little evidence linking topical calcineurin inhibitors to skin cancer or lymphoma overall, and that any excess risk would be small and confined to the first years of use. (Source 21)

• Cohort study, Low certainty.
• Size: 126,908 adults and 32,605 children starting tacrolimus (plus 61,841 adults and 27,961 children on pimecrolimus)
• Who: Adults and children in Denmark, Sweden, the UK and the Netherlands starting a topical calcineurin inhibitor, compared with users of moderate/high-potency topical corticosteroids.
• How long: ≥10 years of follow-up for 19% of adults and 32% of children.
• Result: The authors' overall reading of their own estimates; the individual incidence rate ratios, including the raised ones, are reported separately in the Results section of the same paper.
• Funding: not stated.

Overall, we found little evidence associating use of topical calcineurin inhibitors with skin cancer and lymphoma; confounding by indication, surveillance bias, and reverse causation may have influenced these results.

Intermittent or sequential use of tacrolimus ointment alternating with topical steroids has not been shown to beat simpler treatment. (Source 6)

• Systematic review, Very low certainty.
• Size: 4 controlled trials, 101 patients in total; pooled analysis from 2 trials.
• Who: People with atopic dermatitis given sequential or intermittent topical calcineurin inhibitor regimens.
• How long: not stated in the abstract read.
• Result: Test for overall effect non-significant, p = 0.33; the two pooled studies were highly heterogeneous (I2 = 92%, p = 0.0005). Risk of bias was low in two studies and unclear in two.
• Funding: not stated.

Limit of this finding: The review contradicts itself. Its pooled result across two small trials showed no significant difference from monotherapy or emollients (p = 0.33), and the two trials disagreed with each other so strongly (I2 = 92%) that pooling them is questionable – yet the same paper goes on to call the approach effective and well tolerated. With only 101 patients in four trials, read this as showing the question is unsettled: it is not evidence that intermittent or sequential use works, and not evidence that it fails.

Overall, pooled data from two trials revealed that sequential therapy with TCS/TCI was comparable to monotherapy or emollients, as the test for overall effect determined was non-significant with a p-value of 0.33.

Where the evidence is mixed

The same review put the trade-off in absolute terms: per 100 people treated for a year, tacrolimus avoids 12 acute rejections and 2 graft losses but causes 5 extra cases of insulin-dependent diabetes. (Source 3)

• Systematic review, Moderate certainty.
• Size: 30 randomised trials, 4,102 patients.
• Who: Kidney transplant recipients in the first year after transplantation.
• How long: 1 year.
• Result: Per 100 recipients: 12 fewer acute rejections, 2 fewer graft losses, 5 extra cases of insulin-dependent diabetes.
• Funding: not stated.

Treating 100 recipients with tacrolimus instead of ciclosporin for the first year after transplantation avoids 12 patients having acute rejection and two losing their graft but causes an extra five patients to develop insulin dependent diabetes.

Where the research disagrees

Whether tacrolimus ointment increases the risk of lymphoma or skin cancer

• Castellsague and colleagues, first JOELLE cohort analysis (2018), Multi-country cohort study in four national databases with propensity-score matching: “Use of topical tacrolimus and pimecrolimus was associated with an increased risk of lymphoma.” (Source 16)
• Arana and colleagues, JOELLE extension with ten-year follow-up (2021), Extension of the same cohort programme with ≥10 years of follow-up in 19% of adults and 32% of children: “Overall, we found little evidence associating use of topical calcineurin inhibitors with skin cancer and lymphoma” (Source 21)
• Cochrane review authors (Cury Martins and colleagues, 2015), Systematic review of 20 randomised trials in 5,885 people, with a separate adverse-effects search: “no evidence was found to support the possible increased risk of malignancies or skin atrophy with their use” (Source 20)
• FDA-approved PROTOPIC label (DailyMed, revised June 2009), Regulatory position based on spontaneous reports; retained as a boxed warning: “Although a causal relationship has not been established, rare cases of malignancy (e.g., skin and lymphoma) have been reported in patients treated with topical calcineurin inhibitors, including PROTOPIC Ointment.” (Source 13)

How much

• Reference intake: There is no dietary reference intake for tacrolimus; it is a prescription immunosuppressant and systemic dosing is set by the prescriber and then adjusted to measured whole-blood trough concentrations. As a position, the Prograf label (DailyMed, revised 5/2014) gives an initial adult kidney transplant dose of 0.2 mg/kg/day in two divided doses with azathioprine, or 0.1 mg/kg/day with mycophenolate and an IL-2 receptor antagonist. (Source 4)
• Upper limit: No upper limit is set by a nutrition body. The practical ceiling for systemic tacrolimus is a target blood concentration rather than a milligram dose: the label's observed trough ranges are 7–20 ng/mL in months 1–3 and 5–15 ng/mL in months 4–12 for adult kidney transplant on azathioprine, and 4–11 ng/mL for the mycophenolate regimen. For the ointment, the boxed warning sets the limit differently – avoid continuous long-term use and apply only to affected skin. (Source 4)
• Studied: Transplant trials compared tacrolimus with ciclosporin as initial immunosuppression; the review found the benefit on graft loss shrank and the diabetes excess grew at higher tacrolimus concentrations. (Source 3)
• Studied: Atopic dermatitis trials used tacrolimus ointment at the two marketed strengths, 0.03% and 0.1%, with the 0.1% strength performing better. (Source 5)
• Studied: The label restricts the 0.03% strength to children aged 2–15 and states the ointment is not indicated below 2 years of age. (Source 13)

A common belief, and what the research shows

The belief: Tacrolimus ointment is dangerous because it causes cancer, so topical steroids are always the safer choice.

What the research shows: The boxed warning is about uncertainty, not a demonstrated cause: it says in its own words that “a causal relationship has not been established”. Across 20 randomised trials in 5,885 people, “No cases of lymphoma were noted in the included studies nor in the non-comparative studies.” The largest observational programme first reported an association in children (IRR 3.74, 95% CI 1.00–14.06) and then, with ten years of follow-up, “little evidence associating use of topical calcineurin inhibitors with skin cancer and lymphoma”. The comparison with steroids is also not one-sided: in the same cohort, “Compared with untreated subjects, adults using TCSs had a higher incidence of CTCL (IRR, 10.66; 95% CI, 2.60-43.75).” Both findings are vulnerable to the same bias – severe eczema and early cutaneous lymphoma look alike and get treated alike.

Questions and answers

What is it?

Tacrolimus is a large molecule made by a soil bacterium, Streptomyces tsukubaensis, and developed as an immune-suppressing drug. It comes as capsules and an intravenous solution for transplant patients, and as a greasy ointment at 0.03% or 0.1% strength for eczema. In the ointment the drug sits in a base of mineral oil, paraffin and white petrolatum. Chemically it is a macrolide, and it is also known by its research name FK506. (Source 22)

What does it do in the body?

It switches off one specific step in how T lymphocytes raise an immune response. Tacrolimus binds a protein called FKBP-12 inside the cell; that complex blocks the enzyme calcineurin, which the cell needs to release a signal called NF-AT and start making interleukin-2 and interferon-gamma. Without those signals the T cell cannot mount an attack – so a transplanted organ is left alone, and T-cell-driven skin inflammation settles. (Source 1)

Is it good or bad for you?

Both, and the balance differs completely between the two forms. For a transplanted kidney, systemic tacrolimus is clearly net good: it prevents rejection and graft loss better than the older alternative, at the cost of more insulin-dependent diabetes and frequent kidney injury. For eczema, the ointment is a useful second-line option – better than weak steroids, no better than strong ones – with burning skin as the main nuisance and an unresolved cancer question as the main uncertainty. The Cochrane review's verdict was that both strengths seemed safe but that the evidence was thin. (Source 20)

How do you get more of it?

Tacrolimus is prescription-only in every form; it is not in food and has no supplement equivalent. Systemic doses are started by weight and then steered by regular blood tests, not by how someone feels. As a record of what the regulator approved, the label starts adult kidney transplant recipients at 0.2 mg/kg/day in two divided doses when combined with azathioprine. None of this is a dose for a reader to act on. (Source 4)

If it is harmful, what reduces it?

For the ointment, the answer in the label is to stop applying it and not to use it continuously – the boxed warning directs that continuous long-term use in any age group be avoided and that application be limited to affected skin. For systemic tacrolimus, lowering exposure is done by cutting the dose under blood-level monitoring, or by switching to a different immunosuppressant when kidney function keeps worsening; it is never something to stop unilaterally, because the consequence is rejection. (Source 13)

Why might someone be low in it or missing it?

Tacrolimus is not something a body is naturally low in. Blood levels in a transplant recipient can come out lower than intended for identifiable reasons: another drug or a supplement that induces CYP3A enzymes (St John's wort, rifampicin, phenytoin, carbamazepine, phenobarbital), taking capsules with food when they were titrated without, or missed doses. The label singles out St John's wort as an inducer that lowers tacrolimus concentrations. (Source 8)

Which whole foods contain it or feed it?

No food contains tacrolimus. The food that matters is grapefruit, which pushes levels in the wrong direction by blocking the enzyme that clears the drug – the label tells patients to avoid grapefruit and grapefruit juice outright. Meals in general reduce absorption, so the instruction is to be consistent: always with food, or always without, but not a mixture. (Source 7)

What happens if you do not have it?

Nobody needs tacrolimus unless they have a transplanted organ or a disease it treats. The question that matters is what happens if a transplant recipient stops: the trials measured exactly this trade-off, and the meta-analysis found that tacrolimus rather than ciclosporin for one year prevents 12 acute rejections and 2 graft losses per 100 people. Without adequate immunosuppression of some kind, rejection and graft loss are the expected outcomes. (Source 3)

How can you test for it?

Systemic tacrolimus is one of the few drugs routinely measured in blood: a whole-blood trough concentration, taken just before the next dose, guides every dose adjustment, with published target ranges by organ and time since transplant. The test is reliable enough to be the basis of dosing, but it is a snapshot of exposure, not of effect, and the label notes Black patients may need higher doses to reach the same trough. For the ointment there is no routine test; the Cochrane review found systemic absorption rarely detectable at all. (Source 4)

References

1. DailyMed (US National Library of Medicine). PROGRAF (tacrolimus) capsules and injection — US prescribing information on DailyMed, revised 5/2014 [prograf_moa section]. 2014. Read the source
2. DailyMed (US National Library of Medicine). PROGRAF (tacrolimus) capsules and injection — US prescribing information on DailyMed, revised 5/2014 [prograf_boxed section]. 2014. Read the source
3. BMJ (Clinical research ed.). Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomised trial data.. 2005. PMID 16157605, DOI 10.1136/bmj.38569.471007.ae. Read the source
4. DailyMed (US National Library of Medicine). PROGRAF (tacrolimus) capsules and injection — US prescribing information on DailyMed, revised 5/2014 [prograf_dosing section]. 2014. Read the source
5. The Cochrane database of systematic reviews. Topical tacrolimus for atopic dermatitis (Cochrane Database of Systematic Reviews). 2015. PMID 26132597, DOI 10.1002/14651858.cd009864.pub2. Read the source
6. Cureus. Intermittent or Sequential Topical Tacrolimus in Atopic Dermatitis: Systematic Review and Meta-Analysis.. 2023. PMID 38229798, DOI 10.7759/cureus.50640. Read the source
7. DailyMed (US National Library of Medicine). PROGRAF (tacrolimus) capsules and injection — US prescribing information on DailyMed, revised 5/2014 [prograf_grapefruit section]. 2014. Read the source
8. DailyMed (US National Library of Medicine). PROGRAF (tacrolimus) capsules and injection — US prescribing information on DailyMed, revised 5/2014 [prograf_sjw section]. 2014. Read the source
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