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SIROLIMUS is a brand name for Sirolimus. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: This medicine is indicated for the prophylaxis of organ rejection in adult patients at low to moderate immunological risk receiving a renal transplant. It is recommended that sirolimus be used initially in combination with ciclosporin microemulsion and corticosteroids for 2 to 3 months. Sirolimus may be continued as…
Verbatim from this product's MHRA label. Tap a section to expand.
Posology Prophylaxis of organ rejection Treatment should be initiated by and remain under the guidance of an appropriately qualified specialist in transplantation. Initial therapy (2 to 3 months post-transplantation) The usual dose regimen is a 6 mg single oral loading dose, administered as soon as possible after transplantation, followed by 2 mg once daily until results of therapeutic monitoring of the medicinal product are available (see Therapeutic monitoring of the medicinal product and dose adjustment).
The dose should then be individualised to obtain whole blood trough levels of 4 to 12 ng/mL (chromatographic assay). Therapy should be optimised with a tapering regimen of steroids and ciclosporin microemulsion. 5). 2). Maintenance therapy Ciclosporin should be progressively discontinued over 4 to 8 weeks, and sirolimus dose should be adjusted to obtain whole blood trough levels of 12 to 20 ng/mL (chromatographic assay; see Therapeutic monitoring of the medicinal product and dose adjustment).
Sirolimus should be given with corticosteroids. In patients for whom ciclosporin withdrawal is either unsuccessful or cannot be attempted, the combination of ciclosporin and sirolimus should not be maintained for more than 3 months post-transplantation.
In such patients, when clinically appropriate, sirolimus should be discontinued and an alternative immunosuppressive regimen instituted. 5) and/or (3) if ciclosporin dosing is markedly reduced or discontinued, as these populations are most likely to have special dosing requirements.
Therapeutic monitoring of the medicinal product should not be the sole basis for adjusting sirolimus therapy. Careful attention should be made to clinical signs/symptoms, tissue biopsies, and laboratory parameters. Most patients who received 2 mg of sirolimus 4 hours after ciclosporin had whole blood trough concentrations of sirolimus within the 4 to 12 ng/mL target range (expressed as chromatographic assay values).
Optimal therapy requires therapeutic concentration monitoring of the medicinal product in all patients. Optimally, adjustments in this medicine dose should be based on more than a single trough level obtained more than 5 days after a previous dosing change.
Patients can be switched from this medicine oral solution to the tablet formulation on a mg per mg basis. It is recommended that a trough concentration be taken 1 or 2 weeks after switching formulations or tablet strength to confirm that the trough concentration is within the recommended target range.
Undesirable effects observed with prophylaxis of organ rejection in renal transplantation The most commonly reported adverse reactions (occurring in >10% of patients) are thrombocytopaenia, anaemia, pyrexia, hypertension, hypokalaemia, hypophosphataemia, urinary tract infection, hypercholesterolaemia, hyperglycaemia, hypertriglyceridaemia, abdominal pain, lymphocoele, peripheral oedema, arthralgia, acne, diarrhoea, pain, constipation, nausea, headache, increased blood creatinine, and increased blood lactate dehydrogenase (LDH).
The incidence of any adverse reaction(s) may increase as the trough sirolimus level increases. The following list of adverse reactions is based on experience from clinical studies and on postmarketing experience. Within the system organ classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); not known (cannot be estimated from the available data).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Most patients were on immunosuppressive regimens, which included sirolimus in combination with other immunosuppressive agents. 4); Focal segmental glomerulo- sclerosis* System organ class Very common (≥1/10) Common (≥1/100 to <1/10) Uncommon (≥1/1,000 to <1/100) Rare (≥1/10,000 to <1/1,000) Frequency not known (cannot be estimated from available data) Reproductive system and breast disorders Menstrual disorder (including amenorrhoea and menorrhagia) Ovarian cyst General disorders and administration site conditions Oedema; Oedema peripheral; Pyrexia; Pain; Impaired healing* Investigations Blood lactate dehydrogenase increased; Blood creatinine increased *See section below.
4). Cases of BK virus-associated nephropathy, as well as cases of JC virus-associated progressive multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including sirolimus. Hepatoxicity has been reported.
1). In renal transplant patients with delayed graft function, sirolimus may delay recovery of renal function. 8). Concomitant therapy Immunosuppressive agents (Renal transplant patients only) Sirolimus has been administered concurrently with the following agents in clinical studies: tacrolimus, ciclosporin, azathioprine, mycophenolate mofetil, corticosteroids and cytotoxic antibodies.
Sirolimus in combination with other immunosuppressive agents has not been extensively investigated. Renal function should be monitored during concomitant administration of sirolimus and ciclosporin. Appropriate adjustment of the immunosuppression regimen should be considered in patients with elevated serum creatinine levels.
Caution should be exercised when co-administering other agents that are known to have a deleterious effect on renal function. Patients treated with ciclosporin and sirolimus beyond 3 months had higher serum creatinine levels and lower calculated glomerular filtration rates compared to patients treated with ciclosporin and placebo or azathioprine controls.
Patients who were successfully withdrawn from ciclosporin had lower serum creatinine levels and higher calculated glomerular filtration rates, as well as lower incidence of malignancy, compared to patients remaining on ciclosporin.
The continued co-administration of ciclosporin and sirolimus as maintenance therapy cannot be recommended. 1). Periodic quantitative monitoring of urinary protein excretion is recommended. 1). 8). 1). The concomitant use of sirolimus with a calcineurin inhibitor may increase the risk of calcineurin inhibitor-induced haemolytic uraemic syndrome/thrombotic thrombocytopaenic purpura/thrombotic microangiopathy (HUS/TTP/TMA).
HMG-CoA reductase inhibitors In clinical studies, the concomitant administration of sirolimus and HMG-CoA reductase inhibitors and/or fibrates was well-tolerated. During sirolimus therapy with or without CsA, patients should be monitored for elevated lipids, and patients administered an HMG-CoA reductase inhibitor and/or fibrate should be monitored for the possible development of rhabdomyolysis and other adverse reactions, as described in the respective Summary of Product Characteristics of these agents.
1.
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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Following the discontinuation of ciclosporin therapy, a target trough range of 12 to 20 ng/mL (chromatographic assay) is recommended. Ciclosporin inhibits the metabolism of sirolimus, and consequently sirolimus levels will decrease when ciclosporin is discontinued, unless the sirolimus dose is increased.
On average, the sirolimus dose will need to be 4-fold higher to account for both the absence of the pharmacokinetic interaction (2-fold increase) and the augmented immunosuppressive requirement in the absence of ciclosporin (2-fold increase).
The rate at which the dose of sirolimus is increased should correspond to the rate of ciclosporin elimination. If further dose adjustment(s) are required during maintenance therapy (after discontinuation of ciclosporin), in most patients these adjustments can be based on simple proportion: new medicine dose = current dose x (target concentration/current concentration).
A loading dose should be considered in addition to a new maintenance dose when it is necessary to considerably increase sirolimus trough concentrations: medicine loading dose = 3 x (new maintenance dose – current maintenance dose).
The maximum dose administered on any day should not exceed 40 mg. If an estimated daily dose exceeds 40 mg due to the addition of a loading dose, the loading dose should be administered over 2 days. Sirolimus trough concentrations should be monitored at least 3 to 4 days after a loading dose(s).
The recommended 24-hour trough concentration ranges for sirolimus are based on chromatographic methods. Several assay methodologies have been used to measure the whole blood concentrations of sirolimus. Currently in clinical practice, sirolimus whole blood concentrations are being measured by both chromatographic and immunoassay methodologies.
The concentration values obtained by these different methodologies are not interchangeable. All sirolimus concentrations reported in this Summary of Product Characteristics were either measured using chromatographic methods or have been converted to chromatographic method equivalents.
Adjustments to the targeted range should be made according to the assay being utilised to determine the sirolimus trough concentrations. Since results are assay and laboratory dependent, and the results may change over time, adjustment to the targeted therapeutic range must be made with a detailed knowledge of the site-specific assay used.
Physicians should therefore remain continuously informed by responsible representatives for their local laboratory on the performance of the locally used method for concentration determination of sirolimus. Patients with sporadic lymphangioleiomyomatosis (S-LAM) Treatment should be initiated by and remain under the guidance of an […]
The risk may increase as the trough sirolimus level increases. Rare reports of fatal hepatic necrosis have been reported with elevated trough sirolimus levels. Cases of interstitial lung disease (including pneumonitis and infrequently bronchiolitis obliterans organising pneumonia (BOOP) and pulmonary fibrosis), some fatal, with no identified infectious aetiology have occurred in patients receiving immunosuppressive regimens including sirolimus.
In some cases, the interstitial lung disease has resolved upon discontinuation or dose reduction of this medicine. The risk may be increased as the trough sirolimus level increases. , wound, vascular, airway, ureteral, biliary). Impairments of sperm parameters have been observed among some patients treated with this medicine.
3). In patients with delayed graft function, sirolimus may delay recovery of renal function. The concomitant use of sirolimus with a calcineurin inhibitor may increase the risk of calcineurin inhibitor-induced HUS/TTP/TMA. Focal segmental glomerulosclerosis has been reported.
There have also been reports of fluid accumulation, […]
Cytochrome P450 isozymes and P-glycoprotein Co-administration of sirolimus with strong inhibitors of CYP3A4 and/or the multidrug efflux pump P-glycoprotein (P-gp) (such as ketoconazole, voriconazole, itraconazole, telithromycin or clarithromycin) may increase sirolimus blood levels and is not recommended.
Co-administration with strong inducers of CYP3A4 and/or P-gp (such as rifampin, rifabutin) is not recommended. If co-administration of inducers or inhibitors of CYP3A4 and/or P-gp cannot be avoided, it is recommended that sirolimus whole blood trough concentrations and the clinical condition of the patient be monitored while they are concurrently administered with sirolimus and after their discontinuation.
5). Angioedema The concomitant administration of sirolimus and angiotensin-converting enzyme (ACE) inhibitors has resulted in angioneurotic oedema-type reactions. 5). In some cases, the angioedema has resolved upon discontinuation or dose reduction of sirolimus.
1). Patients receiving sirolimus should be monitored closely if taking ACE inhibitors concomitantly. Vaccination Immunosuppressants may affect response to vaccination. During treatment with immunosuppressants, including sirolimus, vaccination may be less effective.
The use of live vaccines should be avoided during treatment with sirolimus. 8). As usual for patients with increased risk for skin cancer, exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.
Infections Oversuppression of the immune system can also increase susceptibility to infection, including opportunistic infections (bacterial, fungal, viral and protozoal), fatal infections, and sepsis. Among these conditions in renal transplant patients are BK virus-associated […]