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Sirolimus
Overview
What is Sirolimus?
Sirolimus is an immunosuppressive agent. Sirolimus is a macrocyclic lactone produced by
. The chemical name of sirolimus (also known as rapamycin) is (3
,6
,7
,9
,10
,12
,14
,15
,17
,19
,21
,23
,26
,27
,34a
)9,10,12,13,14,21,22,23,24,25,26,27,32,33,34, 34a-hexadecahydro-9,27-dihydroxy-3-[(1
)-2 [(1
,3
,4
)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26 hexamethyl-23,27-epoxy-3
-pyrido[2,1-c][1,4] oxaazacyclohentriacontine-1,5,11,28,29 (4
,6
,31
)-pentone. Its molecular formula is C
H
NO
and its molecular weight is 914.2. The structural formula of sirolimus is illustrated as follows.
Sirolimus is a white to off-white powder and is insoluble in water, but freely soluble in chloroform, acetone and acetonitrile.
Sirolimus tablets are available as a white, triangular shaped tablet containing 1 mg sirolimus, and as a creamish yellow, triangular shaped tablet containing 2 mg sirolimus.
The inactive ingredients in sirolimus tablets includes, carnauba wax, ethyl cellulose, hydroxypropyl methylcellulose 5 cps, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose (avicel pH 105), microcrystalline cellulose (avicel pH 200), poloxamer 188, polyethylene glycol 20000, polyethylene glycol 8000, sucrose, titanium dioxide, vitamin E preparation, seal coating agent opaglos clear NA 7150, and imprinting ink opacode red (S-1-15052). The 2 mg dosage strength also contains iron oxide red and iron oxide yellow.
Seal coating agent opaglos clear NA 7150 contains, acetylated monoglyceride, industrial methylated spirit 74 OP, povidone, and shellac.
Imprinting ink opacode red (S-1-15052) contains, ammonium hydroxide, FD&C Red # 40, propylene glycol, shellac glaze, and titanium dioxide.
What does Sirolimus look like?
What are the available doses of Sirolimus?
What should I talk to my health care provider before I take Sirolimus?
How should I use Sirolimus?
Sirolimus tablets are 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,
see
In patients at high-immunologic risk
see
Sirolimus tablets are to be administered orally once daily, consistently with or without food [
].
Tablets should not be crushed, chewed or split. Patients unable to take the tablets should be prescribed the solution and instructed in its use.
What interacts with Sirolimus?
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What are the warnings of Sirolimus?
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What are the precautions of Sirolimus?
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What are the side effects of Sirolimus?
Sorry No records found
What should I look out for while using Sirolimus?
Sirolimus is contraindicated in patients with a hypersensitivity to sirolimus [
].
Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression. Only physicians experienced in immunosuppressive therapy and management of renal transplant patients should use sirolimus for prophylaxis of organ rejection in patients receiving renal transplants. 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 [
]
The use of sirolimus in combination with tacrolimus was associated with excess mortality and graft loss in a study in
liver transplant patients. Many of these patients had evidence of infection at or near the time of death.
In this and another study in
liver transplant patients, the use of sirolimus in combination with cyclosporine or tacrolimus was associated with an increase in HAT; most cases of HAT occurred within 30 days post-transplantation and most led to graft loss or death [
].
Cases of bronchial anastomotic dehiscence, most fatal, have been reported in
lung transplant patients when sirolimus has been used as part of an immunosuppressive regimen [
].
What might happen if I take too much Sirolimus?
Reports of overdose with sirolimus have been received; however, experience has been limited. In general, the adverse effects of overdose are consistent with those listed in the adverse reactions section [
].
General supportive measures should be followed in all cases of overdose. Based on the low aqueous solubility and high erythrocyte and plasma protein binding of sirolimus, it is anticipated that sirolimus is not dialyzable to any significant extent. In mice and rats, the acute oral LD
was greater than 800 mg/kg.
How should I store and handle Sirolimus?
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].Dispense in well-closed containers as defined in the USP.Keep out of reach of children.Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].Dispense in well-closed containers as defined in the USP.Keep out of reach of children.Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].Dispense in well-closed containers as defined in the USP.Keep out of reach of children.Since sirolimus is not absorbed through the skin, there are no special precautions.
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
Sirolimus inhibits T-lymphocyte activation and proliferation that occurs in response to antigenic and cytokine (Interleukin [IL]-2, IL-4, and IL-15) stimulation by a mechanism that is distinct from that of other immunosuppressants. Sirolimus also inhibits antibody production. In cells, sirolimus binds to the immunophilin, FK Binding Protein-12 (FKBP-12), to generate an immunosuppressive complex. The sirolimus:FKBP-12 complex has no effect on calcineurin activity. This complex binds to and inhibits the activation of the mammalian Target Of Rapamycin (mTOR), a key regulatory kinase. This inhibition suppresses cytokine-driven T-cell proliferation, inhibiting the progression from the G
to the S phase of the cell cycle.
Studies in experimental models show that sirolimus prolongs allograft (kidney, heart, skin, islet, small bowel, pancreatico-duodenal, and bone marrow) survival in mice, rats, pigs, and/or primates. Sirolimus reverses acute rejection of heart and kidney allografts in rats and prolongs the graft survival in presensitized rats. In some studies, the immunosuppressive effect of sirolimus lasts up to 6 months after discontinuation of therapy. This tolerization effect is alloantigen-specific.
In rodent models of autoimmune disease, sirolimus suppresses immune-mediated events associated with systemic lupus erythematosus, collagen-induced arthritis, autoimmune type I diabetes, autoimmune myocarditis, experimental allergic encephalomyelitis, graft-versus-host disease, and autoimmune uveoretinitis.
Non-Clinical Toxicology
Sirolimus is contraindicated in patients with a hypersensitivity to sirolimus [ ].Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression. Only physicians experienced in immunosuppressive therapy and management of renal transplant patients should use sirolimus for prophylaxis of organ rejection in patients receiving renal transplants. 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 [ ]
The use of sirolimus in combination with tacrolimus was associated with excess mortality and graft loss in a study in liver transplant patients. Many of these patients had evidence of infection at or near the time of death.
In this and another study in liver transplant patients, the use of sirolimus in combination with cyclosporine or tacrolimus was associated with an increase in HAT; most cases of HAT occurred within 30 days post-transplantation and most led to graft loss or death [ ].
Cases of bronchial anastomotic dehiscence, most fatal, have been reported in lung transplant patients when sirolimus has been used as part of an immunosuppressive regimen [ ].
Antipsychotic drugs such as phenothiazines or haloperidol; tricyclic antidepressants (see ).
Increased susceptibility to infection and the possible development of lymphoma and other malignancies, particularly of the skin, may result from immunosuppression. The rates of lymphoma/lymphoproliferative disease observed in Studies 1 and 2 were 0.7 to 3.2% (for sirolimus-treated patients) versus 0.6 to 0.8% (azathioprine and placebo control) [ and ]. Oversuppression of the immune system can also increase susceptibility to infection, including opportunistic infections such as tuberculosis, fatal infections, and sepsis. Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should use sirolimus for prophylaxis of organ rejection in patients receiving renal transplants. 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.
The following adverse reactions are discussed in greater detail in other sections of the label.
The most common (≥ 30%) adverse reactions observed with sirolimus in clinical studies for organ rejection prophylaxis in recipients of renal transplantation are: peripheral edema, hypertriglyceridemia, hypertension, hypercholesterolemia, creatinine increased, constipation, abdominal pain, diarrhea, headache, fever, urinary tract infection, anemia, nausea, arthralgia, pain, and thrombocytopenia.
The following adverse reactions resulted in a rate of discontinuation of >5% in clinical trials for renal transplant rejection prophylaxis: creatinine increased, hypertriglyceridemia, and TTP.
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
While we update our database periodically, we cannot guarantee it is always updated to the latest version.
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