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Rapamune
Overview
What is Rapamune?
Rapamune (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 CHNO 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 benzyl alcohol, chloroform, acetone, and acetonitrile.
Rapamune is available for administration as an oral solution containing 1 mg/mL sirolimus. Rapamune is also available as a tan, triangular-shaped tablet containing 0.5 mg sirolimus, as a white, triangular-shaped tablet containing 1 mg sirolimus, and as a yellow-to-beige triangular-shaped tablet containing 2 mg sirolimus.
The inactive ingredients in Rapamune Oral Solution are Phosal 50 PG (phosphatidylcholine, propylene glycol, mono- and di-glycerides, ethanol, soy fatty acids, and ascorbyl palmitate) and polysorbate 80. Rapamune Oral Solution contains 1.5% – 2.5% ethanol.
The inactive ingredients in Rapamune Tablets include sucrose, lactose, polyethylene glycol 8000, calcium sulfate, microcrystalline cellulose, pharmaceutical glaze, talc, titanium dioxide, magnesium stearate, povidone, poloxamer 188, polyethylene glycol 20,000, glyceryl monooleate, carnauba wax, -alpha tocopherol, and other ingredients. The 0.5 mg and 2 mg dosage strengths also contain yellow iron (ferric) oxide and brown iron (ferric) oxide.
What does Rapamune look like?
What are the available doses of Rapamune?
What should I talk to my health care provider before I take Rapamune?
How should I use Rapamune?
Rapamune (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
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In patients at high-immunologic risk
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Rapamune is 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 Rapamune?
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What are the warnings of Rapamune?
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What are the precautions of Rapamune?
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What are the side effects of Rapamune?
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What should I look out for while using Rapamune?
Rapamune is contraindicated in patients with a hypersensitivity to Rapamune [].
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 Rapamune
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 Rapamune 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 Rapamune 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 de novo lung transplant patients when Rapamune has been used as part of an immunosuppressive regimen [].
What might happen if I take too much Rapamune?
Reports of overdose with Rapamune 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 Rapamune?
StorageStore Pantoprazole Sodium Delayed-Release Tablets, USP at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [ ]. StorageStore Pantoprazole Sodium Delayed-Release Tablets, USP at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [ ]. Since Rapamune is not absorbed through the skin, there are no special precautions. However, if direct contact of the oral solution occurs with the skin or eyes, wash skin thoroughly with soap and water; rinse eyes with plain water.Do not use RAPAMUNE after the expiration date that is located on the blister and carton. The expiration date refers to the last day of that month.Since Rapamune is not absorbed through the skin, there are no special precautions. However, if direct contact of the oral solution occurs with the skin or eyes, wash skin thoroughly with soap and water; rinse eyes with plain water.Do not use RAPAMUNE after the expiration date that is located on the blister and carton. The expiration date refers to the last day of that month.
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.
Lymphangioleiomyomatosis involves lung tissue infiltration with smooth muscle-like cells that harbor inactivating mutations of the tuberous sclerosis complex (TSC) gene (LAM cells). Loss of TSC gene function activates the mTOR signaling pathway, resulting in cellular proliferation and release of lymphangiogenic growth factors. Sirolimus inhibits the activated mTOR pathway and thus the proliferation of LAM cells.
Non-Clinical Toxicology
Rapamune is contraindicated in patients with a hypersensitivity to Rapamune [].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 Rapamune
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 Rapamune 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 Rapamune 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 de novo lung transplant patients when Rapamune has been used as part of an immunosuppressive regimen [].
Aminoglutethimide
Amphotericin B Injection and Potassium-depleting agents
Antibiotics
Anticholinesterases
Anticoagulants, Oral
Antidiabetics
Antitubercular Drugs
Cholestyramine
Cyclosporine
Dexamethasone Suppression Test (DST)
Digitalis Glycosides
Ephedrine
Estrogens, Including Oral Contraceptives
Ketoconazole
Nonsteroidal Anti-Inflammatory Agents (NSAIDS)
Phenytoin
Skin Tests
Thalidomide
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 0.7–3.2% (for Rapamune-treated patients) versus 0.6–0.8% (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 Rapamune 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 Rapamune 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 most common (≥ 20%) adverse reactions observed with Rapamune in the clinical study for the treatment of LAM are: stomatitis, diarrhea, abdominal pain, nausea, nasopharyngitis, acne, chest pain, peripheral edema, upper respiratory tract infection, headache, dizziness, myalgia, and hypercholesterolemia.
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. In patients with LAM, 11% of subjects discontinued due to adverse reactions, with no single adverse reaction leading to discontinuation in more than one patient being treated with Rapamune.
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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