RAPAMUNE- sirolimus solution RAPAMUNE- sirolimus tablet, sugar coated

Country: United States

Language: English

Source: NLM (National Library of Medicine)

Active ingredient:

SIROLIMUS (UNII: W36ZG6FT64) (SIROLIMUS - UNII:W36ZG6FT64)

Available from:

Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer Inc.

INN (International Name):

SIROLIMUS

Composition:

SIROLIMUS 1 mg in 1 mL

Administration route:

ORAL

Prescription type:

PRESCRIPTION DRUG

Therapeutic indications:

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 , it is recommended that Rapamune be used initially in a regimen with cyclosporine and corticosteroids; cyclosporine should be withdrawn 2 to 4 months after transplantation [see Dosage and Administration (2.2) ]. In patients at high-immunologic risk (defined as Black recipients and/or repeat renal transplant recipients who lost a previous allograft for immunologic reason and/or patients with high panel-reactive antibodies [PRA; peak PRA level >80%]), it is recommended that Rapamune be used in combination with cyclosporine and corticosteroids for the first year following transplantation [see Dosage and Administration (2.3) , Clinical Studies (14.3) ]. Cyclosporine withdrawal has not been studied in patients with Banff Grade 3 acute rejection or vascular rejection prior to cyclosporine withdrawal, those who are dialysis-dependent, those with serum creatinine >4.5 mg/dL, Black patients, patients of multi-organ transplants, secondary transplants, or those with high levels of panel-reactive antibodies [see Clinical Studies (14.2) ]. In patients at high-immunologic risk , the safety and efficacy of Rapamune used in combination with cyclosporine and corticosteroids has not been studied beyond one year; therefore after the first 12 months following transplantation, any adjustments to the immunosuppressive regimen should be considered on the basis of the clinical status of the patient [see Clinical Studies (14.3) ]. In pediatric patients , the safety and efficacy of Rapamune have not been established in patients <13 years old, or in pediatric (<18 years) renal transplant patients considered at high-immunologic risk [see Adverse Reactions (6.5), Clinical Studies (14.6) ]. The safety and efficacy of de novo use of Rapamune without cyclosporine have not been established in renal transplant patients [see Warnings and Precautions (5.12) ]. The safety and efficacy of conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant patients have not been established [see Clinical Studies (14.4) ]. Rapamune (sirolimus) is indicated for the treatment of patients with lymphangioleiomyomatosis (LAM). Rapamune is contraindicated in patients with a hypersensitivity to Rapamune [see Warnings and Precautions (5.4) ]. Risk Summary Based on animal studies and the mechanism of action, Rapamune can cause fetal harm when administered to a pregnant woman [see Data, Clinical Pharmacology (12.1) ]. There are limited data on the use of sirolimus during pregnancy; however, these data are insufficient to inform a drug-associated risk of adverse developmental outcomes. In animal studies, sirolimus was embryo/fetotoxic in rats at sub-therapeutic doses [see Data ]. Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Data Animal Data Sirolimus crossed the placenta and was toxic to the conceptus. In rat embryo-fetal development studies, pregnant rats were administered sirolimus orally during the period of organogenesis (Gestational Day 6–15). Sirolimus produced embryo-fetal lethality at 0.5 mg/kg (2.5-fold the clinical dose of 2 mg, on a body surface area basis) and reduced fetal weight at 1 mg/kg (5-fold the clinical dose of 2 mg). The no observed adverse effect level (NOAEL) for fetal toxicity in rats was 0.1 mg/kg (0.5-fold the clinical dose of 2 mg). Maternal toxicity (weight loss) was observed at 2 mg/kg (10-fold the clinical dose of 2 mg). The NOAEL for maternal toxicity was 1 mg/kg. In combination with cyclosporine, rats had increased embryo-fetal mortality compared with sirolimus alone. In rabbit embryo-fetal development studies, pregnant rabbits were administered sirolimus orally during the period of organogenesis (Gestational Day 6–18). There were no effects on embryo-fetal development at doses up to 0.05 mg/kg (0.5-fold the clinical dose of 2 mg, on a body surface area basis); however, at doses of 0.05 mg/kg and above, the ability to sustain a successful pregnancy was impaired (i.e., embryo-fetal abortion or early resorption). Maternal toxicity (decreased body weight) was observed at 0.05 mg/kg. The NOAEL for maternal toxicity was 0.025 mg/kg (0.25-fold the clinical dose of 2 mg). In a pre- and post-natal development study in rats, pregnant females were dosed during gestation and lactation (Gestational Day 6 through Lactation Day 20). An increased incidence of dead pups, resulting in reduced live litter size, occurred at 0.5 mg/kg (2.5-fold the clinical dose of 2 mg/kg on a body surface area basis). At 0.1 mg/kg (0.5-fold the clinical dose of 2 mg), there were no adverse effects on offspring. Sirolimus did not cause maternal toxicity or affect developmental parameters in the surviving offspring (morphological development, motor activity, learning, or fertility assessment) at 0.5 mg/kg, the highest dose tested. Risk Summary It is not known whether sirolimus is present in human milk. There are no data on its effects on the breastfed infant or milk production. The pharmacokinetic and safety profiles of sirolimus in infants are not known. Sirolimus is present in the milk of lactating rats. There is potential for serious adverse effects from sirolimus in breastfed infants based on mechanism of action [see Clinical Pharmacology (12.1)]. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Rapamune and any potential adverse effects on the breastfed child from Rapamune. Contraception Females should not be pregnant or become pregnant while receiving Rapamune. Advise females of reproductive potential that animal studies have been shown Rapamune to be harmful to the developing fetus. Females of reproductive potential are recommended to use highly effective contraceptive method. Effective contraception must be initiated before Rapamune therapy, during Rapamune therapy, and for 12 weeks after Rapamune therapy has been stopped [see Warnings and Precautions (5.15), Use in Specific Populations (8.1) ]. Infertility Based on clinical findings and findings in animals, male and female fertility may be compromised by the treatment with Rapamune [see Adverse Reactions (6.7), Nonclinical Toxicology (13.1) ]. Ovarian cysts and menstrual disorders (including amenorrhea and menorrhagia) have been reported in females with the use of Rapamune. Azoospermia has been reported in males with the use of Rapamune and has been reversible upon discontinuation of Rapamune in most cases. Renal Transplant The safety and efficacy of Rapamune in pediatric patients <13 years have not been established. The safety and efficacy of Rapamune Oral Solution and Rapamune Tablets have been established for prophylaxis of organ rejection in renal transplantation in children ≥13 years judged to be at low- to moderate-immunologic risk. Use of Rapamune Oral Solution and Rapamune Tablets in this subpopulation of children ≥ 13 years is supported by evidence from adequate and well-controlled trials of Rapamune Oral Solution in adults with additional pharmacokinetic data in pediatric renal transplantation patients [see Clinical Pharmacology (12.3) ]. Safety and efficacy information from a controlled clinical trial in pediatric and adolescent (< 18 years of age) renal transplant patients judged to be at high-immunologic risk, defined as a history of one or more acute rejection episodes and/or the presence of chronic allograft nephropathy, do not support the chronic use of Rapamune Oral Solution or Tablets in combination with calcineurin inhibitors and corticosteroids, due to the higher incidence of lipid abnormalities and deterioration of renal function associated with these immunosuppressive regimens compared to calcineurin inhibitors, without increased benefit with respect to acute rejection, graft survival, or patient survival [see Clinical Studies (14.6) ]. Lymphangioleiomyomatosis The safety and efficacy of Rapamune in pediatric patients <18 years have not been established. Clinical studies of Rapamune Oral Solution or Tablets did not include sufficient numbers of patients ≥65 years to determine whether they respond differently from younger patients. Data pertaining to sirolimus trough concentrations suggest that dose adjustments based upon age in geriatric renal patients are not necessary. Differences in responses between the elderly and younger patients have not been identified. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, or cardiac function, and of concomitant disease or other drug therapy. The maintenance dose of Rapamune should be reduced in patients with hepatic impairment [see Dosage and Administration (2.7), Clinical Pharmacology (12.3) ]. Dosage adjustment is not required in patients with renal impairment [see Dosage and Administration (2.8), Clinical Pharmacology (12.3) ]. RAPAMUNE / RAAP-a-mune/ (sirolimus) Oral Solution Be sure that you read and understand the following instructions for the correct way to dilute and take RAPAMUNE Oral Solution. Ask your pharmacist or doctor if you are not sure. Important: Each RAPAMUNE Oral Solution carton contains: You will also need: Figure 1: Opening the bottle 1. Open the solution bottle. Figure 2: Inserting adapter 2. The first time you use a bottle of RAPAMUNE Oral Solution: Figure 3: Inserting syringe 3. Use a new disposable amber oral syringe for each dose of RAPAMUNE Oral Solution. Figure 4: Withdrawing solution 4. Withdraw the prescribed amount of RAPAMUNE Oral Solution: Figure 5: Capping syringe 5. If your doctor tells you to carry your medicine with you: Figure 6: Placing syringe in carrying case Figure 7: Emptying syringe into glass 6. Taking a dose of RAPAMUNE Oral Solution: 7. Always store the bottles of medication in the refrigerator. How should I store RAPAMUNE? Keep RAPAMUNE and all medicines out of the reach of children. This Instructions for Use has been approved by the U.S. Food and Drug Administration. LAB-0579-6.0 Revised: August 2022

Product summary:

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. The expiration date refers to the last day of that month. Each Rapamune Oral Solution carton, NDC 0008-1030-06, contains one 2 oz (60 mL fill) amber glass bottle of sirolimus (concentration of 1 mg/mL), one oral syringe adapter for fitting into the neck of the bottle, sufficient disposable oral syringes (amber color) and caps for daily dosing, and a carrying case. Rapamune Oral Solution bottles should be stored protected from light and refrigerated at 2°C to 8°C (36°F to 46°F). Once the bottle is opened, the contents should be used within one month. If necessary, the patient may store the bottles at room temperatures up to 25°C (77°F) for a short period of time (e.g., not more than 15 days for the bottles). A syringe (amber color) and cap are provided for dosing, and the product may be kept in the syringe for a maximum of 24 hours at room temperatures up to 25°C (77°F) or refrigerated at 2°C to 8°C (36°F to 46°F). The syringe should be discarded after one use. After dilution, the preparation should be used immediately. Rapamune Oral Solution provided in bottles may develop a slight haze when refrigerated. If such a haze occurs, allow the product to stand at room temperature and shake gently until the haze disappears. The presence of this haze does not affect the quality of the product. Rapamune Tablets are available as follows: Rapamune Tablets should be stored at 20°C to 25°C [USP Controlled Room Temperature] (68°F to 77°F). Use cartons to protect blister cards and strips from light. Dispense in a tight, light-resistant container as defined in the USP.

Authorization status:

New Drug Application

Patient Information leaflet

RAPAMUNE- SIROLIMUS TABLET, SUGAR COATED
Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer Inc.
----------
This Medication Guide has been approved by the U.S. Food and
Drug Administration.
Revised Aug 2022
MEDICATION GUIDE
RAPAMUNE® (RAAP-a-mune) (sirolimus) Tablets
RAPAMUNE® (RAAP-a-mune) (sirolimus) Oral Solution
What is the most important information I should know about RAPAMUNE?
Rapamune can cause serious side effects, including:
•
Increased risk of getting infections. Serious infections can happen
including infections caused by
viruses, bacteria, and fungi (yeast). Your doctor may put you on
medicine to help prevent some of
these infections.
Call your doctor right away if you have symptoms of infection
including fever or chills while
taking Rapamune.
•
Increased risk of getting certain cancers. People who take Rapamune
have a higher risk of getting
lymphoma, and other cancers, especially skin cancer. Talk with your
doctor about your risk for
cancer.
RAPAMUNE has not been shown to be safe and effective in people who
have had liver or lung
transplants. Serious complications and death may happen in people who
take RAPAMUNE after a liver
or lung transplant. You should not take RAPAMUNE if you have had a
liver or lung transplant without
talking with your doctor.
See the section "What are the possible side effects of RAPAMUNE?" for
information about other side
effects of RAPAMUNE.
What is RAPAMUNE?
RAPAMUNE is a prescription medicine used to prevent rejection
(anti-rejection medicine) in people 13
years of age and older who have received a kidney transplant.
Rejection is when your body's immune
system recognizes the new organ as a "foreign" threat and attacks it.
RAPAMUNE is used with other medicines called cyclosporine (Gengraf,
Neoral, Sandimmune), and
corticosteroids. Your doctor will decide:
•
if RAPAMUNE is right for you, and
•
how to best use it with cyclosporine and corticosteroids after your
transplant.
It is not known if RAPAMUNE is safe and effective in children under 13
years of age.
RAPAMUNE

Summary of Product characteristics

RAPAMUNE- SIROLIMUS SOLUTION
RAPAMUNE- SIROLIMUS TABLET, SUGAR COATED
WYETH PHARMACEUTICALS LLC, A SUBSIDIARY OF PFIZER INC.
----------
HIGHLIGHTS OF PRESCRIBING INFORMATION
THESE HIGHLIGHTS DO NOT INCLUDE ALL THE INFORMATION NEEDED TO USE
RAPAMUNE SAFELY AND
EFFECTIVELY. SEE FULL PRESCRIBING INFORMATION FOR RAPAMUNE.
RAPAMUNE (SIROLIMUS) ORAL SOLUTION
RAPAMUNE (SIROLIMUS) TABLETS, FOR ORAL USE
INITIAL U.S. APPROVAL: 1999
WARNING: IMMUNOSUPPRESSION, USE IS NOT RECOMMENDED IN LIVER OR LUNG
TRANSPLANT PATIENTS
_SEE FULL PRESCRIBING INFORMATION FOR COMPLETE BOXED WARNING._
•
•
RECENT MAJOR CHANGES
Warnings and Precautions, Cannabidiol Drug Interactions (5.21)
8/2022
INDICATIONS AND USAGE
•
•
DOSAGE AND ADMINISTRATION
Renal Transplant Patients:
•
•
•
•
_In renal transplant patients at low-to moderate-immunologic risk_:
INCREASED SUSCEPTIBILITY TO INFECTION AND THE POSSIBLE DEVELOPMENT OF
LYMPHOMA
AND OTHER MALIGNANCIES MAY RESULT FROM IMMUNOSUPPRESSION (5.1). 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.
THE SAFETY AND EFFICACY OF RAPAMUNE AS IMMUNOSUPPRESSIVE THERAPY HAVE
NOT
BEEN ESTABLISHED IN LIVER OR LUNG TRANSPLANT PATIENTS, AND THEREFORE,
SUCH USE IS NOT
RECOMMENDED (5.2_, _5.3).
o
o
LIVER TRANSPLANTATION – EXCESS MORTALITY, GRAFT LOSS, AND HEPATIC
ARTERY
THROMBOSIS (5.2).
LUNG TRANSPLANTATION – BRONCHIAL ANASTOMOTIC DEHISCENCE (5.3).
Rapamune is an mTOR inhibitor immunosuppressant indicated for the
prophylaxis of organ rejection in
patients aged ≥13 years receiving renal transplants:
o
o
Patients at low- to moderate-immunologic risk: Use initially with
cyclosporine (CsA) and
corticosteroids. CsA withdrawal is recommended 2–4 months after
transplantation (1.1).
Patients at high-immunologic risk: Use in combination with CsA and
corticosteroids for the first
12 months following transplantation (1.1). Safety and efficacy of CsA
withdrawal ha