Sirolimus (Page 11 of 12)

14.5 Conversion from a CNI-based Regimen to a Sirolimus-based Regimen in Liver Transplant Patients

Conversion from a CNI-based regimen to a sirolimus-based regimen was assessed in stable liver transplant patients 6 to 144 months post-transplant. The clinical study was a 2:1 randomized, multi-center, controlled trial conducted at 82 centers globally, including the US and Europe, and was intended to show that renal function was improved by conversion from a CNI to sirolimus without adversely impacting efficacy or safety. A total of 607 patients were enrolled.

The study failed to demonstrate superiority of conversion to a sirolimus-based regimen compared to continuation of a CNI-based regimen in baseline-adjusted GFR, as estimated by Cockcroft-Gault, at 12 months (62 mL/min in the sirolimus conversion group and 63 mL/min in the CNI continuation group). The study also failed to demonstrate non-inferiority, with respect to the composite endpoint consisting of graft loss and death (including patients with missing survival data) in the sirolimus conversion group compared to the CNI continuation group (6.6% versus 5.6%). The number of deaths in the sirolimus conversion group (15/393, 3.8%) was higher than in the CNI continuation group (3/214, 1.4%), although the difference was not statistically significant. The rates of premature study discontinuation (primarily due to adverse events or lack of efficacy), adverse events overall (infections, specifically), and biopsy-proven acute liver graft rejection at 12 months were all significantly greater in the sirolimus conversion group compared to the CNI continuation group

14.6 Pediatric Renal Transplant Patients

Sirolimus was evaluated in a 36-month, open-label, randomized, controlled clinical trial at 14 North American centers in pediatric (aged 3 to <18 years) renal transplant patients considered to be at high- immunologic risk for developing chronic allograft nephropathy, defined as a history of one or more acute allograft rejection episodes and/or the presence of chronic allograft nephropathy on a renal biopsy. Seventy-eight (78) subjects were randomized in a 2:1 ratio to sirolimus (sirolimus target concentrations of 5 to 15 ng/mL, by chromatographic assay, n = 53) in combination with a calcineurin inhibitor and corticosteroids or to continue calcineurin-inhibitor-based immunosuppressive therapy (n = 25). The primary endpoint of the study was efficacy failure as defined by the first occurrence of biopsy-confirmed acute rejection, graft loss, or death, and the trial was designed to show superiority of sirolimus added to a calcineurin-inhibitor-based immunosuppressive regimen compared to a calcineurin-inhibitor-based regimen. The cumulative incidence of efficacy failure up to 36 months was 45.3% in the sirolimus group compared to 44.0% in the control group, and did not demonstrate superiority. There was one death in each group. The use of sirolimus in combination with calcineurin inhibitors and corticosteroids was associated with an increased risk of deterioration of renal function, serum lipid abnormalities (including, but not limited to, increased serum triglycerides and cholesterol), and urinary tract infections [ see Warnings and Precautions (5.8) ]. This study does not support the addition of sirolimus oral solution to calcineurin-inhibitor-based immunosuppressive therapy in this subpopulation of pediatric renal transplant patients.

15 REFERENCES

Clinical Therapeutics , Volume 22, Supplement B, April 2000 [ see Dosage and Administration (2.5) ].

16 HOW SUPPLIED/STORAGE AND HANDLING

Since sirolimus oral solution 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 sirolimus oral solution after the expiration date. The expiration date refers to the last day of that month.

16.1 Sirolimus Oral Solution

Each Sirolimus Oral Solution carton, NDC 13668-658-87, 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 amber oral syringes and caps for daily dosing, and a carrying case.

Sirolimus oral solution bottles should be stored protected from light and refrigerated at 2 o C to 8 o C (36 o F to 46 o F). Once the bottle is opened, the contents should be used within one month. If necessary, the patient may store the bottles at 20 o to 25 o C (68 o to 77 o F) [see USP Controlled Room Temperature] for a short period of time (e.g. not more than 15 days for the bottles).

An amber syringe and cap are provided for dosing, and the product may be kept in the syringe for a maximum of 24 hours at room temperatures at 20 o to 25°C (68 o to 77°F) [see USP Controlled Room Temperature] 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.

Sirolimus 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.

17 PATIENT COUNSELING INFORMATION

Advise patients, their families, and their caregivers to read the Medication Guide and Instructions for Use for the oral solution and assist them in understanding its contents. The complete text of the Medication Guide and Instructions for Use for the oral solution are reprinted at the end of the document.

See FDA-Approved Medication Guide and Instructions for Use for the Oral Solution.

17.1 Dosage

Patients should be given complete dosage instructions [ see FDA-Approved Medication Guide ].

17.2 Skin Cancer Events

Advise patients that exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a broad spectrum sunscreen with a high protection factor because of the increased risk for skin cancer [ see Warnings and Precautions (5.18) ].

17.3 Pregnancy and Lactation

Advise female patients of reproductive potential to avoid becoming pregnant throughout treatment and for 12 weeks after sirolimus therapy has stopped. Sirolimus can cause fetal harm if taken during pregnancy. Advise a pregnant woman of the potential risk to her fetus. Before making a decision to breastfeed, inform the patient that the effects of breastfeeding in infants while taking this drug are unknown, but there is potential for serious adverse effects [ see Warnings and Precautions (5.15), Use in Specific Populations (8.1, 8.2, 8.3) ].

17.4 Infertility

Inform male and female patients that sirolimus may impair fertility [see Warnings and Precautions (5.16), Adverse Reactions (6.7), Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].

This product’s label may have been updated. For current Full Prescribing Information, please visit www.torrentpharma.com

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Manufactured by:
Cambrex Whippany, NJ 07981

Manufactured For: TORRENT PHARMA INC., Levittown, PA 19057.

Issued: January 2022

MEDICATION GUIDE

Sirolimus ( sir oh’ li mus ) Oral Solution

What is the most important information I should know about sirolimus oral solution?

Sirolimus oral solution 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 sirolimus oral solution.

Increased risk of getting certain cancers. People who take sirolimus oral solution have a higher risk of getting lymphoma, and other cancers, especially skin cancer. Talk with your doctor about your risk for cancer.

Sirolimus oral solution 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 sirolimus oral solution after a liver or lung transplant. You should not take sirolimus oral solution if you have had a liver or lung transplant without talking with your doctor.

See the section “What are the possible side effects of sirolimus oral solution?” for information about other side effects of sirolimus oral solution.

What is sirolimus oral solution?

Sirolimus oral solution 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.

Sirolimus oral solution is used with other medicines called cyclosporine (Gengraf, Neoral, Sandimmune), and corticosteroids. Your doctor will decide:

  • if sirolimus oral solution is right for you, and
  • how to best use it with cyclosporine and corticosteroids after your transplant.
It is not known if sirolimus oral solution is safe and effective in children under 13 years of age.

Who should not take sirolimus oral solution?

Do not take sirolimus oral solution if you are allergic to sirolimus or any of the other ingredients in sirolimus oral solution. See the end of this leaflet for a complete list of ingredients in sirolimus oral solution

What should I tell my doctor before taking sirolimus oral solution?

  • have liver problems
  • have skin cancer or it runs in your family
  • have high cholesterol or triglycerides (fat in your blood)
  • are pregnant or are a female who can become pregnant. Sirolimus oral solution may harm your unborn baby. You should not become pregnant during treatment with sirolimus oral solution and for 12 weeks after ending treatment with sirolimus oral solution. In order to avoid pregnancy, a female who can get pregnant should use effective birth control during treatment and for 12 weeks after your final dose of sirolimus oral solution. Talk with your doctor about what birth control method is right for you during this time. Tell your doctor right away if you become pregnant or think you are pregnant during treatment with sirolimus oral solution or within 12 weeks after your final dose of sirolimus oral solution.
  • It is not known whether sirolimus passes into breast milk; however, there is a risk of serious side effects in breastfed infants. You and your doctor should decide about the best way to feed your baby if you take sirolimus oral solution.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Using sirolimus oral solution with certain medicines may affect each other causing serious side effects.

Sirolimus oral solution may affect the way other medicines work, and other medicines may affect how sirolimus oral solution works. Especially tell your doctor if you take:

  • a medicine to lower your cholesterol or triglycerides
  • cyclosporine (including Gengraf, Neoral, Sandimmune) or tacrolimus (Prograf) or other medicines that suppress the immune system
  • an antibiotic
  • an antifungal medicine
  • a medicine for high blood pressure or heart problems
  • an anti-seizure medicine
  • medicines used to treat stomach acid, ulcers, or other gastrointestinal problems
  • bromocriptine mesylate (Parlodel, Cycloset)
  • danazol
  • medicines to treat HIV or hepatitis C
  • St. John’s Wort

How should I take sirolimus oral solution?

  • Read the Instructions for Use that comes with your sirolimus oral solution for information about the right way to take sirolimus oral solution.
  • Take sirolimus oral solution exactly as your doctor tells you to take it.
  • Your doctor will tell you how much sirolimus oral solution to take and when to take it. Do not change your dose of sirolimus oral solution unless your doctor tells you to.
  • If you also take cyclosporine (Gengraf, Neoral, Sandimmune), you should take your sirolimus oral solution and cyclosporine about 4 hours apart.
  • Do not stop taking sirolimus oral solution or your other anti-rejection medicines unless your doctor tells you to.
  • Your doctor will check the levels of sirolimus oral solution in your blood. Your doctor may change your dose of sirolimus oral solution depending on your blood test results.
  • Sirolimus oral solution is taken by mouth 1 time each day.
  • Take each dose of sirolimus oral solution the same way, either with or without food. Food can affect the amount of medicine that gets into your bloodstream. Taking each dose of sirolimus oral solution the same way helps keep your blood levels of sirolimus oral solution more stable. Do not take sirolimus oral solution with grapefruit juice.
  • Sirolimus oral solution can develop a slight haze when it is refrigerated. If this happens, bring the sirolimus oral solution to room temperature and then gently shake the bottle until the haze goes away.
  • If you get sirolimus oral solution on your skin, wash the area with soap and water.
  • If you get sirolimus oral solution in your eyes, rinse your eyes with water.
  • If you have taken more medicine than you were told, contact a doctor or go to the nearest hospital emergency department right away.

What should I avoid while taking sirolimus oral solution ?

  • Avoid receiving live vaccines while taking sirolimus oral solution . Some vaccines may not work as well while you are taking sirolimus oral solution .
  • Limit your time in sunlight and UV light. Cover your skin with clothing and use a broad-spectrum sunscreen with a high protection factor because of the increased risk for skin cancer with sirolimus oral solution.

What are the possible side effects of sirolimus oral solution ?

Sirolimus oral solution may cause serious side effects, including:

  • See “What is the most important information I should know about sirolimus oral solution?”
  • Serious allergic reactions. Tell your doctor or get medical help right away if you get any of following symptoms of an allergic reaction:
    • swelling of your face, eyes, or mouth o chest pain or tightness
    • trouble breathing or wheezing o feeling dizzy or faint
    • throat tightness o rash or peeling of your skin
    • Swelling (edema). Fluid may collect in your hands and feet and in various tissues of your body, including in the sac around your heart or lungs. Call your doctor if you have trouble breathing.
    • Poor wound healing. Sirolimus oral solution may cause your wounds to heal slowly or not heal well. Tell your doctor if you have any redness or drainage, your wound does not heal, or the wound opens up.
    • Increased levels of cholesterol and triglycerides (lipids or fat) in your blood. Your doctor should do blood tests to check your lipids during treatment with sirolimus oral solution . Your doctor may prescribe treatment with diet, exercise, or medicine if your lipid levels are too high. During treatment with sirolimus oral solution, your blood levels of cholesterol and triglycerides may remain high even if you follow your prescribed treatment plan.
    • Effects on kidney function. When sirolimus oral solution is taken with cyclosporine (Gengraf, Neoral, Sandimmune), the function of your transplanted kidney may be affected. Your doctor should regularly do tests to check your kidney function while you are taking sirolimus oral solution with cyclosporine (Gengraf, Neoral, Sandimmune).
    • Increased protein in your urine. Your doctor may regularly test your urine protein.
    • Increased risk for viral infections.
      • Certain viruses can live in your body and cause active infections when your immune system is weak. BK virus can affect how your kidney works and cause your transplanted kidney to fail.
      • A certain virus can cause a rare serious brain infection called Progressive Multifocal Leukoencephalopathy (PML). PML usually causes death or severe disability. Call your doctor right away if you notice any new or worsening medical problems such as:
        • confusion
        • sudden change in thinking, walking, strength on one side of your body
        • other problems that have lasted over several days
        • Lung or breathing problems. This can sometimes lead to death. Tell your doctor if you have a new or worsening cough, shortness of breath, difficulty breathing or any new breathing problems. Your doctor may need to stop sirolimus oral solution or lower your dose.
        • Blood clotting problems. When sirolimus oral solution is taken with cyclosporine or tacrolimus, you may develop a blood clotting problem. Tell your doctor if you get any unexplained bleeding or bruising.
        • Possible harm to your unborn baby. Sirolimus oral solution can harm your unborn baby. You should not become pregnant during treatment with sirolimus oral solution and for 12 weeks after ending treatment with sirolimus oral solution . See “What should I tell my doctor before taking sirolimus oral solution?”.

The most common side effects of sirolimus oral solution in people with renal transplant include:

  • high blood pressure o urinary tract infection
  • pain (including stomach and joint pain) o low red blood cell count (anemia)
  • diarrhea o nausea
  • headache o low platelet count (cells that help blood to clot)
  • fever o high blood sugar (diabetes)

Other side effects that may occur with sirolimus oral solution:

  • Sirolimus oral solution may affect fertility in females and may affect your ability to become pregnant. Talk to your healthcare provider if this is a concern for you.
  • Sirolimus oral solution may affect fertility in males and may affect your ability to father a child. Talk to your healthcare provider if this is a concern for you.

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all of the possible side effects of sirolimus oral solution. For more information ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store sirolimus oral solution?

Sirolimus oral solution:
  • Store bottles of sirolimus oral solution in the refrigerator between 36°F to 46°F (2°C to 8°C).
  • Protect from light.
  • If necessary, bottles of sirolimus oral solution can be stored at room temperature up to 77°F (25°C) for up to 15 days.
  • When a bottle of sirolimus oral solution is opened, it should be used within 1 month.
  • Use any diluted sirolimus oral solution right away.

Do not use sirolimus oral solution after the expiration date. The expiration date refers to the last day of that month. Safely throw away medicine that is out of date or no longer needed.

Keep sirolimus oral solution and all medicines out of the reach of children.

General Information about the safe and effective use of sirolimus oral solution.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use sirolimus oral solution for a condition for which it was not prescribed. Do not give sirolimus oral solution to other people even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about sirolimus oral solution . If you would like more information, talk to your doctor. You can ask your pharmacist or doctor for information about sirolimus oral solution that is written for health professionals.

For more information, go to www.torrentpharma.com or call 1-800-912-9561

What are the ingredients in sirolimus oral solution?

Active ingredients: sirolimus

Inactive ingredients: Sirolimus oral solution: Phosal 50 PG ® ( alcohol (ethanol), ascorbyl palmitate,phosphatidylcholine, propylene glycol, soy acid (fatty acid), sunflower seed oil glyceride, and tocopherol ) and polysorbate 80.

Sirolimus oral solution contains 1.5% to 2.5% ethanol.

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Manufactured by: Cambrex Whippany, NJ 07981

Manufactured For TORRENT PHARMA INC., Levittown, PA 19057

This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued 01/2022

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