Sirolimus (Page 4 of 12)

5.12 De Novo Use Without Cyclosporine

The safety and efficacy of de novo use of sirolimus without cyclosporine is not established in renal transplant patients. In a multicenter clinical study, de novo renal transplant patients treated with sirolimus, mycophenolate mofetil (MMF), steroids, and an IL-2 receptor antagonist had significantly higher acute rejection rates and numerically higher death rates compared to patients treated with cyclosporine, MMF, steroids, and IL-2 receptor antagonist. A benefit, in terms of better renal function, was not apparent in the treatment arm with de novo use of sirolimus without cyclosporine. These findings were also observed in a similar treatment group of another clinical trial.

5.13 Increased Risk of Calcineurin Inhibitor-Induced Hemolytic Uremic Syndrome/Thrombotic Thrombocytopenic Purpura/Thrombotic Microangiopathy

The concomitant use of sirolimus with a calcineurin inhibitor may increase the risk of calcineurin inhibitor- induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA) [ see Adverse Reactions (6.7) ].

5.14 Antimicrobial Prophylaxis

Cases of Pneumocystis carinii pneumonia have been reported in transplant patients not receiving antimicrobial prophylaxis. Therefore, antimicrobial prophylaxis for Pneumocystis carinii pneumonia should be administered for 1 year following transplantation.

Cytomegalovirus (CMV) prophylaxis is recommended for 3 months after transplantation, particularly for patients at increased risk for CMV disease

5.15 Embryo-Fetal Toxicity

Based on animal studies and the mechanism of action [ see Clinical Pharmacology (12.1) ], sirolimus can cause fetal harm when administered to a pregnant woman. In animal studies, sirolimus caused embryo-fetal toxicity when administered during the period of organogenesis at maternal exposures that were equal to or less than human exposures at the recommended lowest starting dose. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to avoid becoming pregnant and to use highly effective contraception while using sirolimus and for 12 weeks after ending treatment [ see Use in Specific Populations (8.1) ].

5.16 Male Infertility

Azoospermia or oligospermia may be observed [ see Adverse Reactions (6.2), Nonclinical Toxicology (13.1) ]. Sirolimus is an anti-proliferative drug and affects rapidly dividing cells like the germ cells.

5.17 Different Sirolimus Trough Concentration Reported between Chromatographic and Immunoassay Methodologies

Currently in clinical practice, sirolimus whole blood concentrations are being measured by various chromatographic and immunoassay methodologies. Patient sample concentration values from different assays may not be interchangeable [ see Dosage and Administration (2.5) ].

5.18 Skin Cancer Events

Patients on immunosuppressive therapy are at increased risk for skin cancer. 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 [ see Adverse Reactions (6.1, 6.2, 6.7) ].

5.19 Immunizations

The use of live vaccines should be avoided during treatment with sirolimus; live vaccines may include, but are not limited to, the following: measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid. Immunosuppressants may affect response to vaccination. Therefore, during treatment with sirolimus, vaccination may be less effective.

5.20 Interaction with Strong Inhibitors and Inducers of CYP3A4 and/or P-gp

Avoid concomitant use of sirolimus with strong inhibitors of CYP3A4 and/or P-gp (such as ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, or clarithromycin) or strong inducers of CYP3A4 and/or P-gp (such as rifampin or rifabutin) [ see Drug Interactions (7.2) ].

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the label.

• Increased susceptibility to infection, lymphoma, and malignancy [see Boxed Warning, Warnings and Precautions ( 5.1)]
• Excess mortality, graft loss, and hepatic artery thrombosis in liver transplant patients [see Boxed Warning, Warnings and Precautions ( 5.2)]
• Bronchial anastomotic dehiscence in lung transplant patients [see Boxed Warning, Warnings and Precautions ( 5.3)]
• Hypersensitivity reactions [see Warnings and Precautions ( 5.4)]
• Exfoliative dermatitis [see Warnings and Precautions ( 5.4)]
• Angioedema [see Warnings and Precautions ( 5.5)]
• Fluid accumulation and impairment of wound healing [see Warnings and Precautions ( 5.6)]
• Hypertriglyceridemia, hypercholesterolemia [see Warnings and Precautions ( 5.7)]
• Decline in renal function in long-term combination of cyclosporine with sirolimus [see Warnings and Precautions ( 5.8)]
• Proteinuria [see Warnings and Precautions ( 5.9)]
• Interstitial lung disease [see Warnings and Precautions ( 5.11)]
• Increased risk of calcineurin inhibitor-induced HUS/TTP/TMA [see Warnings and Precautions ( 5.13)]
• Embryo-fetal toxicity [see Warnings and Precautions ( 5.15)] • Male infertility [see Warnings and Precautions ( 5.16)].

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.

6.1 Clinical Studies Experience in Prophylaxis of Organ Rejection Following Renal Transplantation

The safety and efficacy of sirolimus oral solution for the prevention of organ rejection following renal transplantation were assessed in two randomized, double-blind, multicenter, controlled trials [see Clinical Studies (14.1)]. The safety profiles in the two studies were similar.

The incidence of adverse reactions in the randomized, double-blind, multicenter, placebo-controlled trial (Study 2) in which 219 renal transplant patients received sirolimus oral solution 2 mg/day, 208 received sirolimus oral solution 5 mg/day, and 124 received placebo is presented in Table 1 below. The study population had a mean age of 46 years (range 15 to 71 years), the distribution was 67% male, and the composition by race was: White (78%), Black (11%), Asian (3%), Hispanic (2%), and Other (5%). All patients were treated with cyclosporine and corticosteroids. Data (12 months post-transplant) presented in the following table show the adverse reactions that occurred in at least one of the sirolimus treatment groups with an incidence of 20%.

The safety profile of the tablet did not differ from that of the oral solution formulation [ see Clinical Studies (14.1) ].

In general, adverse reactions related to the administration of sirolimus were dependent on dose/concentration. Although a daily maintenance dose of 5 mg, with a loading dose of 15 mg, was shown to be safe and effective, no efficacy advantage over the 2 mg dose could be established for renal transplant patients. Patients receiving 2 mg of sirolimus oral solution per day demonstrated an overall better safety profile than did patients receiving 5 mg of sirolimus oral solution per day.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in one clinical trial of a drug cannot be directly compared with rates in the clinical trials of the same or another drug and may not reflect the rates observed in practice.

TABLE 1: ADVERSE REACTIONS OCCURRING AT A FREQUENCY OF ≥ 20% IN AT LEAST ONE OF THE SIROLIMUS TREATMENT GROUPS IN A STUDY OF PROPHYLAXIS OF ORGAN REJECTION FOLLOWING RENAL TRANSPLANTATION (%) AT ≥ 12 MONTHS POST-TRANSPLANTATION (STUDY 2) a

Adverse Reaction

─ Sirolimus Oral Solution ─

2 mg/day

(n=218)

5 mg/day

(n=208)

Placebo (n=124)

Peripheral edema

54

58

48

Hypertriglyceridemia

45

57

23

Hypertension

45

49

48

Hypercholesterolemia

43

46

23

Creatinine increased

39

40

38

Constipation

36

38

31

Abdominal pain

29

36

30

Diarrhea

25

35

27

Headache

34

34

31

Fever

23

34

35

Urinary tract infection

26

33

26

Anemia

23

33

21

Nausea

25

31

29

Arthralgia

25

31

18

Thrombocytopenia

14

30

9

Pain

33

29

25

Acne

22

22

19

Rash

10

20

6

Edema

20

18

15

a: Patients received cyclosporine and corticosteroids.

The following adverse reactions were reported less frequently (≥3%, but <20%)

  • Body as a Whole – Sepsis, lymphocele, herpes zoster, herpes simplex.
  • Cardiovascular – Venous thromboembolism (including pulmonary embolism, deep venous thrombosis), tachycardia.
  • Digestive System – Stomatitis.
  • Hematologic and Lymphatic System – Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), leukopenia.
  • Metabolic/Nutritional – Abnormal healing, increased lactic dehydrogenase (LDH), hypokalemia, diabetes mellitus.
  • Musculoskeletal System – Bone necrosis.
  • Respiratory System – Pneumonia, epistaxis.
  • Skin – Melanoma, squamous cell carcinoma, basal cell carcinoma.
  • Urogenital System – Pyelonephritis, decline in renal function (creatinine increased) in long-term combination of cyclosporine with sirolimus [ see Warnings and Precautions (5.8) ], ovarian cysts, menstrual disorders (including amenorrhea and menorrhagia).

Less frequently (<3%) occurring adverse reactions included: lymphoma/post-transplant lymphoproliferative disorder, mycobacterial infections (including M. tuberculosis), pancreatitis, cytomegalovirus (CMV), and Epstein-Barr virus.

Increased Serum Cholesterol and Triglycerides

The use of sirolimus in renal transplant patients was associated with increased serum cholesterol and triglycerides that may require treatment.

In Studies 1 and 2, in de novo renal transplant patients who began the study with fasting, total serum cholesterol <200 mg/dL or fasting, total serum triglycerides <200 mg/dL, there was an increased incidence of hypercholesterolemia (fasting serum cholesterol >240 mg/dL) or hypertriglyceridemia (fasting serum triglycerides >500 mg/dL), respectively, in patients receiving both sirolimus 2 mg and sirolimus 5 mg compared with azathioprine and placebo controls.

Treatment of new-onset hypercholesterolemia with lipid-lowering agents was required in 42 to 52% of patients enrolled in the sirolimus arms of Studies 1 and 2 compared with 16% of patients in the placebo arm and 22% of patients in the azathioprine arm. In other sirolimus renal transplant studies, up to 90% of patients required treatment for hyperlipidemia and hypercholesterolemia with anti-lipid therapy (e.g., statins, fibrates). Despite anti-lipid management, up to 50% of patients had fasting serum cholesterol levels >240 mg/dL and triglycerides above recommended target levels [ see Warnings and Precautions (5.7) ].

Abnormal Healing

Abnormal healing events following transplant surgery include fascial dehiscence, incisional hernia, and anastomosis disruption (e.g., wound, vascular, airway, ureteral, biliary).

Malignancies

Table 2 below summarizes the incidence of malignancies in the two controlled trials (Studies 1 and 2) for the prevention of acute rejection [ see Clinical Studies (14.1) ].

At 24 months (Study 1) and 36 months (Study 2) post-transplant, there were no significant differences among treatment groups.

TABLE 2: INCIDENCE (%) OF MALIGNANCIES IN STUDY 1 (24 MONTHS) AND STUDY 2 (36 MONTHS) POST-TRANSPLANT a,b

Sirolimus

Oral Solution

2 mg/day

Sirolimus

Oral Solution

5 mg/day

Azathioprine

2 to 3

mg/kg/day

Malignancy

Study 1

(n = 284)

Study 2

(n = 227)

Study 1

(n = 274)

Study 2

(n = 219)

Study 1

(n = 161)

Placebo Study 2

(n = 130)

Lymphoma/lymphoproliferative disease

0.7

1.8

1.1

3.2

0.6

0.8

Skin Carcinoma

Any Squamous Cell c

0.4

2.7

2.2

0.9

3.8

3.0

Any Basal Cell c

0.7

2.2

1.5

1.8

2.5

5.3

Melanoma

0.0

0.4

0.0

1.4

0.0

0.0

Miscellaneous/Not Specified

0.0

0.0

0.0

0.0

0.0

0.8

Total

1.1

4.4

3.3

4.1

4.3

7.7

Other Malignancy

1.1

2.2

1.5

1.4

0.6

2.3

a: Patients received cyclosporine and corticosteroids.

b: Includes patients who prematurely discontinued treatment.

c: Patients may be counted in more than one category.

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