ASTAGRAF XL (Page 4 of 13)

6.1 Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In addition, the clinical trials were not designed to establish comparative differences across study arms with regards to the adverse reactions discussed below.

Kidney transplant patients were treated with ASTAGRAF XL (N=214) or tacrolimus immediate-release product (N=212) and concomitant immunosuppressants (median duration of exposure of 12 months) in a randomized, open-label, active-controlled trial of mostly U.S. patients (Study 1) [see Clinical Studies (14.1)]. The types of adverse reactions seen in Study 1 were similar to the adverse reactions seen in Study 2 [non-U.S. trial in kidney transplant patients treated with ASTAGRAF XL (N=331) or tacrolimus immediate-release product (N=336) and concomitant immunosuppressants] [see Clinical Studies (14.2)].

In Study 1, the proportion of patients who discontinued treatment due to adverse reactions was 9% and 11% in the ASTAGRAF XL and tacrolimus immediate-release treatment groups, respectively, through 12 months of treatment. The most common adverse reactions leading to discontinuation in ASTAGRAF XL-treated patients were related to infections or renal/urinary disorders.

InfectionsThe overall incidence of infections, serious infections, and infections with identified etiology reported in patients treated with the ASTAGRAF XL or tacrolimus immediate-release product in Study 1 are shown in Table 2.

Table 2: Percentage of Patients with Infections in Study 1a Through One Year Post-Kidney Transplant
a Study 1 was not designed to support comparative claims of ASTAGRAF XL compared to tacrolimus immediate-release product for the adverse reactions reported in this table.

ASTAGRAF XL, MMF, steroids, basiliximab

induction N=214

Tacrolimus immediate-release

product, MMF, steroids, basiliximab induction

N=212

All Infections

69%

69%

Respiratory Infections

34%

31%

Urinary Tract Infections

16%

25%

Cytomegalovirus Infections

10%

11%

Bacterial Infections

8%

12%

Gastroenteritis

7%

3%

Polyomavirus Infections

3%

5%

Serious Infections

22%

23%

New Onset Diabetes After Transplant (NODAT)The incidence of new onset diabetes after transplantation (defined by the composite occurrence of ≥ 2 fasting plasma glucose values that were > 126 mg/dL at ≥ 30 days apart, insulin use for ≥ 30 consecutive days, oral hypoglycemic use for ≥ 30 consecutive days, and/or HbA1C ≥ 6.5%) is summarized in Table 3 below for Study 1 through one year post-transplant [see Warnings and Precautions (5.5)].

Table 3: Percentage of Patients with NODAT Through One Year Post-Kidney Transplant in Study 1a
ASTAGRAF XL, MMF, steroids, basiliximab induction N=162 Tacrolimus immediate-release product, MMF, steroids, basiliximab induction N=151
a Study 1 was not designed to support comparative claims of ASTAGRAF XL compared to tacrolimus immediate-release product for the adverse reactions reported in this table.

Composite NODAT

36%

35%

≥ 2 Fasting Plasma Glucose Values

≥ 126 mg/dL ≥ 30 days apart

26%

23%

HbA1C ≥ 6.5%

19%

22%

Oral hypoglycemic use ≥ 30 consecutive days

14%

9%

Insulin use ≥ 30 consecutive days

6%

8%

Hyperkalemia
In Study 1 [see Clinical Studies (14.1)], 73 of 214 (34.1%) patients on ASTAGRAF XL had a serum potassium level greater than 5.4 up to 6.4 mEq/L, and 8 out of 214 (3.7%) patients had a serum potassium level greater than 6.4 mEq/L [see Warnings and Precautions (5.8)].

Common Adverse ReactionsThe most common (≥ 30%) adverse reactions observed with ASTAGRAF XL in Study 1 were: diarrhea, constipation, nausea, peripheral edema, tremor, and anemia. The incidence of adverse reactions that occurred in ≥ 15% of ASTAGRAF XL-treated patients compared to tacrolimus immediate-release product through one year of treatment in Study 1 is shown by treatment groups in Table 4.

Table 4: Adverse Reactions (≥ 15%) in Kidney Transplant Patients Through One Year Post-Transplant in Study 1a
ASTAGRAF XL, MMF, steroids, basiliximab induction N=214 Tacrolimus immediate-release product, MMF, steroids, basiliximab induction N=212
a Study 1 was not designed to support comparative claims of ASTAGRAF XL compared to tacrolimus immediate-release for the adverse reactions reported in this table.

Diarrhea

45%

44%

Constipation

40%

32%

Nausea

36%

35%

Peripheral Edema

36%

34%

Tremor

35%

34%

Anemia

33%

29%

Hypertension

28%

30%

Vomiting

25%

25%

Hypomagnesemia

24%

27%

Insomnia

24%

28%

Hypophosphatemia

23%

28%

Headache

22%

24%

Hyperkalemia

20%

23%

Increased Blood Creatinine

19%

23%

Fatigue

16%

10%

Leukopenia

16%

16%

Hyperlipidemia

16%

17%

Hyperglycemia

16%

18%

Less Frequently Reported Adverse Reactions (< 15% in ASTAGRAF XL-treated patients) by System Organ Class

The following adverse reactions were reported in clinical studies of kidney transplant patients who were treated with ASTAGRAF XL, MMF, and steroids (Studies 1 and 2):

Blood and Lymphatic System Disorders: Hemolytic anemia, leukocytosis, neutropenia, thrombocytopenia, thrombotic microangiopathy
Cardiac Disorders: Atrial fibrillation, atrial flutter, tachycardia
Ear Disorders: Tinnitus
Eye Disorders: Vision blurred, conjunctivitis
Gastrointestinal Disorders: Abdominal distension, abdominal pain, aphthous stomatitis, dyspepsia, esophagitis, flatulence, gastritis, gastroesophageal reflux disease
General Disorders and Administration Site Conditions: Anasarca, asthenia, edema, pyrexia
Hepatobiliary Disorders: Abnormal hepatic function, cholestasis, hepatitis (acute and chronic), hepatotoxicity
Infections and Infestations: Condyloma acuminatum, tinea versicolor
Injury: Fall
Investigations: Increased blood lactate dehydrogenase, increased blood urea, increased hepatic enzyme
Metabolism and Nutrition Disorders: Anorexia, hyperphosphatemia, hyperuricemia, hypokalemia, hyponatremia, metabolic acidosis
Musculoskeletal and Connective Tissue Disorders: Arthralgia, osteopenia, osteoporosis
Neoplasms: Kaposi’s sarcoma
Nervous System Disorders: Convulsion, dizziness, hypoesthesia, neurotoxicity, paresthesia, peripheral neuropathy
Psychiatric Disorders: Agitation, anxiety, confusional state, depression, hallucination, mood swings, nightmare
Renal and Urinary Disorders: Anuria, oliguria, proteinuria, renal failure, renal tubular necrosis, toxic nephropathy
Respiratory, Thoracic and Mediastinal Disorders: Acute respiratory distress syndrome, dyspnea, pulmonary edema, productive cough
Skin and Subcutaneous Tissue Disorders: Acne, alopecia, dermatitis, hyperhidrosis, hypotrichosis, pruritus, rash
Vascular Disorders: Deep vein thrombosis, flushing

Pediatrics

De Novo Pediatric Transplant Patients

A study was conducted in 44 de novo pediatric transplant patients (including 25 kidney transplant patients; 13 randomized to ASTAGRAF XL and 12 randomized to Prograf), who were started on 0.3 mg/kg daily of tacrolimus product, given once daily for ASTAGRAF XL and divided into two doses for Prograf. Two kidney transplant patients on Prograf discontinued the study (withdrawn consent, sapovirus enteritis). Thirteen (13) pediatric kidney transplant patients completed 52 weeks on ASTAGRAF XL. The most common adverse reactions were diarrhea [7/13 (54%)], increased blood creatinine [6/13 (46%)], hypertension [3/13 (23%)], cough [4/13 (31%)], and upper respiratory tract infection [4/13 (31%)].

Stable Pediatric Transplant Patients

Another study was conducted in 81 stable pediatric allograft recipients (including 48 kidney transplant patients) 5 to 16 years of age converted 1:1 (mg:mg) from Prograf to ASTAGRAF XL. Seventy-six (76) pediatric patients completed at least one year of ASTAGRAF XL-based treatment. Treatment-related adverse reactions were reported in 35%, including 13% serious adverse reactions. The most frequent adverse reactions by system organ class were infections (55.7%), followed by gastrointestinal disorders (27.8%), skin and subcutaneous tissue disorders (21.5%), respiratory, thoracic and mediastinal disorders (20.3% each). The most common adverse reactions were diarrhea (13.9%), headache (13.9%) and cough (11.4%).

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