FDA Approves New Higher Dose Formulation of FOSRENOL

• Drug News • Nov 29, 05

The U.S. Food and Drug Administration (FDA) has approved a new, higher dose formulation of the chewable(1) non-calcium phosphate binder FOSRENOL(R) (lanthanum carbonate). The new, higher dose strengths of 750 milligrams (mg) and 1.0 gram (g) will be available in the U.S. by year end. This formulation will help to reduce the number of pills end-stage renal disease (ESRD) patients must take to achieve target phosphorus levels, thereby helping to simplify the treatment of hyperphosphatemia. FOSRENOL(R) is marketed by Shire Pharmaceuticals.

Even with a low phosphorus diet, 60 percent of ESRD patients on dialysis in the United States may develop hyperphosphatemia (high phosphorus levels in the blood) and up to 70 percent are considered noncompliant when using currently prescribed phosphate binders. Without effective treatment, hyperphosphatemia may lead to increased rates of death, renal bone disease, hyperparathyroidism and calcification of tissues. Also, evidence shows hyperphosphatemia may contribute to cardiovascular disease, which accounts for almost half of all deaths among dialysis patients. FOSRENOL(R) is indicated to reduce serum phosphorus in patients with ESRD.

“As a result of the FDA approval, FOSRENOL(R) is now available in a new formulation, offering water-sparing, chewable tablets that are smaller than the original formulation. Additionally, FOSRENOL(R) is now available in a broader range of dosage strengths, including the new higher strengths of 750 milligram and 1.0 gram tablets,” said Eliseo Salinas, M.D., Shire’s Chief Scientific Officer and Executive Vice President of Global Research & Development. “The newly formulated, higher dosage strengths of FOSRENOL(R) allow patients the potential to achieve phosphorus control with as little as three tablets per day.”

According to recent data presented at the American Society of Nephrology annual meeting in Philadelphia, PA, the new, higher dose formulation of FOSRENOL(R) is preferred by both patients and physicians when compared with previous phosphate binder therapies. Interim results from this ongoing phase IIIb study(2) (n=297) demonstrate that approximately 82 percent of patients reported a significantly higher level of “overall satisfaction” after four weeks of treatment with the new, higher dose formulation of FOSRENOL(R) compared to 63 percent with their previous phosphate binders (p <.001). Physicians (n=303) also report higher “overall satisfaction” at week four with FOSRENOL(R) (84 percent vs. 66 percent; p<.001).

Overall, patients and physicians (n=351) are much more likely to prefer FOSRENOL(R) compared to previous phosphate binders (patients: 64 percent vs. 15 percent; physicians: 68 percent vs. 6 percent). Most patients were previously taking sevelamer HCl (48 percent) or calcium acetate (31 percent).

“Compliance is often a problem with phosphate binder use because of the pill burden. I’m glad that physicians treating ESRD patients now have the option to use the higher dosage strength tablets of FOSRENOL(R), which may allow them to take just one tablet per meal for a total of three tablets daily, for doses up to 3.0 grams per day. This helps lead to an important reduction in pill burden for dialysis patients,” said Rajnish Mehrotra, M.D., Associate Professor of Medicine at the David Geffen School of Medicine at UCLA, Los Angeles and Los Angeles Biomedical Research Institute. “Based on my experience in clinical trials with the new, higher dose formulation, a majority of ESRD patients should find the new FOSRENOL(R) tablets effective and generally well tolerated.”

FOSRENOL(R) has been clinically tested in more than 5,500 patients. Nearly 1,000 patients have been treated with lanthanum carbonate for more than one year. Long-term safety was demonstrated in patients treated for up to six years (n=32). Trials involving patients treated with FOSRENOL(R) showed sustained serum phosphorus reduction in a majority of patients.

Managing Hyperphosphatemia
Phosphorus, an element found in nearly all foods, is absorbed from the gastrointestinal tract into the bloodstream. When the kidneys fail, they no longer effectively remove phosphorus, even with the help of blood-cleansing dialysis machines. While the normal adult range for phosphorus is 2.5 to 4.5 mg/dL, the blood phosphorus levels of many patients on dialysis often exceed 6.5 mg/dL. Such levels have been linked to a significantly higher illness and death risk for patients who have undergone at least one year of dialysis.

Of the approximately 20 million Americans who have some form of kidney disease, more than 512,000 have developed ESRD, a figure that has grown 400 percent over the last 20 years. Hyperphosphatemia is managed with a combination of diet restriction and phosphorus-binding agents, since diet alone generally cannot adequately control phosphorus levels. Such binders “soak up” phosphorus in the gastrointestinal tract, before it can be absorbed into the blood. Because dietary phosphorus absorption begins as soon as phosphorus enters the stomach, it is important for phosphate binders to work at the variety of pH levels found throughout the gastrointestinal tract.

Despite the availability of phosphorus-binding agents, it remains a challenge for many ESRD patients to maintain target ranges. According to the K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease, Guideline 3, Evaluation of Serum Phosphorus Levels, fewer than 30 percent of dialysis patients are able to maintain serum phosphorus levels in the target range.

The K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease also note in Guideline 5, Use of Phosphate Binders in Chronic Kidney Disease (CKD), that non-calcium and non-aluminum phosphate binders are a first-line treatment option in lowering serum phosphorus levels.

FOSRENOL(R)
FOSRENOL(R), a non-calcium phosphate binder, which received FDA approval in October 2004 to reduce serum phosphorus in patients with end-stage renal disease, is formulated as an easy-to-use, chewable(1) only tablet that can be taken without water, an important consideration for ESRD patients who must restrict their fluid intake. FOSRENOL(R) is available in 250 mg, 500 mg, 750 mg and 1.0 g strengths and the recommended initial daily dose is 750 mg to 1.5 g for adults; physicians should adjust the dose to reach target serum phosphorus levels. Most patients require a total daily dose between 1.5 and 3.0 g to achieve serum phosphorus control, which equates to as little as one FOSRENOL(R) tablet per meal. The daily dose should be divided and taken with, or immediately after, meals.

The most common adverse events were gastrointestinal, such as nausea and vomiting, and generally abated over time with continued dosing. The most common side effects leading to discontinuation in clinical trials were gastrointestinal events (nausea, vomiting, and diarrhea). Other side effects reported in trials included dialysis graft complications, headache, abdominal pain and hypotension. Although studies were not designed to detect differences in risk of fracture and mortality, there were no differences demonstrated in patients treated with FOSRENOL(R) compared to alternative therapy for up to three years. The duration of treatment exposure and time of observation in the clinical program are too short to conclude that FOSRENOL(R) does not affect the risk of fracture or mortality beyond three years. While lanthanum has been shown to accumulate in the GI tract, liver, and bone in animals, the clinical significance in humans is unknown. Patients with acute peptic ulcer, ulcerative colitis, Crohn’s disease or bowel obstruction were not included in FOSRENOL(R) clinical studies. Caution should be used in patients with these conditions. FOSRENOL(R) should not be taken if you are nursing or pregnant. FOSRENOL(R) should not be taken if you are under 18 years of age. For further information on FOSRENOL(R), please visit http://www.fosrenol.com.

Shire plc
Shire’s strategic goal is to become the leading specialty pharmaceutical company that focuses on meeting the needs of the specialist physician. Shire focuses its business on central nervous system (CNS), gastrointestinal (GI), general products (GP) and human genetic therapies (HGT)—all being areas in which Shire has a commercial presence. The structure is sufficiently flexible to allow Shire to target new therapeutic areas to the extent opportunities arise through acquisitions. Shire believes that a carefully selected portfolio of products with a strategically aligned and relatively small-scale sales force will deliver strong results.

Shire’s focused strategy is to develop and market products for specialty physicians. This approach aims to deliver increased returns and lower risks. Shire’s in-licensing and merger and acquisition efforts are focused on products in niche markets with strong intellectual property protection either in the US or Europe.

For further information on Shire, please visit the Company’s website: http://www.shire.com.