VELPHORO

1 Dosing Considerations  Velphoro is a chewable tablet and must be taken with meals.  In order to maximise the adsorption of dietary phosphate, the total daily dose should be divided across the meals of the day, taking into consideration the size of the meals.

 Tablets must be chewed and not swallowed whole. Tablets may be crushed into small pieces to aid with chewing and swallowing.  Serum phosphorus levels must be monitored during titration as needed until an acceptable serum phosphorous level is reached, with regular monitoring thereafter.

2 Recommended Dose and Dosage Adjustment Starting Dose The recommended starting dose of Velphoro is 3 tablets (1,500 mg iron) per day administered as 1 tablet (500 mg iron) 3 times daily with meals. Titration and Maintenance Serum phosphorus levels must be monitored and the dose of Velphoro titrated up or down in increments of 500 mg iron (1 tablet) per day every 2-4 weeks until an acceptable serum phosphorus level is reached, with regular monitoring thereafter.

Page 5 of 29 In clinical practice, treatment will be based on the need to control serum phosphorus levels, though patients who respond to Velphoro therapy, usually achieve optimal serum phosphorus levels at doses of 1,500-2,000 mg iron (3 to 4 tablets) per day.

Maximum Daily Dose The maximum recommended dose is 3,000 mg iron (6 tablets) per day. Health Canada has not authorized an indication for pediatric use. 3 Administration Velphoro tablets must be consistently taken with meals and must be chewed and not swallowed whole.

Tablets may be crushed into small pieces to aid with chewing and swallowing. 4 Missed Dose If one or more doses are missed, the normal dose of Velphoro should be resumed with the next meal.

1 Adverse Reaction Overview The safety of Velphoro has been investigated in 2 active-controlled, pivotal clinical studies: a 6- week dose finding study and a safety and efficacy study of up to 55 weeks. A total of 778 patients on hemodialysis and 57 patients on peritoneal dialysis were treated for up to 55 weeks.

The majority of the ADRs reported from trials were gastrointestinal disorders. As expected with oral preparations containing iron, discoloured feces was very common (see WARNINGS AND PRECAUTIONS). Diarrhea was also very common, however the majority of these events were mild and transient, occurring soon after initiation of treatment and resolving with continued treatment.

1% of patients. 2 Clinical Trial Adverse Reactions Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should no t be compared to the rates in the clinical trials of another drug.

Adverse reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. e. sevelamer) in data combined from the following two pivotal studies conducted with Velphoro (doses from 250 mg iron/day to 3,000 mg iron/day): a 6-week, parallel design, dose-finding study in hemodialysis patients treated with either Velphoro (N=128) or an active-control (sevelamer hydrochloride; N=26); and a 55-week, open- label, active-controlled, parallel design, safety and efficacy study involving 969 hemodialysis patients and 86 peritoneal dialysis patients treated with either Velphoro (N=707 including 57 peritoneal dialysis patients) or the active-control (sevelamer carbonate; N=348 including 29 peritoneal dialysis patients).

9 Note: hypophosphatemia, hyperphosphatemia and blood phosphorus increased are not included in Table 2 but were reported as TEAEs as well as treatment related-TEAEs during the clinical studies in the Velphoro and in the sevelamer group.

General Velphoro contains starches. 116 bread units). This quantity can generally be considered insignificant in comparison to total daily food intake. Patients with rare hereditary problems of fructose intolerance should be made aware that th e sucrose included in Velphoro can be digested to glucose and fructose.

These compounds can be absorbed in the blood. Patients with rare hereditary problems of glucose-galactose malabsorption or sucrase- isomaltase insufficiency should be made aware that the sucrose and starch components of Velphoro can be digested to glucose and fructose, and maltose and glucose, respectively.

Carcinogenesis and Mutagenesis Carcinogenicity studies were performed in mice and rats. There was no clear evidence of a carcinogenic effect in mice (see section NON-CLINICAL TOXICOLOGY). Gastrointestinal Patients with peritonitis, significant gastric disorders and patients who have undergone major gastrointestinal surgery were not included in clinical studies with Velphoro .

Velphoro should only be used in these patients if the benefits outweigh the risks. Velphoro can cause discoloured (black) stool, which may visually mask gastrointestinal bleeding. However, Velphoro does not affect guaiac based or immunological based fecal occult blood tests.

Hepatic/Biliary/Pancreatic Patients with significant hepatic disorders were not included in clinical studies with Velphoro . However, no evidence of hepatic impairment or significant alteration of hepatic enzymes were observed in clinical studies with Velphoro.

Velphoro should only be used in these patients if the benefits outweigh the risks.

Monitoring and Laboratory Tests:

Serum Phosphorus: Serum phosphorus levels must be monitored during titration as needed until an acceptable serum phosphorous level is reached, with regular monitoring thereafter .

Velphoro is contraindicated in:  Patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see Dosage Forms, Strengths, Composition and Packaging.

 Patients with hemochromatosis or any other iron accumulation disorders.