Summary Basis of Decision for Fosrenol ®
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Fosrenol®
Lanthanum carbonate hydrate, 250 mg, 500 mg, 750 mg, 1000 mg, Tablets, Oral
Shire BioChem Inc.
Submission control no: 102240
Date issued: 2007-11-05
Health Products and Food Branch
Our mission is to help the people of Canada maintain and improve their health.
Health Canada
HPFB's Mandate is to take an integrated approach to the management of the risks and benefits to health related to health products and food by:
- Minimizing health risk factors to Canadians while maximizing the safety provided by the regulatory system for health products and food; and,
- Promoting conditions that enable Canadians to make healthy choices and providing information so that they can make informed decisions about their health.
Health Products and Food Branch
Également disponible en français sous le titre : Sommaire des motifs de décision (SMD), PrFOSRENOLMD, Carbonate de lanthane hydraté, 200 mg, 500 mg, 750 mg, 1 000 mg comprimés, Shire Biochem Inc., No de contrôle de la présentation 102240
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02287145 - 250 mg tablets
- 02287153 - 500 mg tablets
- 02287161 - 750 mg tablets
- 02287188 - 1000 mg tablets
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On October 17, 2006, Health Canada issued a Notice of Compliance to Shire BioChem Inc. for the drug product Fosrenol®.
Fosrenol® contains the medicinal ingredient lanthanum carbonate hydrate which is a phosphate binder.
Fosrenol® is indicated as a phosphate binding agent in patients with end stage renal disease (ESRD) on dialysis. The risk versus benefit from administration beyond two years should be carefully considered as experience with therapy beyond two years is limited.
Patients with ESRD can develop hyperphosphataemia as a result of phosphate retention that may be associated with secondary hyperparathyroidism and elevated calcium phosphate product. Fosrenol® binds dietary phosphate and inhibits gastrointestinal tract absorption of phosphate by forming highly insoluble lanthanum phosphate complexes that cannot easily pass through the wall of the gastrointestinal tract, and are excreted in the faeces.
The market authorization was based on submitted data from quality (chemistry and manufacturing) studies, as well as data from pre-clinical and clinical studies.Fosrenol® reduced serum phosphate in ESRD patients in one short-term, placebo-controlled, double-blind, dose-ranging study (n=144); two placebo-controlled, randomized, withdrawal studies (n=185); and two long-term, active-controlled, open-label studies in both haemodialysis and peritoneal dialysis patients (n=2159).
Fosrenol® (250 mg, 500 mg, 750 mg, 1000 mg lanthanum carbonate hydrate) is presented as chewable tablets. The recommended initial daily dose for adults is between 750 mg to 1500 mg taken in divided doses with or immediately after a meal. The dose should be titrated every 2-3 weeks to a level that achieves maintenance of acceptable serum phosphate levels. Dosing guidelines are available in the Product Monograph.
Fosrenol® is contraindicated in patients with hypophosphatemia and/or patients who are hypersensitive to lanthanum carbonate or to any ingredient in the formulation or component of the container. Fosrenol® should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Fosrenol® are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Fosrenol® is acceptable as a phosphate binding agent in patients with end stage renal disease on dialysis. Experience with therapy beyond two years is limited.
3 Scientific and Regulatory Basis for Decision
The New Drug Submission for lanthanum carbonate hydrate, filed as Control No. 078183, received a Notice of Non-compliance (NON) in 2003, due to quality issues as well as safety and efficacy issues. The current submission (Control No. 102240) included new data to address the issues in the NON. The timeline of these events are reported in section 4 Submission Milestones. Review of the safety and efficacy data are included in section 3.3 Clinical Basis for Decision.
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Fosrenol® contains the medicinal ingredient lanthanum carbonate hydrate which is a phosphate binding agent. Patients with end stage renal disease (ESRD) can develop hyperphosphataemia as a result of phosphate retention that may be associated with secondary hyperparathyroidism and elevated calcium phosphate product. Fosrenol® binds dietary phosphate and inhibits gastrointestinal tract absorption of phosphate by forming highly insoluble lanthanum phosphate complexes. These complexes cannot easily pass through the wall of the gastrointestinal tract and are excreted in the faeces.
Manufacturing Process and Process Controls
Lanthanum carbonate hydrate, the drug substance, is a rare earth salt. The materials used in the manufacture of the drug substance are considered to be suitable and/or meet standards appropriate for their intended use. The manufacturing process is considered to be adequately controlled within justified limits.
Characterization
Detailed characterization studies were performed to provide assurance that lanthanum carbonate hydrate consistently exhibits the desired characteristic structure.
Impurities arising from manufacturing and/or storage were reported and characterized. The proposed limits are considered adequately qualified from toxicological studies. Control of the impurities is therefore considered acceptable.
Control of Drug Substance
Copies of the analytical methods and, where appropriate, validation reports are considered satisfactory for all analytical procedures used for release and stability testing of lanthanum carbonate hydrate.
The specifications are considered acceptable for the drug substance. Batch analysis results were reviewed and are within the proposed acceptance criteria.
The drug substance packaging is considered acceptable.
Stability
Based on the long-term and accelerated stability data submitted, the proposed re-test period, storage and shipping conditions for the drug substance are supported and considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Fosrenol® (lanthanum carbonate hydrate) is presented as a chewable tablet in four dosage strengths: 250 mg, 500 mg, 750 mg and 1000 mg. The tablets are white to off-white, round, and flat with a bevelled edge. One side of each tablet is embossed with 'S405' and the dosage strength. The container for each dosage strength is an opaque, white, high-density polyethylene bottle fitted with a child-resistant closure and seal. The bottle sizes differ for the various strengths of tablets.
The non-medicinal ingredients are colloidal silicon dioxide, dextrates (hydrated), and magnesium stearate. All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of lanthanum carbonate hydrate with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.
Manufacturing Process and Process Controls
The tablets are made by dry blending the excipients with the drug substance followed by direct compression. The strengths of the tablets are directly proportional and are compressed from a common granulation.
All manufacturing equipment, in-process manufacturing steps and detailed operating parameters were adequately described in the submitted documentation and are found to be acceptable. The manufacturing process is considered to be adequately controlled within justified limits.
Control of Drug Product
Fosrenol® is tested to verify that the identity, appearance, assay, mean weight, uniformity, hardness, dissolution, and levels of moisture and impurities are within acceptance criteria. The test specifications are considered acceptable.
Copies of the analytical methods and, where appropriate, validation reports are considered satisfactory for all analytical procedures used for release and stability testing.
Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.
Although impurities arising from manufacturing and/or storage were reported and characterized, these were found to be within acceptable limits and/or were qualified from batch analysis and therefore, are considered to be acceptable.
Stability
Based upon the long-term and accelerated stability study data submitted, the proposed 24-month shelf-life at 15-25°C for Fosrenol® is considered acceptable. Excursions are permitted at temperatures up to 30°C. The drug product should be protected from moisture.
The compatability of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.
3.1.3 Facilities and Equipment
The design, operations and controls of the facility and equipment that are involved in the production are considered suitable for the activities and products manufactured. All of the proposed manufacturing sites comply with the requirements of Division 2 of the Food and Drug Regulations. All sites are compliant with Good Manufacturing Practices (GMP).
3.1.4 Adventitious Agents Safety Evaluation
The European Directorate for the Quality of Medicines and Healthcare's Certification of Suitability for the magnesium stearate used in the manufacture of Fosrenol® tablets was submitted. Raw materials of animal origin have been adequately tested to ensure freedom from adventitious agents.
3.1.5 Summary and Conclusion
The Chemistry and Manufacturing information submitted for Fosrenol® has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
The primary pharmacodynamic activity of Fosrenol® is the binding and removal of excess phosphate from the gastrointestinal (GI) tract. In vitro assays demonstrated that lanthanum carbonate bound >97% of the available phosphate at a pH level of 3 and only 66% at pH 7. In addition, very low levels of lanthanum metal ions were detected in solution.
In vivo assays with rats demonstrated that the potential for systemic exposure was low. Lanthanum carbonate significantly decreased inorganic phosphate levels in both plasma and serum while causing no significant variations in total calcium in plasma or serum, and no significant variations in ionized calcium in whole blood. The increased faecal excretion of phosphate was consistent with a reduction in the absorption of phosphorus due to the binding and precipitation of insoluble phosphate salts in the GI tract.
3.2.2 Pharmacokinetics
Absorption
Pharmacokinetic studies of Fosrenol® in mice and rats found that the drug reached maximum plasma levels relatively quickly, however the plasma concentrations remained very low. In mice, peak plasma concentration levels (Cmax) were achieved approximately 2 hours post dose following a single oral (gavage) administration of 1500 mg/kg/day. Similar values were obtained 2 and 4 hours after repeat administration for males and females. In rats, peak concentrations were apparent approximately 1-2 hours post dose following a single oral (gavage) administration of 600 mg/kg lanthanum. In almost all of the rat samples, very low plasma lanthanum concentrations were obtained with plasma levels being 5-fold higher than the limits of detection (0.1 ng/g). Given the high oral dose, systemic plasma levels were extremely low.
Distribution
Lanthanum was extensively (>99%) bound to mouse, rat, rabbit, dog and human plasma proteins in vitro over the concentration range 0.1 to 250 ng/mL (where lanthanum levels were measurable in the ultracentrifuge supernatant).
Increased concentrations of lanthanum occurred in the body, particularly the GI tract following dosing, despite the very low plasma concentrations. Studies of long-term dosing, tissue clearance, and distribution discovered that the lanthanum concentrations in the femur were among the slowest tissues to clear lanthanum. The potential is that there could be a long-term build-up of lanthanum in the body with unknown results. Additional studies for human bone safety were therefore requested and the discussion of these results are included in section 3.3.4 Clinical Safety.
In a transplacental study in rats, the drug showed no effects on the number of corpora lutea, the number of implantations, or the number of live embryos. The pre- and post-implantation losses were also similar between groups. The lanthanum level in amniotic fluid was more than 10-fold lower than those found in plasma in the dosed animals.
Metabolism
Lanthanum is not metabolized.
Excretion
In rats, lanthanum was excreted predominately in faeces (74.13%), with the majority (64.15%) being excreted in the first two weeks. Only 1.90% was excreted in the urine (0.78% in the first 24 hours alone), suggesting that the excretion period for lanthanum is extremely long, with approximately 25% of the dose remaining in the carcass.
Drug Interactions
The potential for a physico-chemical interaction (precipitation) between lanthanum and six commonly used medications (warfarin, digoxin, furosemide, phenytoin, metoprolol and enalapril) was investigated in simulated gastric fluid. The results suggest that precipitation in the stomach of insoluble complexes of these drugs with lanthanum is unlikely. Lanthanum chloride is a likely precipitate, but it has been shown to have a similar toxicology profile as lanthanum carbonate.
Lanthanum carbonate is not a significant inhibitor of cytochrome P450 isoenzymes.
Other Studies
Lanthanum carbonate did not enhance the transport of Ca2+ ions from the blood into the gut lumen. In fact, there was a 29% increase in the retention of Ca2+ ions in the gut lumen in the presence of lanthanum carbonate. However, it was felt that the effect would be negligible at clinical doses.
The drug had no effect on body temperature, spontaneous motor activities, sleeping times, and produced no proconvulsant and anticonvulsant activities. No significant differences in respiratory or cardiovascular parameters were noted. No gastric lesions were produced. Lanthanum carbonate showed no evidence of disturbing intestinal function.
A series of in vitro bone culture studies clearly demonstrated that lanthanum caused a dose-dependent inhibition of osteoblast and osteoclast differentiation. Lanthanum stimulated the activity of mature osteoblasts at all concentrations tested; however, lanthanum did not significantly affect the activity nor the number of mature osteoclasts. Although the results were not significant, at the lower concentrations tested, lanthanum slightly decreased bone resorption activity of the mature osteoclasts, whereas at the higher concentrations tested, lanthanum slightly increased bone resorption activity of the mature osteoclasts. The clinical significance of these in vitro studies remain to be determined.
3.2.3 Toxicology
Acute Toxicity
The acute toxicological studies were conducted using two different compounds, lanthanum carbonate and lanthanum chloride. The basis for this was that lanthanum carbonate is basically insoluble, whereas lanthanum chloride is highly soluble. Results from the lanthanum chloride testing characterized the target organs for lanthanum toxicity and presented potential safety issues. There were no acute effects found with lanthanum carbonate, however, lanthanum chloride administered intravenously to dogs for 4 weeks was shown to have a toxic effect localized in the liver.
Long-Term Toxicity
Similar to the acute toxicity studies, lanthanum carbonate and lanthanum chloride were both assessed for toxicity. The long-term toxicity studies with lanthanum carbonate showed that there was a bioaccumulation in both the liver and bone (femur) ranging from 1000 ng/g to 10 000 ng/g body weight in dogs after 52 weeks of dosing at 2000 mg/kg/day. Tissue lanthanum concentrations were also elevated in the GI tract where there was a higher concentration in week 52 compared to week 26. Despite these levels, there were no visible toxic effects exerted on the dogs. Dogs that received doses of 1 mg/kg/day lanthanum chloride intravenously for 4 weeks developed chronic hepatitis.
In studies conducted with nephrectomized rats, the likelihood of developing renal osteodystrophy (specifically osteomalacia) increased, particularly as the dosage of lanthanum carbonate increased; non-dietary phosphate supplements minimized this effect. The long-term effects of lanthanum carbonate on bone in the preclinical studies are considered to raise cause for concern.
Carcinogenicity
Two carcinogenicity studies were conducted for 99 and 104 weeks, in mice and rats, respectively. In male mice, there was an increase in the incidence of gladular stomach adenomas at doses of 1500 mg/kg/day lanthanum carbonate. In rats, there was no evidence of increased tumour formation related to the drug.
Mutagenicity/Genotoxicity
Lanthanum carbonate demonstrated no mutagenic activity in the Ames test and in the in vitro tests using mammalian cells. In the cytogenicity test, no clastogenic effect of lanthanum carbonate was noted.
In the genotoxicity studies, lanthanum chloride was used as it provided a higher systemic exposure to lanthanum. In rats, lanthanum was not genotoxic at doses up to 0.1 mg/kg/day. Lanthanum chloride did not induce micronuclei in the polychromatic erythrocytes of the bone marrow and did not induce unscheduled DNA synthesis in the liver.
Reproductive and Development Toxicity
In the reproductive studies, doses of 2000 mg/kg/day lanthanum carbonate resulted in low birth weights. This was most likely due to GI irritation in the F0 generation resulting in both limited food intake and loss of weight as opposed to a direct effect on the pups. In the F1 generation of rabbits dosed 1500 mg/kg/day of lanthanum carbonate, there was delayed fetal ossification suggesting lanthanum carbonate effects bone development, particularly at increased dose levels. In the F1 generation of rats dosed with 2000 mg/kg/day during pregnancy and lactation, eye opening was delayed. Sexual development, as indicated by preputial separation for the males and vaginal perforation for the females, was significantly delayed in the group with maternal treatment at 2000 mg/kg/day when compared with the control group. There was also a delay in vaginal opening in females with maternal treatment at 200 and 600 mg/kg/day.
3.2.4 Conclusion
Lanthanum carbonate has been shown to be an effective phosphate binder, and when administered in either single or repeat-dose regimens, lanthanum carbonate was well tolerated in all animal species tested. Lanthanum carbonate does not accumulate in the plasma, however animal studies showed that lanthanum accumulates in the bone, liver and GI tract. Toxicity in the bone was also examined in the clinical setting. Additional clinical studies to assess toxicity in the liver and GI tract were not available. Precautionary measures and the identified safety concerns are adequately addressed in the Product Monograph. The non-clinical studies did not raise any issues that would prevent authorization of Fosrenol® for the proposed indication.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
The clinical pharamacodynamic studies indicate that lanthanum carbonate dissociates in the acid environment of the upper GI tract and the lanthanum ions bind dietary phosphate in the lumen of the gut forming highly insoluble lanthanum phosphate complexes. These complexes cannot easily pass through the wall of the GI tract and are excreted in the faeces. Administration of Fosrenol® resulted in significantly reduced levels of serum phosphate and calcium phosphate product in the blood. Levels of phosphates in urinary excretion were also low. The decreases in the amount of phosphate in the blood and urine suggest that decreased GI uptake of phosphate was achieved by administering Fosrenol®. The plasma levels of lanthanum after single doses of 2000 mg Fosrenol® were in the sub ng/mL range. Administration of Fosrenol® did not significantly affect other pharmacodynamic markers such as serum levels of sodium, calcium, creatinine, creatinine clearance, and parathyroid hormone; and levels of creatinine in the urine.
3.3.2 Pharmacokinetics
Absorption
Absorption of lanthanum from the GI tract is very low. Mean plasma levels of lanthanum after long-term administration were shown to be less than 1 ng/mL. The highest individual level recorded was 5.2 ng/mL. The plasma drug exposure appeared to be higher among a group of patients that underwent dialysis than a control group with normal renal function, following either single or multiple dosing.
Fosrenol® is to be administered with food. The timing of food intake relative to Fosrenol® administration appeared to have a negligible effect on the systemic absorption of lanthanum.
Distribution
Lanthanum was highly bound to human plasma proteins in vitro. Study results suggest that lanthanum accumulates after repeated dosing both in healthy subjects and in patients with renal impairment. Plasma levels of lanthanum were several times higher after repeated dosing compared to single administration.
Rising levels of lanthanum in bone were noted over time. No clinical data is available on the deposition of lanthanum in other tissues, including the liver and GI tract.
Metabolism
Lanthanum is not metabolized.
Excretion
Lanthanum carbonate is primarily eliminated in the faeces. The amount of lanthanum recovered in urine over a total seven day collection period was only 3.1 x 10-5 % of the administered dose.
Drug Interactions
Lanthanum carbonate appears to have a low potential to elicit systemic drug-drug interactions suggesting that clinically significant interactions are not likely to occur in patients with commonly co-prescribed medications. No effects of lanthanum were found on the absorption of digoxin (0.5 mg), metoprolol (100 mg), or warfarin (10 mg) in healthy subjects co-administered lanthanum carbonate (three doses of 1000 mg on the day prior to exposure and one dose of 1000 mg on the day of co-administration). Potential pharmacodynamic interactions between lanthanum and these drugs (e.g. bleeding time or prothrombin time) were not evaluated. None of the drug interaction studies were done with the maximum recommended therapeutic dose of lanthanum carbonate.
Special Populations
No significant differences in drug exposure are expected between male and female patients, nor between different racial groups. Plasma lanthanum concentrations were comparable among the subjects/patients in studies conducted in Japan, North America, and Europe. Elderly patients have been included in the clinical studies and there were no apparent differences in plasma lanthanum levels or apparent differences in safety. The use of Fosrenol® is not recommended for the pediatric population as clinical trials were not conducted in patients <18 years of age. In the non-clinical studies, lanthanum was deposited in the developing bones of the animals under study. The possibility and consequences of deposition in the developing bones of children are unknown.
Drug exposure appeared to be higher among a group of patients undergoing dialysis as compared to a control group with normal renal function, following single or multiple dosing. No data are available for patients with severe hepatic impairment.
3.3.3 Clinical Efficacy
The effectiveness of Fosrenol® in reducing serum phosphorus in ESRD patients was demonstrated in one short-term, placebo-controlled, double-blind dose-ranging study (n = 144), two placebo-controlled randomized withdrawal studies (n = 185) and two Phase III, long-term, active-controlled, open-label studies (LAM-IV-301 and LAM-IV-307) in both hemodialysis and peritoneal dialysis patients (n = 2159).
With regard to the placebo-controlled studies, although greater efficacy has been demonstrated over placebo in the reduction of serum phoshate in ESRD, the design of the studies, the populations analysed, and the substantial rate of withdrawal, made it difficult to interpret.
LAM-IV-301 assessed both the efficacy and safety of lanthanum carbonate. The primary efficacy parameter was the reduction of serum phosphate to ≤ 1.80 mmol/L. The secondary efficacy parameters included the maintenance of controlled phosphate levels ≤1.80 mmol/L. Patients were randomized to receive lanthanum carbonate or calcium carbonate.
LAM-IV-307 had the primary objective of evaluating the long-term safety of lanthanum carbonate in chronic renal failure patients on hemodialysis. Patients were randomized to receive lanthanum carbonate or standard therapy. Standard therapy consisted of a variety of phosphate binders/dietary supplement products marketed for hyperphosphatemia and/or as dietary supplements. The products included: calcium carbonate, calcium acetate, sevelamer hydrochloride, aluminum hydroxide and Magnabind (magnesium and calcium). The secondary efficacy endpoint was the ability of lanthanum carbonate to maintain phosphate levels within the clinically acceptable limits, defined as < 5.9 mg/dL.
With regard to the active comparator studies (LAM-IV-301 and LAM-IV-307), the design and implementation of the protocols does not allow firm conclusions as to the comparability of lanthanum versus alternate therapy. The first active comparator study (LAM-IV-301) was designed as a superiority study. At the end of the maintenance phase of the study, the mean phosphate level was 1.73 mmol/L (representing -0.74 mmol/L change from baseline) in the Fosrenol® group (doses up to 3000 mg/day), and 1.73 mmol/L (representing -0.75 mmol/L change from baseline) in the calcium group (doses up to 9000 mg/day) in patients who completed the maintenance period. Superiority of lanthanum over calcium-based phosphate binders was not demonstrated. The second active comparator study (LAM-IV-307) was not designed to assess the relative efficacy of lanthanum over 'standard therapy'. No conclusion can be drawn as to the relative efficacy of lanthanum over 'standard therapy' in the control of serum phosphate in patients with ESRD. No conclusion can be drawn as to the comparative efficacy of lanthanum verus alternate therapy in the control of serum phosphate in ESRD patients other than the fact that lanthanum is not superior to calcium-based binders.
Restrictions to manage risks associated with unknown long-term effects of this drug have been incorporated into the indication, labelling, and Product Monograph to manage the use of Fosrenol®.
3.3.4 Clinical Safety
Two Phase III, long-term, open-label studies (LAM-IV-301 and LAM-IV-307) provided the majority of the Fosrenol® data for the study of tolerability and adverse reactions. The two studies compared lanthanum carbonate with a standard phosphate-binding agent, calcium carbonate or with active control phosphate binders (ACPBs), including calcium-based agents, aluminum hydroxide, and sevelamer hydrochloride. The study design and implementation of the protocols did not allow for firm conclusions to be made regarding the comparability of tolerance for lanthanum versus alternative therapies.
Laboratory and hematology results as well as vital signs and ECG parameters indicated no clinically meaningful differences between patients on lanthanum versus those on placebo or ACPB, respectively.
Among the patients treated with lanthanum carbonate, the most frequently reported adverse events (AEs) were nausea, vomiting, abdominal pain, diarrhea, and constipation. A large number of patients treated with lanthanum carbonate discontinued the studies due to GI-related AEs. Among the patients treated with ACPB, the most frequently reported related AEs were nausea, vomiting, diarrhea, abdominal pain, hypercalcemia and constipation. In general, the AEs that appeared to have a relationship to lanthanum carbonate treatment are all gastrointestinal in nature: abdominal pain, nausea, and vomiting. Patients in the ACPB group had a higher incidence of hypercalcemia. Compared to standard therapy, lanthanum carbonate had less propensity to cause hypercalcemia.
No serious AEs were reported as having a statistically significant frequency among patients treated with lanthanum carbonate compared to patients treated with ACPB. The data presented does not reveal any major concerns with respect to serious adverse effects (excluding potential problems associated with long term deposition in bone, liver and GI tract). The only tissue measured for lanthanum concentration was bone. After one year of treatment, the levels in bone were up to 1000x higher than the highest concentration measured in plasma which indicates that after long-term treatment there is an accumulation of lanthanum in the body.
In the long-term studies, all deaths were considered to be unrelated or unlikely to be related to study medication. The majority of those treated with lanthanum carbonate or ACPB died of cardiac arrest or myocardial infarction.
Bone Safety
Reports included data collected from a limited number of iliac crest bone biopsies from patients in clinical studies who were treated with Fosrenol® or standard therapy for periods up to 5 years. Data collected included bone lanthanum concentrations, bone histomorphometry data, serum biochemistry, and fracture data. Although the clinical data provided information on bone safety, there was a lack of evidence to conclusively rule out bone toxicity.
A comprehensive investigation of lanthanum on bone toxicity should include a detailed evaluation of the effects of lanthanum on bone quality. Bone quality is a function of mechanical, material and architectural bone properties that can be used collectively to predict fracture risk and bone fragility. The use of bone histomorphometry as the only assessment of lanthanum's adverse effect on bone is a major limitation of the bone safety evaluation protocol. The impacts of lanthanum on bone mechanics and material properties cannot be assessed using bone histomorphometry alone. Fracture data was provided for review, however, the low number of fractures reported and the observation period were too short to provide solid conclusions on lanthanum and risk of bone fragility.
Data collected from paired iliac crest bone biopsies treated with lanthanum
(study LAM-IV 303, n = 33; study LAM-IV 307, n = 31 at 1-year follow-up and n = 31 at 2-year follow-up) were insufficient to conclude the long-term safety of the effect of lanthanum on bone. Study LAM-IV-307 was not designed to address the question of lanthanum-induced bone toxicity, but rather designed to rule out aluminium-like bone toxicity. The study demonstrated that no aluminium-like toxicity (osteomalacia) was observed in the limited number of bone biopsies obtained up to 2 years on treatment. The data also showed an increase in mineralization lag-time in most of the patients treated with lanthanum carbonate. Lanthanum continued to be deposited into bone up to 4-5 years of exposure and did not reach a steady state at that point in time. The rate of accumulation and elimination of lanthanum is uncertain and the fate of eliminated bone lanthanum is unknown. Results from single biopsies from patients treated up to 4-5 years were provided, however the information collected from single biopsies cannot provide long-term safety conclusions as there was no baseline for comparison. Furthermore, the conclusions that can be drawn from the single biopsies are limited to determining if aluminum-like toxicity (osteomalacia) was taking place.
Lanthanum could potentially cause other changes to bone which were not evaluated in the non-clinical or clinical program, and may not present themselves symptomatically until a much longer exposure period. Also, the mechanism of lanthanum deposition in bone is still unclear, and since lanthanum continues to be deposited in bone as long as there is exposure, long-term safety is uncertain.
It is not feasible to obtain the type of paired bone biopsy data that would be required to confirm long-term bone safety. It would be difficult to obtain a large enough patient population that will provide paired bone biopsy data over a long enough period of time of observation to generate concrete conclusions on long-term bone safety. Currently, the short-term bone biopsy data collected did not indicate aluminum-like toxicity, and the limited biopsies from patients exposed to lanthanum for 4-5 years (n = 11) did not show delayed bone mineralization. Although lanthanum is minimally absorbed, it is steadily accumulated in bone tissues. Furthermore, lanthanum implications on other clinical aspects of bone safety (i.e. fracture, bone pain) have not been established. However, the pivotal piece of information in this risk/benefit analysis is that most of the patients with ESRD will develop some type of renal osteodystrophy without proper serum phosphate management. Therefore, lanthanum carbonate could be considered as possible phosphate binding therapy when the risks and benefits have been carefully considered.
Warnings are incorporated into the Product Monograph regarding the lack of information on long-term bone safety. With the current data available, the risk/benefit of Fosrenol® should be carefully considered beyond 2 years, since the long-term effects of lanthanum are unknown at this point. Safety has only been demonstrated up to 2 years and the data cannot be extrapolated to long-term safety.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/risk Assessment
Although Fosrenol® was efficacious when compared to placebo, it could not be concluded that it was superior to other phosphate binding therapies tested in clinical trials. The incidence of nausea and vomiting was higher with Fosrenol® than with other phosphate binders. Furthermore, the mechanism of lanthanum incorporation into bone and its long-term effects on bone quality are uncertain, which generates long-term safety concerns as this drug product is meant for chronic use.
Uncontrolled hyperphosphatemia can lead to increased morbidity and mortality in ESRD patients. Furthermore, ESRD patients will develop renal osteodystrophy (kidney failure related bone disease) as part of the disease progression if serum phosphate is not well controlled. Control of hyperphosphatemia with Fosrenol® is expected to have beneficial effects in ESRD; however, the benefit versus risk from administration of Fosrenol® should be carefully considered, because the consequences of continuous accumulation of lanthanum in bone during long-term therapy are unknown.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and effectiveness, Health Canada considers that the benefit/risk profile of Fosrenol® is acceptable as a phosphate binding agent in patients with end stage renal disease on dialysis. Experience with therapy beyond 2 years is limited. The risk versus benefit from administration beyond two years should be carefully considered. The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: Fosrenol®
| Submission Milestone | Date |
|---|---|
| Control No. 078183: Submission filed: | 2002-06-12 |
| Screening | |
| Screening Acceptance Letter issued: | 2002-07-08 |
| Review | |
| Quality Evaluation complete: | 2003-06-26 |
| Clinical Evaluation complete: | 2003-05-07 |
| NON issued by the Director General (safety, effectiveness, and quality issues): | 2003-07-21 |
| NON/W issued by Director General (no response to NON): | 2003-11-12 |
| Control No. 101909: Pre-submission meeting: 2005/05/10 | 2005-05-10 |
| Submission filed: | 2005-10-18 |
| Submission cancelled - administrative: | 2005-11-04 |
| Control No. 102240: Submission filed: | 2005-11-04 |
| Screening | |
| Screening Acceptance Letter issued: | 2005-12-22 |
| Review | |
| Quality Evaluation complete: | 2006-10-05 |
| Clinical Evaluation complete: | 2006-10-13 |
| Labelling Review complete: | 2006-10-16 |
| NOC issued by Director General: | 2006-10-17 |