Fosrenol Chewable Tablets - Product Information
|Condition:||Hyperphosphatemia of Renal Failure|
|Ingredients:||lanthanum carbonate hydrate, colloidal silicon dioxide, dextrates (hydrated), magnesium stearate|
lanthanum carbonate hydrate
Summary Product Information
|Route of |
|Dosage Form |
|Clinically Relevant Nonmedicinal |
|Oral||Chewable tablets / 250, 500, 750 and 1000mg||For a complete listing see Dosage Forms, Composition and Packaging section.|
Indications and Clinical Use
FOSRENOL (lanthanum carbonate hydrate) is indicated as a phosphate binding agent in patients with end stage renal disease on dialysis. The use of FOSRENOL in controlled clinical studies beyond 2 years is limited. The risk versus benefit from administration beyond two years should be carefully considered. (see Warnings and Precautions - Bone, Pharmacokinetics –Distribution, and Clinical Trials –Bone Safety)
Geriatrics (>65 Years of Age)
Of the total number of patients in clinical studies of FOSRENOL, 32% (538) were ≥65 years of age while 9.3% (159) were ≥75 years of age. No overall differences in safety or efficacy were observed between patients ≥65 years of age and younger patients.
Pediatrics (>18 Years of Age)
The safety and efficacy of FOSRENOL have not been established in children. (see Warnings and Precautions)
FOSRENOL (lanthanum carbonate hydrate) is contraindicated in patients with:
- Bowel obstruction, ileus and fecal impaction
- Hypersensitivity to lanthanum carbonate or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the Product Monograph.
Warnings and Precautions
Carcinogenesis and Mutagenesis
See Toxicology – Mutagenicity and Carcinogenicity sections.
Serious cases of gastrointestinal obstruction, ileus, subileus, gastrointestinal perforation and fecal impaction have been reported in post–marketing follow–up of patients treated with FOSRENOL (lanthanum carbonate hydrate), some requiring surgery or hospitalization.
Lanthanum is known to cause constipation (see Adverse Reactions – Clinical Trial Adverse Drug Reactions). Exercise caution in all patients predisposed to gastrointestinal obstruction, ileus, subileus and perforation; for example those with altered gastrointestinal anatomy (e.g., diverticular disease, peritonitis, history of gastrointestinal surgery, gastrointestinal cancer and gastrointestinal ulceration) and hypomotility disorders (e.g., constipation, diabetic gastroparesis). Some cases were reported in patients with no history of gastrointestinal disease.
The safety of FOSRENOL in patients with acute peptic ulcer, ulcerative colitis or Crohn’s disease has not been established in clinical studies. Caution should be used in patients with these conditions.
Advise patients to chew the tablet completely and not swallow whole (see Dosage and Administration – Administration) to reduce the risk of serious adverse gastrointestinal events such as those described above.
No studies have been done in patients with hepatic impairment. Although lanthanum is not metabolized, it is excreted in the bile. Caution should be exercised in patients with hepatic impairment or biliary obstruction, as elimination of absorbed lanthanum may be reduced.
Tissue deposition of lanthanum has been shown with FOSRENOL in animal and human studies. The use of FOSRENOL in controlled clinical studies beyond 2 years is limited. The risk/benefit from longer-term administration should be carefully considered. In bone biopsies of patients treated with FOSRENOL for up to 4.5 years, rising levels of lanthanum were noted over time (see Pharmacokinetics – Distribution; Warnings and Precautions – Long-term effects; Clinical Trials – Bone Safety). There is no information on the re–distribution of lanthanum eliminated from bone into other tissues upon termination of lanthanum carbonate therapy.
The effect of iron or aluminum chelation on serum lanthanum released from bone has not been studied. Patients requiring chelation treatment who are taking FOSRENOL should be monitored closely.
There were no differences in the rates of fracture in patients treated with FOSRENOL compared to Standard Therapy⚹ for up to 3 years. The duration of treatment exposure and time of observation in the clinical program is too short to conclude that FOSRENOL does not adversely affect bone quality or the risk for fracture or mortality beyond 3 years. (see Clinical Trials – Bone Safety)
⚹ Standard Therapy: Patients randomized to Standard Therapy continued to take their prescribed binder at the optimal dose required to control their phosphate levels at ≤5.9mg/dL. Patients were allowed to switch phosphate binders throughout the study and could also take a combination of binders in order to achieve optimal phosphate control.
No adequate and well-controlled studies have been conducted in pregnant women. The effect of FOSRENOL on the absorption of vitamins and other nutrients has not been studied in pregnant women. FOSRENOL is not recommended for use during pregnancy. (see Toxicology – Reproduction and Teratology)
The excretion of lanthanum in milk has not been studied in animals. It is not known whether lanthanum is excreted in human breast milk. Therefore, the use of FOSRENOL in women who are breastfeeding is not recommended.
Geriatrics (>65 years of age)
Of the total number of patients in clinical studies of FOSRENOL, 32% (538) were ≥65 years of age while 9.3% (159) were ≥75 years of age. No overall differences in safety or efficacy were observed between patients ≥65 years of age and younger patients.
Pediatrics (>18 years of age)
The safety and efficacy of FOSRENOL have not been established in patients below the age of 18 years. While growth abnormalities were not identified in long–term animal studies, lanthanum was deposited into developing bone including growth plate. The consequences of such deposition in developing bone in pediatric patients are unknown. Therefore, the use of FOSRENOL in pediatric patients is not recommended.
Monitoring and Laboratory Tests
Patients should adhere to recommended diets in order to control phosphate and fluid intake. FOSRENOL is presented as a chewable tablet therefore avoiding the need to take additional fluid. Serum phosphate levels should be monitored and the dose of FOSRENOL titrated every 2–3 weeks until an acceptable serum phosphate level is reached, with regular monitoring thereafter.
Adverse Drug Reaction Overview
Gastrointestinal symptoms including, but not limited to, nausea, vomiting, abdominal cramps and diarrhea were observed in patients taking FOSRENOL. These symptoms were less frequent when taking FOSRENOL with or immediately after food.
Clinical Trial Adverse Drug 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 not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug–related adverse events and for approximating rates.
In three placebo-controlled studies in end stage renal disease (ESRD) patients, the most common adverse events for FOSRENOL were gastrointestinal events such as nausea and vomiting, and they generally abated over time with continued dosing. Adverse events that were more frequent (≥5% difference) in the FOSRENOL group are presented in the following table.
|System Organ Class|
Preferred Terminology (WHOART)
|Dialysis Graft Occlusion||7.8||1.1|
|Gastrointestinal System Disorders|
WHOART = World Health Organization Adverse Reactions Thesaurus.
NW = non-WHOART term developed by Sponsor for the clinical development program.
The safety of FOSRENOL was studied in two long-term clinical trials that included 1215 patients treated with FOSRENOL and 944 with alternative therapy. Sixteen percent (16%) of patients in these comparative, open-label studies discontinued in the FOSRENOL-treated group due to adverse events. Gastrointestinal adverse events, such as nausea, diarrhea and vomiting, were the most common type of event leading to discontinuation.
The number of withdrawals and the most common adverse events (≥5% in either treatment group) in both the long-term (2-year), open-label, active-controlled, study of FOSRENOL vs. alternative therapy (Study A) and the 6-month, comparative study of FOSRENOL vs. calcium carbonate (Study B) are shown in Table 2 and Table 3, respectively. In Table 3, Study A events have been adjusted for mean exposure differences between treatment groups (with a mean exposure of 1.0 year on lanthanum and 1.4 years on alternative therapy). The adjustment for mean exposure was achieved by multiplying the observed adverse event rates in the alternative therapy group by 0.74.
|Study A⚹||Study B⚹⚹|
|Titration Phase||98/668 (14.67%)||38/670 (5.67%)||60/510 (11.96%)||41/257 (15.95%)|
|Maintenance Phase||374/570 (65.61%)||311/632 (49.21%)||188/450 (41.78%)||103/207 (49.76%)|
|MEAN SERUM PHOSPHATE LEVEL ACHIEVED|
|Titration Phase||6.43mg/dL⚹ (2.06mmol/L)||5.71mg/dL⚹ (1.85mmol/L)||1.87mmol/L⚹⚹||1.66mmol/L ⚹⚹|
|Maintenance Phase||6.17mg/dL 1.97mmol/L)||6.05mg/dL (1.94mmol/L)||1.73mmol/L||1.72mmol/L|
⚹Study A: Patients in the FOSRENOL group were titrated over a six-week period starting from a dose of 750mg/day and then maintained on doses up to 3000mg/day. The alternative therapy group started the titration phase at their optimal dose and were subsequently maintained at their optimal dose with the allowance of switching/adding phosphate binders if they wished.
⚹⚹Study B: Patients in the FOSRENOL group were titrated from 375mg/day up to their optimal dose and then maintained on doses up to 3000mg/day. The calcium carbonate group started the titration phase at their optimal dose and were maintained on doses up to 9000mg/day.
|Dialysis graft complication||25||24||3||5|
|Dialysis graft occlusion||21||21||4||6|
⚹Alternative Therapy: Patients randomized to alternative therapy continued to take their prescribed binder at the optimal dose required to control their phosphate levels at ≤5.9mg/dL. Patients were allowed to switch phosphate binders throughout the study and could also take a combination of binders in order to achieve optimal phosphate control.
The dose range used in Study B was FOSRENOL 375mg–3000mg as elemental lanthanum and calcium carbonate 1500mg-9000mg elemental calcium.
Less Common Clinical Trial Adverse Events
In clinical studies, the following other, less common (≥0.1% and <5%), adverse drug reactions were reported:
Infections and Infestations: Gastroenteritis, laryngitis
Blood and Lymphatic System Disorders: Eosinophilia
Endocrine Disorders: Hyperparathyroidism
Metabolism and Nutrition Disorders: Anorexia, appetite increased, hyperglycemia, hyperphosphatemia, hypocalcemia, hypophosphatemia
Nervous System Disorders:Dizziness, taste alteration
Ear and Labyrinth Disorders: Vertigo
Gastrointestinal Disorders: Dry mouth, dyspepsia, eructation, esophagitis, flatulence, gastrointestinal disorder NOS (not otherwise specified), indigestion, irritable bowel syndrome, loose stools, stomatitis, tooth disorder
Skin and Subcutaneous Tissue Disorders: Alopecia, erythematous rash, itching, pruritus, sweating increased
Musculoskeletal and Connective Tissue Disorders: Arthralgia, myalgia, osteoporosis
General Disorders and Administration Site Conditions: Asthenia, chest pain, fatigue, malaise, pain, peripheral edema, thirst
Investigations: Alkaline phosphatase increased, blood aluminum increased, GGT increased, hepatic transaminases increased, weight decrease
Although there have been a number of additional isolated events reported, none of these were considered unexpected in this patient population.In a comparative clinical study, patients on FOSRENOL had a lower incidence of hypercalcemic episodes relative to patients on calcium-based phosphate binder (p<0.001).
Post-Market Adverse Drug Reactions
The following adverse reactions have been identified during post-approval use of FOSRENOL:
Gastrointestinal disorders: dyspepsia, ileus, intestinal obstruction, intestinal perforation, subileus
General disorder: tooth injury
Skin and subcutaneous tissue disorders: allergic skin reactions (including pruritus, skin rashes and urticaria)
Lanthanum carbonate hydrate is not a substrate for cytochrome P450 and does not significantly inhibit the activities of the major human cytochrome P450 isoenzymes, CYP1A2, CYP2D6, CYP3A4, CYP2C9 or CYP2C19 in vitro.
FOSRENOL does not alter gastric pH. Therefore, FOSRENOL drug interactions based on altered gastric pH are not expected.
In Vitro Drug Interactions
Gastric Fluid: 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.
In Vivo Drug Interactions
No effects of lanthanum were found on the absorption of digoxin (0.5mg), metoprolol (100mg), or warfarin (10mg) in healthy subjects co-administered lanthanum carbonate (three doses of 1000mg on the day prior to exposure and one dose of 1000mg 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.
In healthy subjects, the absorption and pharmacokinetics of a single dose of 1000mg of FOSRENOL was unaffected by co-administration of citrate.
FOSRENOL appears not to affect the intestinal absorption of fat soluble vitamins (A, D, E and K), vitamin B12 or other nutrients (see Clinical Trials - Open-Label, Active-Controlled Studies).
Co-administration of FOSRENOL (1000mg TID for 1 day) with calcitriol (2 x 0.5µg) to healthy subjects did not significantly alter peak concentrations or overall extent of absorption of calcitriol (1,25-dihydroxyvitamin D3).
Co-administration of FOSRENOL with quinolone antibiotics may reduce the extent of their absorption as a result of complex formation. The bioavailability of oral ciprofloxacin was decreased by approximately 50% when taken with FOSRENOL in a single dose study in healthy volunteers. FOSRENOL should not be taken simultaneously with oral quinolone antibiotics.
The bioavailability of levothyroxine was decreased by approximately 40% when taken together with FOSRENOL. FOSRENOL should not be taken simultaneously with thyroid hormones replacement therapy and closer monitoring of TSH levels is recommended in patients receiving both medicinal products.
Other Possible Interactions
Interactions with drugs such as tetracycline and doxycycline are theoretically possible. If these compounds are to be co-administered, it is recommended that they not be taken within 2 hours of dosing with FOSRENOL.
There is a potential for FOSRENOL to interact with compounds which bind to cationic antacids (e.g., aluminium-, magnesium-, or calcium-based). It is recommended that compounds known to interact with antacids should not be taken within 2 hours of dosing with FOSRENOL (e.g., chloroquine, hydroxychloroquine and ketoconazole).
No drug interaction studies assessed the effects of drugs on phosphate binding by lanthanum carbonate.
The drug interactions profile of FOSRENOL is characterized by the potential of lanthanum to bind to drugs with anionic functions (e.g., carboxyl, carbonyl and hydroxyl groups). When administering any such medications where a reduction in the bioavailability of that medication would have a clinically significant effect on safety or efficacy, the physician should consider dosing that medicine apart from FOSRENOL or monitoring blood levels.
Interactions of FOSRENOL with herbs have not been established.
Drug-Laboratory Test Interactions
Abdominal X-rays of patients taking lanthanum carbonate may have a radio-opaque appearance typical of an imaging agent.
Interactions of FOSRENOL with lifestyle have not been established.
Dosage and Administration
Serum phosphorus levels should be monitored as needed during titration until an optimal serum phosphorus level is reached, and then on a regular basis thereafter.
Recommended Dose and Dosage Adjustment
The recommended initial daily dose of FOSRENOL (lanthanum carbonate hydrate) for adults is 750mg-1500mg. The dose should be titrated every 2-3 weeks to a level that achieves maintenance of acceptable serum phosphorus levels. The daily dose should be divided and taken with or immediately after meals. Patients should adhere to recommended diets in order to control phosphate and fluid intake. FOSRENOL is presented as a chewable tablet, therefore avoiding the need to take additional fluid.
In clinical studies in ESRD patients, FOSRENOL doses up to 4500mg were evaluated. Most patients required a total daily dose between 1500 and 3000mg of FOSRENOL to reduce serum phosphorus levels to less than 6.0mg/dL (1.92mmol/L). Doses were generally titrated in increments of 750mg/day.
A missed dose should be taken at the next scheduled dose with a meal. Taking a dose at a time other than mealtime may lead to nausea and vomiting. Patients should not double-up the dose to catch up.
Tablets should be chewed completely before swallowing. The tablets may be crushed as an aid to chewing. Intact tablets should not be swallowed. Consider crushing tablets completely for patients with poor dentition.
The highest daily dose of lanthanum carbonate administered to healthy adult subjects during a Phase I study was 9000mg/day for 3 days. The symptoms associated with overdose are adverse reactions such as headache, nausea and vomiting. Given the local activity of FOSRENOL in the gut, and the excretion in feces of the majority of the dose, supportive therapy is recommended in case of overdosage. Lanthanum carbonate was not acutely toxic in animals by the oral route (see Toxicology – Single- and Repeat-Dose Toxicity).
|For management of a suspected drug overdose, contact your regional Poison Control Centre.|
Action and Clinical Pharmacology
Patients with ESRD can develop hyperphosphatemia as a result of phosphorus retention, which may be associated with secondary hyperparathyroidism and elevated calcium phosphate product.
Treatment of hyperphosphatemia usually includes all of the following: reduction in dietary intake of phosphate, removal of phosphate by dialysis and inhibition of intestinal phosphate absorption with phosphate binders.
Mechanism of Action
FOSRENOL (lanthanum carbonate hydrate) acts in the lumen of the gut to bind dietary phosphorus released from food during digestion. Lanthanum carbonate hydrate inhibits the absorption of phosphorus by the formation of highly insoluble lanthanum phosphate complexes that cannot easily pass through the wall of the gastrointestinal tract, and are excreted in the feces.
Lanthanum carbonate dissociates in the acid environment of the upper GI tract to release lanthanum ions that bind dietary phosphate released from food during digestion. FOSRENOL inhibits absorption of phosphate by forming highly insoluble lanthanum phosphate complexes, consequently reducing both serum phosphate and calcium phosphate product.
In vitro studies have shown that in the physiologically relevant pH range of 3 to 5 in gastric fluid, lanthanum binds approximately 97% of the available phosphate when lanthanum is present in a two-fold molar excess to phosphate. In order to bind dietary phosphate efficiently, lanthanum should be administered with or immediately after a meal.
Since the binding of dietary phosphorus occurs in the lumen of the stomach and upper small intestine, plasma lanthanum concentrations are not predictive of lanthanum carbonate hydrate’s efficacy.
Following single or multiple dose oral administration of FOSRENOL to healthy subjects, the concentration of lanthanum in plasma was very low, with oral bioavailability estimated to be <0.002%.
In healthy subjects, plasma AUC and Cmax increased as a function of dose, but in a less than proportional manner, after single oral doses of 250 to 1000mg lanthanum, consistent with dissolution-limited absorption. The apparent plasma elimination half-life in healthy subjects was 36 hours.
In renal dialysis patients dosed for 10 days with 1000mg lanthanum carbonate hydrate three times daily, the mean (±sd) lanthanum Cmax was 1.06 (±1.04) ng/mL, and the mean AUClast was 31.1 (±40.5) ng·h/mL. During long-term administration (52 weeks) in renal dialysis patients, the mean lanthanum concentration in plasma was approximately 0.6ng/mL. Regular blood level monitoring in renal dialysis patients taking lanthanum carbonate hydrate (with increasing doses within the therapeutic dose range) for up to 2 years showed minimal increase in plasma lanthanum concentrations over this time period.
The effect of food on the bioavailability of FOSRENOL has not been evaluated, but the timing of food intake relative to lanthanum administration (during and 30 minutes after food intake) has a negligible effect on the systemic level of lanthanum.
Lanthanum is present in the environment. Measurement of background levels in non-lanthanum carbonate-treated ESRD patients on dialysis during Phase III clinical trials revealed concentration of <0.05 to 0.90ng/mL in plasma, and <0.006 to 1.0µg/g in bone biopsy samples.
In vitro, lanthanum is highly bound (>99%) to human plasma proteins, including human serum albumin, α1-acid glycoprotein, and transferrin. Binding to erythrocytes in vivo is negligible in rats.
In long-term studies in mice, rats and dogs, absorbed lanthanum was widely distributed to systemic tissues, predominantly bone, liver and the gastrointestinal tract, including the mesenteric lymph nodes. Lanthanum concentrations in several tissues, including the gastrointestinal tract, bone and liver, increased over time and were several orders of magnitude higher than plasma concentrations. Changes in tissue lanthanum levels after withdrawal of treatment varied between tissues. A relatively high proportion of lanthanum was retained in tissues for longer than 6 months after cessation of dosing [median percent retained in bone ≤100% (rat) and ≤87% (dog) and in the liver ≤6% (rat) and ≤82% (dog)]. There is no evidence from animal studies that lanthanum crosses the blood-brain barrier.
In 105 bone biopsies from patients treated with FOSRENOL for up to 4.5 years, rising levels of lanthanum were noted over time. Steady-state bone concentrations were not reached during the period studied (see Clinical Trials –Bone Safety). No clinical data are available on deposition of lanthanum in other tissues in humans, including liver and gastrointestinal tract.
Lanthanum carbonate is not metabolized and is not a substrate of CYP450. In vitro metabolic inhibition studies showed that lanthanum at concentrations of 10 and 40µg/mL does not have relevant inhibitory effects on any of the CYP450 isoenzymes tested (1A2, C9, 2C19, 2D6 and 3A4).
Lanthanum was cleared from plasma following discontinuation of therapy with an elimination half-life of 53 hours.
No information is available regarding the mass balance of lanthanum in humans after oral administration. In healthy subjects, the majority of an orally administered dose was excreted in the feces with only around 0.000031% of the oral dose excreted in the urine (representing <2% of total plasma clearance).
Studies in chronic renal failure patients with hepatic impairment have not been conducted. In patients with co-existing hepatic disorders at the time of entry into Phase III clinical studies, there was no evidence of increased plasma exposure to lanthanum or worsening hepatic function after treatment with FOSRENOL for periods up to 2 years.
Paired bone biopsies from 11 patients were collected after 12 months of lanthanum carbonate treatment and 24-26 months after stopping lanthanum carbonate treatment. The mean bone lanthanum concentration at the end of the treatment period was 2806µg/kg (range 530 to 5513µg/kg) and the mean concentration was 1903µg/kg (range 543 to 5683µg/kg) after 24-26 months off-treatment. This limited data demonstrated that lanthanum is slowly cleared from bone. Its clearance showed considerable variability between individuals.
Storage and Stability
Store between 15-25°C; excursions permitted up to 30°C. Protect from moisture.Keep in a safe place out of the reach of children and pets.
Dosage Forms, Composition and Packaging
FOSRENOL is supplied as a chewable tablet in four dosage strengths for oral administration: 250mg tablets, 500mg tablets, 750mg tablets and 1000mg tablets. Each chewable tablet is white to off-white, round, flat with a beveled edge, and embossed on one side with ❛S405❜ and the dosage strength corresponding to the content of the elemental lanthanum.
FOSRENOL 250mg chewable tablets are supplied in bottles of 90 and 400 tablets.
FOSRENOL 500mg chewable tablets are supplied in bottles of 45 tablets.
FOSRENOL 750mg chewable tablets are supplied in bottles of 15 tablets.
FOSRENOL 1000mg chewable tablets are supplied in bottles of 10 tablets.
Each chewable tablet of FOSRENOL (lanthanum carbonate hydrate) contains either 250, 500, 750 or 1000mg of elemental lanthanum (as lanthanum carbonate hydrate) and the following non-medicinal ingredients: colloidal silicon dioxide, dextrates (hydrated), and magnesium stearate.