Actonel with Calcium

Actonel with Calcium information, interactions and side effects, Actonel® with Calcium (risedronate sodium with calcium carbonate) is a co-package product containing Actonel® (risedronate sodium tablets, 35 mg) for once weekly dosing and calcium carbonate tablets, USP (1250 mg, equivalent to 500 mg elemental calcium) for daily dosing for the remaining 6 days of the week. Each package contains a 28-day course of therapy.

Actonel

Actonel (risedronate sodium tablets) is a pyridinyl bisphosphonate that inhibits osteoclast-mediated bone resorption and modulates bone metabolism. Each Actonel tablet in the Actonel with Calcium (risedronate sodium with calcium carbonate) co-package contains the equivalent of 35 mg of anhydrous risedronate sodium in the form of the hemi-pentahydrate with small amounts of monohydrate. The empirical formula for risedronate sodium hemi-pentahydrate is C7H10NO7P2Na •2.5 H2O. The chemical name of risedronate sodium is [1-hydroxy-2-(3-pyridinyl)ethylidene]bis[phosphonic acid] monosodium salt. The chemical structure of risedronate sodium hemi-pentahydrate is the following:

actonelca

Molecular Weight:
Anhydrous: 305.10
Hemi-pentahydrate: 350.13

Risedronate sodium is a fine, white to off-white, odorless, crystalline powder. It is soluble in water and in aqueous solutions, and essentially insoluble in common organic solvents.

Calcium

The empirical formula for calcium carbonate is CaCO3 and the molecular weight is 100.09.

Calcium carbonate is supplied as a calcium carbonate tablet, USP containing 1250 mg calcium carbonate (equivalent to 500 mg elemental calcium). Calcium carbonate is a fine, white, odorless, tasteless powder. It is stable and non-hygroscopic.

Calcium carbonate is formulated per USP standards to meet disintegration or dissolution, weight, purity, and potency requirements.

Inactive Ingredients

Actonel

Crospovidone, ferric oxide red, ferric oxide yellow, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, silicon dioxide, titanium dioxide.

Calcium

Pregelatinized starch, sodium starch glycolate, FD&C Blue #2, magnesium stearate, polyethylene glycol 3350, hypromellose, Opaspray Light Blue, polysorbate 80.

INDICATIONS

Postmenopausal Osteoporosis

Actonel with Calcium (risedronate sodium with calcium carbonate) is indicated for the treatment and prevention of osteoporosis in postmenopausal women.

Treatment of Osteoporosis

In postmenopausal women with osteoporosis, Actonel increases BMD and reduces the incidence of vertebral fractures and a composite endpoint of nonvertebral osteoporosis-related fractures. Osteoporosis may be confirmed by the presence or history of osteoporotic fracture, or by the finding of low bone mass (for example, at least 2 SD below the premenopausal mean).

Prevention of Osteoporosis

Actonel may be considered in postmenopausal women who are at risk of developing osteoporosis and for whom the desired clinical outcome is to maintain bone mass and to reduce the risk of fracture.

Factors such as family history of osteoporosis, previous fracture, smoking, BMD (at least 1 SD below the premenopausal mean), high bone turnover, thin body frame, Caucasian or Asian race, and early menopause are associated with an increased risk of developing osteoporosis and fractures. The presence of these risk factors may be important when considering the use of Actonel for prevention of osteoporosis.

The safety and effectiveness of Actonel with Calcium (risedronate sodium with calcium carbonate) for the treatment of osteoporosis are based on clinical data of three years duration. The optimal duration of use has not been determined. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis.

DOSAGE AND ADMINISTRATION

Treatment and Prevention of Postmenopausal Osteoporosis

One 35 mg Actonel tablet orally, taken once-a-week (Day 1 of the 7-day treatment cycle)

Actonel should be taken at least 30 minutes before the first food or drink of the day other than water. Actonel should not be taken at the same time as other medications, including calcium.

To facilitate delivery to the stomach, Actonel should be swallowed while the patient is in an upright position and with a full glass of plain water (6 to 8 oz). Patients should not lie down for 30 minutes after taking the medication. Actonel is not recommended for use in patients with severe renal impairment (creatinine clearance < 30 mL/min). No dosage adjustment is necessary in patients with a creatinine clearance ≥ 30 mL/min or in the elderly.

One 1250 mg calcium carbonate tablet (500 mg elemental calcium) orally, taken with food daily on each of the remaining six days (Days 2 through 7 of the 7-day treatment cycle)

The recommended total (diet and otherwise) daily calcium intake in postmenopausal women is 1200 mg of elemental calcium. If patients need calcium in excess of that provided by Actonel with Calcium (risedronate sodium with calcium carbonate) , this should be taken with food at a separate time of day.

Patients should receive additional vitamin D if dietary intake is inadequate. Co-administration of calcium tablets and calcium-, aluminum-, and magnesium-containing medications may interfere with the absorption of Actonel.

HOW SUPPLIED

Actonel® with Calcium (risedronate sodium with calcium carbonate) is supplied in blister packages containing a 28-day course of therapy.

Four Actonel Tablets:
35 mg film-coated, oval, orange tablets with RSN on 1 face and 35 mg on the other

Twenty-four Calcium Carbonate Tablets, USP:
1250 mg calcium carbonate (equivalent to 500 mg elemental calcium) film-coated, oval, light blue tablets with NE 2 engraved on both faces

NDC 0430-0475-14

Store at 20° – 25° C (68° – 77° F); excursions permitted between 15° – 30° C (59° – 86° F).

SIDE EFFECTS

Actonel

Osteoporosis

Actonel has been studied in over 5700 patients enrolled in the Phase 3 glucocorticoid-induced osteoporosis clinical trials and in postmenopausal osteoporosis trials of up to 3-years duration. The overall adverse event profile of Actonel 5 mg in these studies was similar to that of placebo. Most adverse events were either mild or moderate and did not lead to discontinuation from the study. The incidence of serious adverse events in the placebo group was 24.9% and in the Actonel 5 mg group was 26.3%. The percentage of patients who withdrew from the study due to adverse events was 14.4% and 13.5% for the placebo and Actonel 5 mg groups, respectively. Table 4 lists adverse events from the Phase 3 osteoporosis trials reported in ≥ 2% of patients and in more Actonel-treated patients than placebo-treated patients. Adverse events are shown without attribution of causality.

Table 4 : Adverse Events Occurring at a Frequency ≥ 2% and in More Actonel-Treated Patients than Placebo-Treated Patients Combined Phase 3 Osteoporosis Trials

 

Body System Placebo %
(N = 1914)
Actonel 5 mg
%
(N = 1916)
Body as a Whole
  Infection 29.7 29.9
  Back Pain 23.6 26.1
  Pain 13.1 13.6
  Abdominal Pain 9.4 11.6
  Neck Pain 4.5 5.3
  Asthenia 4.3 5.1
  Chest Pain 4.9 5.0
  Neoplasm 3.0 3.3
  Hernia 2.5 2.9
Cardiovascular
  Hypertension 9.0 10.0
  Cardiovascular Disorder 1.7 2.5
  Angina Pectoris 2.4 2.5
Digestive
  Nausea 10.7 10.9
  Diarrhea 9.6 10.6
  Flatulence 4.2 4.6
  Gastritis 2.3 2.5
  Gastrointestinal Disorder 2.1 2.3
  Rectal Disorder 1.9 2.2
  Tooth Disorder 2.0 2.1
Hemic and Lymphatic
  Ecchymosis 4.0 4.3
  Anemia 1.9 2.4
Musculoskeletal
  Arthralgia 21.1 23.7
  Joint Disorder 5.4 6.8
  Myalgia 6.3 6.6
  Bone Pain 4.3 4.6
  Bone Disorder 3.2 4.0
  Leg Cramps 2.6 3.5
  Bursitis 2.9 3.0
  Tendon Disorder 2.5 3.0
Nervous
  Depression 6.2 6.8
  Dizziness 5.4 6.4
  Insomnia 4.5 4.7
  Anxiety 3.0 4.3
  Neuralgia 3.5 3.8
  Vertigo 3.2 3.3
  Hypertonia 2.1 2.2
  Paresthesia 1.8 2.1
Respiratory
  Pharyngitis 5.0 5.8
  Rhinitis 5.0 5.7
  Dyspnea 3.2 3.8
  Pneumonia 2.6 3.1
Skin and Appendages
  Rash 7.2 7.7
  Pruritus 2.2 3.0
  Skin Carcinoma 1.8 2.0
Special Senses
  Cataract 5.4 5.9
  Conjunctivitis 2.8 3.1
  Otitis Media 2.4 2.5
Urogenital
  Urinary Tract Infection 9.7 10.9
  Cystitis 3.5 4.1

Duodenitis and glossitis have been reported uncommonly (0.1% to 1%). There have been rare reports ( < 0.1%) of abnormal liver function tests.

Laboratory Test Findings

Asymptomatic and small decreases were observed in serum calcium and phosphorus levels. Overall, mean decreases of 0.8% in serum calcium and of 2.7% in phosphorus were observed at 6 months in patients receiving Actonel. Throughout the Phase 3 studies, serum calcium levels below 8 mg/dL were observed in 18 patients, 9 (0.5%) in each treatment arm (Actonel and placebo). Serum phosphorus levels below 2 mg/dL were observed in 14 patients, 11 (0.6%) treated with Actonel and 3 (0.2%) treated with placebo.

Endoscopic Findings

Actonel clinical studies enrolled over 5700 patients, many with pre-existing gastrointestinal disease and concomitant use of NSAIDs or aspirin. Investigators were encouraged to perform endoscopies in any patients with moderate-to-severe gastrointestinal complaints, while maintaining the blind. These endoscopies were ultimately performed on equal numbers of patients between the treated and placebo groups [75 (14.5%) placebo; 75 (11.9%) Actonel]. Across treatment groups, the percentage of patients with normal esophageal, gastric, and duodenal mucosa on endoscopy was similar (20% placebo; 21% Actonel). The number of patients who withdrew from the studies due to the event prompting endoscopy was similar across treatment groups. Positive findings on endoscopy were also generally comparable across treatment groups. There was a higher number of reports of mild duodenitis in the Actonel group, however there were more duodenal ulcers in the placebo group. Clinically important findings (perforations, ulcers, or bleeding) among this symptomatic population were similar between groups (51% placebo; 39% Actonel).

Once-a-week Dosing

In a 1-year, double-blind, multicenter study comparing Actonel 5 mg daily and Actonel 35 mg once-a-week in postmenopausal women, the overall safety and tolerability profiles of the 2 oral dosing regimens were similar. Table 5 lists the adverse events in ≥ 2% of patients from this trial. Events are shown without attribution of causality.

Table 5: Adverse Events Occurring in ≥ 2% of Patients of Either Treatment Group in the Daily vs. Weekly Osteoporosis Treatment Study in Postmenopausal Women

 

Body System 5 mg Daily Actonel
%
(N = 480)
35 mg Weekly Actonel
%
(N = 485)
Body as a Whole
  Infection 19.0 20.6
  Accidental Injury 10.6 10.7
  Pain 7.7 9.9
  Back Pain 9.2 8.7
  Flu Syndrome 7.1 8.5
  Abdominal Pain 7.3 7.6
  Headache 7.3 7.2
  Overdose 6.9 6.8
  Asthenia 3.5 5.4
  Chest Pain 2.3 2.7
  Allergic Reaction 1.9 2.5
  Neoplasm 0.8 2.1
  Neck Pain 2.7 1.2
Cardiovascular System
  Hypertension 5.8 4.9
  Syncope 0.6 2.1
  Vasodilatation 2.3 1.4
Digestive System
  Constipation 12.5 12.2
  Dyspepsia 6.9 7.6
  Nausea 8.5 6.2
  Diarrhea 6.3 4.9
  Gastroenteritis 3.8 3.5
  Flatulence 3.3 3.1
  Colitis 0.8 2.5
  Gastrointestinal Disorder 1.9 2.5
  Vomiting 1.9 2.5
  Dry Mouth 2.5 1.4
Metabolic and Nutritional Disorders
  Peripheral Edema 4.2 1.6
Musculoskeletal System
  Arthralgia 11.5 14.2
  Traumatic Bone Fracture 5.0 6.4
  Myalgia 4.6 6.2
  Arthritis 4.8 4.1
  Bursitis 1.3 2.5
  Bone Pain 2.9 1.4
Nervous System
  Dizziness 5.8 4.9
  Anxiety 0.6 2.7
  Depression 2.3 2.3
  Vertigo 2.1 1.6
Respiratory System
  Bronchitis 2.3 4.9
  Sinusitis 4.6 4.5
  Pharyngitis 4.6 2.9
  Cough Increased 3.1 2.5
  Pneumonia 0.8 2.5
  Rhinitis 2.3 2.1
Skin and Appendages
  Rash 3.1 4.1
  Pruritus 1.9 2.3
Special Senses
  Cataract 2.9 1.9
Urogenital System
  Urinary Tract Infection 2.9 5.2

 

Osteoporosis Prevention

There were no deaths in a 1-year, double-blind, placebo-controlled study of Actonel 35 mg once-a-week for prevention of bone loss in 278 postmenopausal women without osteoporosis. More treated subjects on risedronate experienced arthralgia (risedronate 13.9%; placebo 7.8%), myalgia (risedronate 5.1%; placebo 2.1%), and nausea (risedronate 7.3%; placebo 4.3%) than subjects on placebo.

Post-marketing Experience

Very rare hypersensitivity and skin reactions have been reported, including angioedema, generalized rash and bullous skin reactions, some severe.

Musculoskeletal: bone, joint, or muscle pain, rarely described as severe or incapacitating.

Very rare reactions of eye inflammation including iritis and uveitis have been reported. Osteonecrosis of the jaw has been reported very rarely.

Calcium

Calcium carbonate may cause gastrointestinal adverse effects such as constipation, flatulence, nausea, abdominal pain, and bloating. Administration of calcium may increase the risk of kidney stones, particularly in patients with a history of this condition.

DRUG INTERACTIONS

Actonel

No specific drug-drug interaction studies were performed. Risedronate is not metabolized and does not induce or inhibit hepatic microsomal drug-metabolizing enzymes (Cytochrome P450).

Calcium Supplements/Antacids

Co-administration of Actonel and calcium, antacids, or oral medications containing divalent cations will interfere with the absorption of Actonel.

Hormone Replacement Therapy

One study of about 500 early postmenopausal women has been conducted to date in which treatment with Actonel (5 mg/day) plus estrogen replacement therapy was compared to estrogen replacement therapy alone. Exposure to study drugs was approximately 12 to 18 months and the primary endpoint was change in BMD. If considered appropriate, Actonel may be used concomitantly with hormone replacement therapy.

Aspirin/Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Of over 5700 patients enrolled in the Actonel Phase 3 osteoporosis studies, aspirin use was reported by 31% of patients, 24% of whom were regular users (3 or more days per week). Forty-eight percent of patients reported NSAID use, 21% of whom were regular users. Among regular aspirin or NSAID users, the incidence of upper gastrointestinal adverse experiences in Actoneltreated patients (24.5%) was similar to that in placebo-treated patients (24.8%).

H2 Blockers and Proton Pump Inhibitors (PPIs)

Of over 5700 patients enrolled in the Actonel Phase 3 osteoporosis studies, 21% used H2 blockers and/or PPIs. Among these patients, the incidence of upper gastrointestinal adverse experiences in the Actonel-treated patients was similar to that in placebo-treated patients.

Calcium

Bisphosphonates

Oral bisphosphonates (such as risedronate, alendronate, etidronate, ibandronate): Decreased absorption of the bisphosphonate may occur when the bisphosphonate and calcium are taken together.

Thyroid hormones

Levothyroxine: Concomitant intake of levothyroxine and calcium carbonate was found to reduce levothyroxine absorption and increase serum thyrotropin levels.

Fluoroquinolones

Fluoroquinolones (such as ciprofloxacin, moxifloxacin, and ofloxacin): Concomitant administration of a fluoroquinolone and calcium carbonate may decrease the absorption of the fluoroquinolone.

Systemic glucocorticoids

Calcium absorption is reduced when calcium carbonate is taken concomitantly with systemic glucocorticoids.

Tetracyclines

Tetracyclines (such as doxycycline, minocycline, tetracycline): Concomitant administration of a tetracycline and calcium carbonate may decrease the absorption of the tetracycline.

Thiazide diuretics

Reduced urinary excretion of calcium has been reported during concomitant use of calcium carbonate and thiazide diuretics.

Vitamin D

Vitamin D and vitamin D analogues (such as calcitriol, doxercalciferol, and paricalcitol): Absorption of calcium may be increased when calcium carbonate is given concomitantly with vitamin D analogues.

Iron

Calcium may interfere with the absorption of iron. Patients being treated for iron deficiency should take iron and calcium at different times of the day.

Drug/Laboratory Test Interactions

Actonel

Bisphosphonates are known to interfere with the use of bone-imaging agents. Specific studies with Actonel have not been performed.

WARNINGS

Actonel

Bisphosphonates may cause upper gastrointestinal disorders such as dysphagia, esophagitis, and esophageal or gastric ulcer.

PRECAUTIONS

General

Actonel

Hypocalcemia and other disturbances of bone and mineral metabolism should be effectively treated before starting Actonel therapy. Adequate intake of calcium and vitamin D is important in all patients. Actonel is not recommended for use in patients with severe renal impairment (creatinine clearance < 30 mL/min).

Bisphosphonates have been associated with gastrointestinal disorders such as dysphagia, esophagitis, and esophageal or gastric ulcers. This association has been reported for bisphosphonates in postmarketing experience, but has not been found in most pre-approval clinical trials, including those conducted with Actonel. Patients should be advised that taking the medication according to the instructions is important to minimize the risk of these events. They should take Actonel with sufficient plain water (6 to 8 oz) to facilitate delivery to the stomach, and should not lie down for 30 minutes after taking the drug.

Osteonecrosis, primarily in the jaw, has been reported in patients treated with bisphosphonates. Most cases have been in cancer patients undergoing dental procedures such as tooth extraction, but some have occurred in patients with postmenopausal osteoporosis or other diagnoses. Most reported cases have been in patients treated with bisphosphonates intravenously but some have been in patients treated orally.

For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment, prior to the procedure, reduces the risk of osteonecrosis of the jaw. Clinical judgement should guide the management plan of each patient based on individual benefit/risk assessment.

Musculoskeletal Pain

In postmarketing experience, there have been infrequent reports of severe and occasionally incapacitating bone, joint, and/or muscle pain in patients taking bisphosphonates. The time to onset of symptoms varied from one day to several months after starting the drug. Most patients had relief of symptoms after stopping medication. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.

Atypical Subtrochanteric and Diaphyseal Femoral Fractures:

Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported in bisphosphonate-treated patients. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are traverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with bisphosphonates.

Atypical femur fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture.

Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patients presenting with an atypical fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of bisphosphonate therapy should be considered, pending a risk/benefit assessment, on an individual basis.

Calcium

Actonel with Calcium (risedronate sodium with calcium carbonate) should not be used to treat hypocalcemia. Total daily intake of calcium above 1500 mg has not demonstrated additional bone benefits while daily intake above 2000 mg has been associated with increased risk of adverse effects, including hypercalcemia and kidney stones.

Administration of calcium has been associated with a slight increase in the risk of kidney stones.

In patients with a history of kidney stones or hypercalciuria, metabolic assessment to seek treatable causes of these conditions is warranted. If administration of calcium tablets should be needed in these patients, urinary calcium excretion and other appropriate testing should be monitored periodically.

Patients with achlorhydria may have decreased absorption of calcium. Taking calcium with food enhances absorption.

Concomitant use of calcium-containing antacids should be monitored to avoid excessive intake of calcium.

Information for Patients

Actonel

The patient should be informed to pay particular attention to the dosing instructions as clinical benefits may be compromised by failure to take the drug according to instructions. Specifically, Actonel should be taken at least 30 minutes before the first food or drink of the day other than water.

To facilitate delivery to the stomach, and thus reduce the potential for esophageal irritation, patients should take Actonel while in an upright position (sitting or standing) with a full glass of plain water (6 to 8 oz). Patients should not lie down for 30 minutes after taking the medication. Patients should not chew or suck on the tablet because of a potential for oropharyngeal irritation.

Patients should be instructed that if they develop symptoms of esophageal disease (such as difficulty or pain upon swallowing, retrosternal pain or severe persistent or worsening heartburn) they should consult their physician before continuing Actonel.

Patients should be instructed that if they miss a dose of Actonel 35 mg once-a-week, they should take 1 tablet on the morning after they remember and return to taking 1 tablet once-a-week, as originally scheduled on their chosen day. Patients should not take 2 tablets on the same day.

Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate. Calcium supplements or calcium-, aluminum-, and magnesium-containing medications may interfere with the absorption of Actonel and should be taken at a different time of the day, as with food.

Weight-bearing exercise should be considered along with the modification of certain behavioral factors, such as excessive cigarette smoking, and/or alcohol consumption, if these factors exist.

Physicians should instruct their patients to read the PATIENT INFORMATION before starting therapy with Actonel 35 mg and to re-read it each time the prescription is renewed.

Patients should be reminded to give all of their healthcare providers an accurate medication history. Instruct patients to tell all of their healthcare providers that they are taking Actonel. Patients should be instructed that any time they have a medical problem they think may be from Actonel, they should talk to their doctor.

Calcium

Calcium should be used as an adjunct to osteoporosis therapies.

The patient should be informed to take the calcium tablets with food to facilitate calcium absorption.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a 104-week carcinogenicity study, rats were administered daily oral doses of risedronate up to 24 mg/kg/day (approximately 50 times the systemic exposure following a 35 mg/week human dose based on surface area, mg/m²). There were no significant drug-induced tumor findings in male or female rats. The high dose male group of 24 mg/kg/day was terminated early in the study (Week 93) due to excessive toxicity, and data from this group were not included in the statistical evaluation of the study results. In an 80-week carcinogenicity study, mice were administered daily oral doses up to 32 mg/kg/day (approximately 30 times the systemic exposure following a 35 mg/week human dose based on surface area, mg/m²). There were no significant drug-induced tumor findings in male or female mice.

Mutagenesis

Risedronate did not exhibit genetic toxicity in the following assays: In vitro bacterial mutagenesis in Salmonella and E. coli (Ames assay), mammalian cell mutagenesis in CHO/HGPRT assay, unscheduled DNA synthesis in rat hepatocytes and an assessment of chromosomal aberrations in vivo in rat bone marrow.

Impairment of Fertility

In female rats, ovulation was inhibited at an oral dose of risedronate of 16 mg/kg/day (approximately 30 times the systemic exposure following a 35 mg/week human dose based on surface area, mg/m²). Decreased implantation was noted in female rats treated with doses ≥ 7 mg/kg/day (14 times the systemic exposure following a 35 mg/week human dose based on surface area, mg/m²). In male rats, testicular and epididymal atrophy and inflammation were noted at 40 mg/kg/day (80 times the systemic exposure following a 35 mg/week human dose based on surface area, mg/m²). Testicular atrophy was also noted in male rats after 13 weeks of treatment at oral doses of 16 mg/kg/day (approximately 30 times the systemic exposure following a 35 mg/week human dose based on surface area, mg/m²). There was moderate-tosevere spermatid maturation block after 13 weeks in male dogs at an oral dose of 8 mg/kg/day (approximately 50 times the systemic exposure following a 35 mg/week human dose based on surface area, mg/m²).

Pregnancy

Pregnancy Category C

Survival of neonates was decreased in rats treated during gestation with oral doses of risedronate ≥ 16 mg/kg/day (approximately 30 times the systemic exposure following a 35 mg/week human dose based on surface area, mg/m²). Body weight was decreased in neonates from dams treated with 80 mg/kg (approximately 160 times the 35 mg/week human dose based on surface area, mg/m²). In rats treated during gestation, the number of fetuses exhibiting incomplete ossification of sternebrae or skull was statistically significantly increased at 7.1 mg/kg/day (approximately 14 times the 35 mg/week human dose based on surface area, mg/m²). Both incomplete ossification and unossified sternebrae were increased in rats treated with oral doses ≥ 16 mg/kg/day (approximately 30 times the 35 mg/week human dose based on surface area, mg/m²). A low incidence of cleft palate was observed in fetuses from female rats treated with oral doses ≥ 3.2 mg/kg/day (approximately 20 times the 35 mg/week human dose based on surface area, mg/m²). The relevance of this finding to human use of Actonel is unclear. No significant fetal ossification effects were seen in rabbits treated with oral doses up to 10 mg/kg/day during gestation (40 times the 35 mg/week human dose based on surface area, mg/m²). However, in rabbits treated with 10 mg/kg/day, 1 of 14 litters were aborted and 1 of 14 litters were delivered prematurely.

Similar to other bisphosphonates, treatment during mating and gestation with doses as low as 3.2 mg/kg/day (approximately 20 times the 35 mg/week human dose based on surface area, mg/m²) has resulted in periparturient hypocalcemia and mortality in pregnant rats allowed to deliver.

Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over periods of weeks to years. The amount of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the dose and duration of bisphosphonate use. There are no data on fetal risk in humans. However, there is a theoretical risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been studied.

There are no adequate and well-controlled studies of Actonel in pregnant women. Actonel should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.

Nursing Women

Risedronate was detected in feeding pups exposed to lactating rats for a 24-hour period post-dosing, indicating a small degree of lacteal transfer. It is not known whether risedronate is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from bisphosphonates, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Actonel

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Actonel

Of the patients receiving Actonel in postmenopausal osteoporosis studies, 47% were between 65 and 75 years of age, and 17% were over 75. No overall differences in efficacy or safety were observed between these patients and younger patients but greater sensitivity of some older individuals cannot be ruled out.

Calcium

There are no published data that specifically compare the efficacy and safety between postmenopausal women above and below the age of 65 years.

Use in Men

Actonel

The safety and effectiveness in men for the treatment of primary osteoporosis have not been established.

This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

Actonel

Decreases in serum calcium and phosphorus following substantial overdose may be expected in some patients. Signs and symptoms of hypocalcemia may also occur in some of these patients. Milk or antacids containing calcium should be given to bind Actonel and reduce absorption of the drug.

In cases of substantial overdose, gastric lavage may be considered to remove unabsorbed drug. Standard procedures that are effective for treating hypocalcemia, including the administration of calcium intravenously, would be expected to restore physiologic amounts of ionized calcium and to relieve signs and symptoms of hypocalcemia.

Lethality after single oral doses was seen in female rats at 903 mg/kg and male rats at 1703 mg/kg. The minimum lethal dose in mice and rabbits was 4000 mg/kg and 1000 mg/kg. These values represent > 1000 times the 35 mg/week human dose based on surface area (mg/m²).

Calcium

Because of its limited intestinal absorption, overdosage with calcium carbonate is unlikely. However, prolonged use of very high doses can lead to hypercalcemia. Clinical manifestations of hypercalcemia may include anorexia, thirst, nausea, vomiting, constipation, abdominal pain, muscle weakness, fatigue, mental disturbances, polydipsia, polyuria, bone pain, nephrocalcinosis, renal calculi and in severe cases, cardiac arrhythmias.

Treatment: Calcium should be discontinued. Other therapies that may be contributing to the condition, such as thiazide diuretics, lithium, vitamin A, vitamin D and cardiac glycosides should also be discontinued. Gastric emptying of any residual calcium should be considered. Rehydration, and, according to severity, isolated or combined treatment with loop diuretics, bisphosphonates, calcitonin and corticosteroids should also be considered. Serum electrolytes, renal function and vital signs must be monitored.

CONTRAINDICATIONS

Actonel

  • Hypocalcemia
  • Known hypersensitivity to any component of this product
  • Inability to stand or sit upright for at least 30 minutes

Calcium

  • Hypercalcemia from any cause including, but not limited to, hyperparathyroidism, hypercalcemia of malignancy, or sarcoidosis.
  • Known hypersensitivity to any component of the product.

This monograph has been modified to include the generic and brand name in many instances.

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