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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 (see PRECAUTIONS, Musculoskeletal Pain).

Very rare reactions of eye inflammation including iritis and uveitis have been reported. Osteonecrosis of the jaw has been reported very rarely (see PRECAUTIONS, General).

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 (see PRECAUTIONS).