Side Effects of Atelvia (risedronate)

Atelvia (risedronate) is a bisphosphonate used to treat Paget’s disease of bone (osteitis deformans), to treat and prevent postmenopausal osteoporosis in women, and to treat osteoporosis in men. It also is used to prevent and treat osteoporosis caused by steroid medications (glucocorticoid-induced osteoporosis). 

Bone is continually being formed and dissolved. New bone is laid down by cells called osteoblasts while old bone is removed by cells called osteoclasts. Bisphosphonates strengthen bone by inhibiting bone removal (resorption) by osteoclasts.

By slowing down the rate at which bone is dissolved, Atelvia increases the amount of bone. Atelvia is more potent in blocking the dissolution of bone than other bisphosphonates such as etidronate and alendronate.

Common side effects of Atelvia include

• headache,
• joint pain,
• diarrhea,
• abdominal pain,
• rash,
• indigestion,
• constipation,
• high blood pressure (hypertension), and
• nausea.

Less common side effects of Atelvia include

• flu-like symptoms,
• depression,
• chest pain,
• dizziness,
• sore throat, and
• runny nose.

Serious side effects of Atelvia include

• diaphyseal femur,
• difficulty swallowing,
• esophageal cancer,
• severe irritation of the esophagus (for example, esophagitis, esophageal ulcers, esophageal erosions),
• femur fracture,
• stomach and duodenal ulcer,
• osteonecrosis, and
• jaw problems (osteonecrosis of the jaw) associated with delayed healing and infection after tooth extraction (rare).

Drug interactions of Atelvia include food, calcium, antacids, and medications containing iron, magnesium, or aluminum, which can reduce the absorption of Atelvia, resulting in loss of effectiveness.

Atelvia should be taken with plain water only.

The safety and effectiveness of Atelvia has not been established in pregnant women. Physicians must weigh the potential benefits and unknown risks of Atelvia use during pregnancy carefully. The safety of Atelvia for the infant has not been established in women who are breastfeeding. Consult your doctor before breastfeeding.

The most common side effects of risedronate include:

• Headache
• Joint pain
• Diarrhea
• Abdominal pain
• Rash
• Indigestion
• Constipation
• High blood pressure
• Nausea

Other less common side effects include:

• Flu-like syndrome
• Depression
• Chest pain
• Dizziness
• pharyngitis
• rhinitis

Possible serious side effects include:

• Diaphyseal femur
• Difficulty swallowing (dysphagia)
• Esophageal cancer
• Esophageal ulcer
• Femur fracture
• Stomach and duodenal ulcer
• Osteonecrosis

Severe irritation of the esophagus (for example, esophagitis, esophageal ulcers, esophageal erosions) can occur. This occurs more often when patients do not drink enough water with risedronate, or do not wait 30 minutes before lying down.

Rarely, patients may experience jaw problems (osteonecrosis of the jaw) associated with delayed healing and infection after tooth extraction.

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Treatment of Postmenopausal Osteoporosis

Once-a-Week Dosing with Atelvia (risedronate sodium) Delayed-release Tablets

The safety of Atelvia 35 mg once-a-week in the treatment of postmenopausal osteoporosis was assessed in a 1-year, double-blind, multicenter study comparing Atelvia 35 mg once-a-week to risedronate sodium immediate-release 5 mg daily in postmenopausal women 50 years of age or older.

Atelvia was administered either at least 30 minutes before (N = 308) or immediately following (N = 307) breakfast, and risedronate sodium immediate-release 5 mg daily (N = 307) was administered at least 30 minutes before breakfast.

Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors, and H2 antagonists were included in this clinical trial.

All women received daily supplementation with 1000 mg of elemental calcium plus 800 to 1000 international units vitamin D.

As treatment with Atelvia resulted in a significantly higher incidence of abdominal pain when administered before breakfast under fasting conditions, safety results that follow refer only to Atelvia 35 mg once-a-week immediately following breakfast and risedronate sodium immediate-release 5 mg daily.

The incidence of all-cause mortality was 0.0% in the Atelvia 35 mg once-a-week group and 0.3% in the risedronate sodium immediate-release 5 mg daily group. The incidence of serious adverse reactions was 6.5% in the Atelvia 35 mg once-a-week group and 7.2% in the risedronate sodium immediate-release 5 mg daily group.

The percentage of patients who withdrew from the study due to adverse reactions was 9.1% in the Atelvia 35 mg once-a-week group and 8.1% in the risedronate sodium immediate-release 5 mg daily group.

The overall safety and tolerability profiles of the two dosing regimens were similar. Table 1 lists adverse reactions reported in greater than or equal to 2% of patients. Adverse reactions are shown without attribution of causality.

Table 1 : Adverse Reactions Occurring at a Frequency of greater than or equal to 2% in Either Treatment Group

Acute Phase Reactions

Symptoms consistent with acute phase reaction have been reported with bisphosphonate use. The overall incidence of acute phase reaction was 2.3% in the Atelvia 35 mg once-a-week group and 1.3% in the risedronate sodium immediate-release 5 mg daily group.

These incidence rates are based on reporting of one or more pre-specified acute phase reaction-like symptoms within 3 days of the first dose and for a duration of 7 days or less.

Gastrointestinal Adverse Reactions

Adverse reactions related to the upper gastrointestinal tract occurred in 16% of subjects treated with Atelvia 35 mg once-a-week and 15% of subjects treated with risedronate sodium immediate-release 5 mg daily.

The incidence of upper gastrointestinal tract adverse reactions in the Atelvia 35 mg once-a-week and risedronate sodium immediate-release 5 mg daily groups were:

• abdominal pain (5.2% versus 2.9%),
• dyspepsia (3.9% versus 3.9%),
• upper abdominal pain (2.9% versus 2.3%),
• gastritis (1.0% versus 1.0%), and
• gastroesophageal reflux disease (1.0% versus 1.6%).

Study discontinuation due to abdominal pain occurred in 1.3% of the Atelvia 35 mg once-a-week group and 0.7% of the risedronate sodium immediate-release 5 mg daily group.

Musculoskeletal Adverse Reactions

Selected musculoskeletal adverse reactions were reported in 16% of subjects treated with Atelvia 35 mg once-a-week and 15% of subjects treated with risedronate sodium immediate-release 5 mg daily.

The incidence of musculoskeletal adverse reactions in the Atelvia 35 mg once-a-week and risedronate sodium immediate-release 5 mg daily groups were:

• arthralgia (6.8% versus 7.8%),
• back pain (6.8% versus 5.9%),
• musculoskeletal pain (2.0% versus 1.6%), and
• myalgia (1.3% versus 1.0%).

Laboratory Test Findings

Parathyroid Hormone

The effect of Atelvia 35 mg once-a-week and risedronate sodium immediate-release 5 mg daily on parathyroid hormone was evaluated in postmenopausal women with osteoporosis.

At week 52, in subjects with normal levels at baseline, PTH levels greater than 65 pg/mL (upper limit of normal) were noted in 9% of subjects receiving Atelvia 35 mg once-aweek and 8% of subjects receiving risedronate sodium immediate-release 5 mg daily.

In subjects with normal levels at baseline, PTH levels greater than 97 pg/mL (1.5 times the upper limit of normal) were seen in 2% of subjects receiving Atelvia 35 mg once-a-week and no subjects receiving risedronate sodium immediate-release 5 mg daily. There were no clinically significant differences between treatment groups for levels of calcium, phosphorus and magnesium.

Daily Dosing With Risedronate Sodium Immediate-Release 5 Mg Tablets

• The safety of risedronate sodium immediate-release 5 mg once daily in the treatment of postmenopausal osteoporosis was assessed in four randomized, double-blind, placebo-controlled multinational trials of 3232 women aged 38 to 85 years with postmenopausal osteoporosis.
• The duration of the trials was up to three years, with 1619 patients exposed to placebo and 1613 patients exposed to risedronate sodium immediate-release 5 mg daily.
• Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors (PPIs), and H2 antagonists were included in these clinical trials.
• All women received 1000 mg of elemental calcium plus vitamin D supplementation up to 500 international units per day if their 25-hydroxyvitamin D3 level was below normal at baseline.
• The incidence of all-cause mortality was 2.0% in the placebo group and 1.7% in the risedronate sodium immediate-release 5 mg daily group. The incidence of serious adverse reactions was 24.6% in the placebo group and 27.2% in the risedronate sodium immediate-release 5 mg daily group.
• The percentage of patients who withdrew from the study due to adverse reactions was 15.6% in the placebo group and 14.8% in the risedronate sodium immediate-release 5 mg daily group. The most common adverse reactions reported in greater than 10% of subjects were: back pain, arthralgia, abdominal pain and dyspepsia.

Gastrointestinal Adverse Reactions

The incidence of adverse reactions in the placebo and risedronate sodium immediate-release 5 mg daily groups were:

• abdominal pain (9.9% versus 12.2%),
• diarrhea (10.0% versus 10.8%),
• dyspepsia (10.6% versus 10.8%), and
• gastritis (2.3% versus 2.7%).

Duodenitis and glossitis have been reported uncommonly in the risedronate sodium immediate-release 5 mg daily group (0.1% to 1%).

In patients with active upper gastrointestinal disease at baseline, the incidence of upper gastrointestinal adverse reactions was similar between the placebo and risedronate sodium immediate-release 5 mg daily groups.

Musculoskeletal Adverse Reactions

The incidence of adverse reactions in the placebo and risedronate sodium immediate-release 5 mg daily groups were:

• back pain (26.1% versus 28.0%),
• arthralgia (22.1% versus 23.7%),
• myalgia (6.2% versus 6.7%), and
• bone pain (4.8% versus 5.3%).

Laboratory Test Findings

Throughout the Phase 3 studies, transient decreases from baseline in serum calcium (less than 1%) and serum phosphate (less than 3%) and compensatory increases in serum PTH levels (less than 30%) were observed within 6 months in patients in osteoporosis clinical trials treated with risedronate sodium immediate-release 5 mg daily.

There were no significant differences in serum calcium, phosphate, or PTH levels between placebo and risedronate sodium immediate-release 5 mg daily at 3 years.

Serum calcium levels below 8 mg/dL were observed in 18 patients, 9 (0.5%) in each treatment arm (placebo and risedronate sodium immediate-release 5 mg daily).

Serum phosphorus levels below 2 mg/dL were observed in 14 patients, 3 (0.2%) treated with placebo and 11 (0.6%) treated with risedronate sodium immediate-release 5 mg daily. There have been rare reports (less than 0.1%) of abnormal liver function tests.

Endoscopic Findings

In the risedronate sodium immediate-release 5 mg daily clinical trials, endoscopic evaluation was encouraged in any patient with moderate-to-severe gastrointestinal complaints, while maintaining the blind.

Endoscopies were performed on equal numbers of patients between the placebo and treated groups [75 (14.5%) placebo; 75 (11.9%) risedronate sodium immediate-release 5 mg daily].

Clinically important findings (perforations, ulcers, or bleeding) among this symptomatic population were similar between groups (51% placebo; 39% risedronate sodium immediate-release 5 mg daily).

Postmarketing Experience

The following adverse reactions have been reported with the use of Atelvia. Because these adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hypersensitivity Reactions

Hypersensitivity and skin reactions have been reported, including angioedema, generalized rash, bullous skin reactions, Stevens-Johnson syndrome and toxic epidermal necrolysis.

Gastrointestinal Adverse Reactions

Reactions involving upper gastrointestinal irritation, such as esophagitis and esophageal or gastric ulcers, have been reported.

Musculoskeletal Pain

Bone, joint, or muscle pain, described as severe or incapacitating, have been reported rarely.

Eye Inflammation

Reactions of eye inflammation including iritis and uveitis have been reported rarely.

Jaw Osteonecrosis

Osteonecrosis of the jaw has been reported rarely.

Pulmonary

Asthma exacerbations

Risedronate is not metabolized and does not induce or inhibit hepatic microsomal drug-metabolizing enzymes (for example, Cytochrome P450).

Calcium Supplements/Antacids

When Atelvia was administered following breakfast, the co-administration of a tablet containing 600 mg of elemental calcium and 400 international units vitamin D reduced risedronate bioavailability by approximately 38%.

Calcium supplements, antacids, magnesium-based supplements or laxatives, and iron preparations interfere with the absorption of Atelvia and should not be taken together.

Histamine 2 (H2) Blockers And Proton Pump Inhibitors (PPIs)

Drugs that raise stomach pH (for example, PPIs or H2 blockers) may cause faster drug release from enteric coated (delayed-release) drug products such as Atelvia. Co-administration of Atelvia with the PPI, esomeprazole, increased risedronate bioavailability.

The maximum plasma concentration (Cmax ) and the area under the plasma concentration (AUC) were increased by 60 percent and 22 percent, respectively.

Concomitant administration of Atelvia and H2 blockers or PPIs is not recommended.

Hormone Therapy

Concomitant use of Atelvia with estrogens and estrogen agonist/antagonists has not been studied.

Aspirin/Nonsteroidal Anti-Inflammatory Drugs

In the Phase 3 study comparing Atelvia 35 mg once-a-week immediately following breakfast and risedronate sodium 5 mg daily, 18% of NSAID users (any use) in both groups developed upper gastrointestinal adverse reactions.

Among non-users, 13% of patients taking Atelvia 35 mg once-a-week immediately following breakfast developed upper gastrointestinal adverse reactions, compared to 12% taking risedronate sodium 5 mg daily.