Summary Of Exposure |
A) USES: Bisphosphonates have been used in the treatment of diseases associated with excessive bone turnover including osteoporosis, Paget's disease of bone, hypercalcemia of malignancy, and osteolysis bone lesions of multiple myeloma.
B) PHARMACOLOGY: Bisphosphonates have a high affinity for mineralized bone and inhibit osteoclast-mediated bone resorption resulting in a net gain in bone mass.
C) EPIDEMIOLOGY: Overdose of these medications are rare.
D) WITH THERAPEUTIC USE
1) COMMON: The most commonly occurring adverse effects with therapeutic administration are nausea, vomiting, dyspepsia, abdominal pain, diarrhea, and musculoskeletal pain.
2) INFREQUENT: Other adverse effects that occur on a less frequent basis include hypocalcemia, hypophosphatemia, hypokalemia, hypomagnesemia, upper gastrointestinal irritation (ie, esophagitis, esophageal ulcers, erosions, and dysphagia), rashes, hypertension, renal insufficiency, ocular inflammation (eg, iritis, uveitis, scleritis), headaches, dizziness, insomnia, paresthesias, fever, cough, dyspnea, atypical low-trauma femoral fractures, and osteonecrosis of the jaw.
3) RARE: Anaphylactic reactions, including fatalities, have been rarely reported.
E) WITH POISONING/EXPOSURE
1) Hypocalcemia has been reported following single dose ingestions of 4000 to 6000 mg etidronate and total doses of 225 to 300 mg pamidronate given intravenously over 2.5 to 4 days. Fever and hypotension have also been reported with intravenous administration of 285 mg pamidronate daily for 3 days. In general, overdose effects are anticipated to be an extension of adverse effects at therapeutic doses.
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Vital Signs |
3.3.1) SUMMARY
A) WITH THERAPEUTIC USE 1) Transient pyrexia with parenteral use of bisphosphonates may appear at the beginning of therapy.
3.3.3) TEMPERATURE
A) FEVER : Transient pyrexia with parenteral use of bisphosphonates may appear at the beginning of therapy (Fleisch, 1994; Rosen & Kessenich, 1996). 1) PAMIDRONATE : Transient increases in temperature (greater than 1 degree) have been frequently observed (19% to 41%) during the initiation of therapy and have lasted approximately 1 to 2 days (Prod Info pamidronate disodium intravenous injection, 2015; Diener, 1996; Nussbaum et al, 1993). Flu-like symptoms and rigor have been occasionally reported with febrile episodes (Gallacher et al, 1989).
B) CHILLS : In one study, rigor was reported in 3% to 8% of patients during the first infusion; recurrence did not occur with subsequent doses (Gallacher et al, 1989). C) WITH POISONING/EXPOSURE 1) PAMIDRONATE a) An obese woman (95 kg) who received 285 mg of pamidronate/day for 3 days experienced high fever (39.5 degrees Celsius); the fever was rapidly corrected with steroids (Prod Info pamidronate disodium intravenous injection, 2015).
2) ZOLEDRONIC ACID a) During an open-label study of 4 mg zoledronic acid in breast cancer patients, a single episode of hyperthermia (38 degrees C) occurred in a patient 2 days after inadvertent administration of a single 48-mg dose of zoledronic acid (Prod Info ZOMETA(R) intravenous injection concentrate, 2016).
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Heent |
3.4.3) EYES
A) WITH THERAPEUTIC USE 1) SUMMARY: Bisphosphonate therapy may be associated with the development of ocular inflammation, including iritis, uveitis and scleritis (Prod Info ZOMETA(R) intravenous injection concentrate, 2016; Prod Info BONIVA(R) oral tablets, 2015; Prod Info pamidronate disodium intravenous injection, 2015; Prod Info ACTONEL(R) oral tablets, 2015; Prod Info Reclast(R) intravenous injection, 2015). 2) PAMIDRONATE : Adverse ocular drug reactions (uveitis, transitory conjunctivitis, iritis, and retrobulbar optic neuritis) in a patient with a history of cutaneous porphyria have been rarely reported following therapeutic intravenous pamidronate administration (Des Grottes et al, 1997; Macarol & Fraunfelder, 1994); (Siris, 1993). a) Ocular symptoms generally appeared within the first 24 to 48 hours following drug administration (Des Grottes et al, 1997; Meyer & Crisp, 1995; Macarol & Fraunfelder, 1994) It is suggested that the presence of the drug in tears, may cause transitory irritation (conjunctivitis) (Macarol & Fraunfelder, 1994).
b) INCIDENCE : 1% of patients receiving intravenous pamidronate may experience iritis (Stewart et al, 1996).
3) RISEDRONATE : Iritis has been reported rarely following risedronate therapy (Siris, 1993). a) Acute iritis developed in 3 patients with Paget's disease who received oral risedronate 30 mg daily. All 3 patients recovered when treated with topical steroids; however, iritis recurred in 1 patient during risedronate therapy. Symptoms resolved several weeks after discontinuation of risedronate. The same patient experienced iritis 1 year later after an infusion of pamidronate (Prod Info ACTONEL(R) oral tablets, 2015; Siris, 1993a).
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Cardiovascular |
3.5.2) CLINICAL EFFECTS
A) HYPERTENSIVE EPISODE 1) WITH THERAPEUTIC USE a) IBANDRONATE 1) During clinical trials, hypertension was reported in 7.3% of 395 patients who received ibandronate 2.5 mg orally once daily and in 6.3% of 396 patients who received ibandronate 150 mg orally once monthly (Prod Info BONIVA(R) oral tablets, 2015).
b) PAMIDRONATE 1) During clinical trials involving patients with hypercalcemia of malignancy, at least 15% of patients developed hypertension as did at least 10% of patients with Paget's disease (Prod Info pamidronate disodium intravenous injection, 2015).
c) ZOLEDRONIC ACID 1) During randomized placebo-controlled clinical trials, hypertension was reported in 12.7% of patients with post-menopausal osteoporosis (n=3862) treated with zoledronic acid 5 mg IV once per year compared to 12.4% of placebo-treated patients (n=3852), and in 6.8% of osteoporosis patients with recent low-trauma hip fractures (n=1054) treated with zoledronic acid 5 mg IV once per year compared to 5.4% of placebo-treated patients (n=1057) (Prod Info Reclast(R) intravenous injection, 2015).
B) HYPOTENSIVE EPISODE 1) WITH THERAPEUTIC USE a) ZOLEDRONIC ACID 1) During a clinical trial, involving patients with hypercalcemia of malignancy, hypotension was reported in 9 of 86 patients (11%) who received zoledronic acid 4 mg as a 5-minute IV infusion compared to 2 of 103 patients (2%) who received pamidronate 90 mg as a 2-hour IV infusion (Prod Info ZOMETA(R) intravenous injection concentrate, 2016).
2) WITH POISONING/EXPOSURE a) PAMIDRONATE 1) Hypotension (from 170/90 mmHg to 90/60 mmHg) , high fever, and transient taste perversion were reported in an obese woman, weighing 95 kg, who was treated with 285 mg pamidronate daily for 3 days. Symptom onset occurred approximately 6 hours after the first infusion, and resolved with corticosteroids (Prod Info pamidronate disodium intravenous injection, 2015).
C) CHEST PAIN 1) WITH THERAPEUTIC USE a) RISEDRONATE 1) During a study which compared risedronate 30 mg daily for 2 months (n=61) with etidronate 400 mg daily for 6 months (n=61) in patients with Paget's disease, the incidence of chest pain was 6.6% and 3.3%, respectively (Prod Info ACTONEL(R) oral tablets, 2015).
D) CONDUCTION DISORDER OF THE HEART 1) WITH THERAPEUTIC USE a) RISEDRONATE 1) During a study which compared risedronate 35 mg weekly (n=191) with placebo (n=93) for the treatment of osteoporosis in men, the incidence of dysrhythmia was 2% and 0%, respectively (Prod Info ACTONEL(R) oral tablets, 2009a).
b) ZOLEDRONIC ACID 1) During randomized placebo-controlled clinical trials, atrial fibrillation was reported in 2.4% of patients with post-menopausal osteoporosis (n=3862) treated with zoledronic acid 5 mg IV once per year compared to 1.9% of placebo-treated patients (n=3852), and in 2.8% of osteoporosis patients with recent low-trauma hip fractures (n=1054) treated with zoledronic acid 5 mg IV once per year compared to 2.6% of placebo-treated patients (n=1057) (Prod Info Reclast(R) intravenous injection, 2015).
E) THROMBOPHLEBITIS 1) WITH THERAPEUTIC USE a) PAMIDRONATE 1) Venous irritation may occur with intravenous administration if the fluid volume is insufficient (Cortet et al, 1997).
2) Mild thrombophlebitis and soft-tissue symptoms including redness, swelling, and pain have been reported during treatment with pamidronate(Prod Info pamidronate disodium intravenous injection, 2015; Harinck et al, 1987). The incidence, considering all treatment events, is 41% (Prod Info Aredia(R), pamidronate disodium, 1996).
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Respiratory |
3.6.2) CLINICAL EFFECTS
A) DISORDER OF RESPIRATORY SYSTEM 1) WITH THERAPEUTIC USE a) PAMIDRONATE 1) Rales (6%) and rhinitis (6%) were reported during clinical trials in patients with hypercalcemia of malignancy (Prod Info pamidronate disodium intravenous injection, 2015).
B) ULCER OF LARYNX 1) WITH POISONING/EXPOSURE a) ALENDRONATE 1) CASE REPORT: A 77-year-old man presented to the emergency department with a 3-day history of hemoptysis, after inadvertently taking his alendronate daily for 5 days, in the evening before bed, (normally prescribed as 70 mg once weekly) instead of his daily omeprazole. Besides his hemoptysis, the patient was also experiencing progressive dysphagia and a worsening cough. A laryngoscopy identified the source of the hemoptysis as a small mucosal tear at the laryngeal side of the epiglottis. With administration of antibiotics, H2-blockers, and IV corticosteroids, the patient's condition improved and he was discharged on hospital day 4 (Hanna et al, 2012).
C) DYSPNEA 1) WITH THERAPEUTIC USE a) PAMIDRONATE 1) In a pooled analysis of 3 controlled clinical trials, dyspnea was reported in 30% of patients who received pamidronate disodium 90 mg over 2 or 4 hours (n=572) compared with 23% of patients who received placebo (n=573) (Prod Info pamidronate disodium intravenous injection, 2015).
2) Dyspnea persisting for 2 hours was described in a patient with lung cancer following intravenous pamidronate. Recurrence of dyspnea was observed on several occasions with repeat intravenous infusions in this patient. It is suggested that these episodes represent an idiosyncratic reaction to pamidronate (Mannix et al, 1989).
b) ZOLEDRONIC ACID 1) In 3 randomized, double-blind, active, placebo-controlled clinical trials in patients with multiple myeloma and bone metastases, the incidence of dyspnea in patients receiving zoledronic acid 4 mg (n=1031) compared with pamidronate 90 mg (n=556) and with placebo (n=455) was 27% vs 28% vs 24%, respectively. Median durations of total zoledronic acid exposure, including core and safety extension phases, were 12.8 months (breast cancer and multiple myeloma), 10.8 months (prostate cancer), and 4 months (other solid tumors) (Prod Info ZOMETA(R) intravenous injection concentrate, 2016).
2) In a 2-year, randomized, multicenter, double-blind study of 302 men (aged 25 to 86 years) with osteoporosis or osteoporosis secondary to hypogonadism, dyspnea occurred in 6.5% of patients receiving zoledronic acid 5 mg IV annually (n=153) vs 4.7% taking a bisphosphonate active control (n=148) (Prod Info Reclast(R) intravenous injection, 2015).
D) COUGH 1) WITH THERAPEUTIC USE a) PAMIDRONATE 1) In a pooled analysis of 3 controlled clinical trials, dyspnea was reported in 26% of patients who received pamidronate disodium 90 mg over 2 or 4 hours (n=572) compared with 21% of patients who received placebo (n=573) (Prod Info pamidronate disodium intravenous injection, 2015).
b) ZOLEDRONIC ACID 1) In 3 randomized, double-blind, active, placebo-controlled clinical trials in patients with multiple myeloma and bone metastases, the incidence of cough in patients receiving zoledronic acid 4 mg (n=973) compared with pamidronate 90 mg (n=536) and with placebo (n=415) was 22% vs 23% vs 14%, respectively. Median durations of total zoledronic acid exposure, including core and safety extension phases, were 12.8 months (breast cancer and multiple myeloma), 10.8 months (prostate cancer), and 4 months (other solid tumors) (Prod Info ZOMETA(R) intravenous injection concentrate, 2016).
E) PULMONARY ASPIRATION 1) WITH THERAPEUTIC USE a) ALENDRONATE 1) CASE REPORT: An 84-year-old woman developed progressively worsening cough, hoarseness, and severe dyspnea after swallowing a 70 mg alendronate tablet without sitting upright. A physical examination demonstrated bilateral diffuse inhibitory and expiratory wheezes and severe rhonchi, and a chest CT revealed mucous impaction and calcified particulate matter in the bronchus, indicating aspiration of a foreign body. A bronchoscopy showed intermittent sloughing off of pseudomembranous material that was occluding the trachea, necessitating mechanical debridement. Following two rounds of debridement and supportive care, including administration of corticosteroids and antibiotics, the patient gradually improved with continued hoarseness, but improving stridor and no dyspnea. Follow-up 4 weeks post-discharge indicated complete resolution of all symptoms (Maceachern et al, 2013).
F) RESPIRATORY FAILURE 1) WITH THERAPEUTIC USE a) PAMIDRONATE 1) CASE REPORT/CHILD: A 3.5-year-old child with osteogenesis imperfecta developed dizziness and facial mottling, and complained of mouth pain approximately 1 hour after beginning a second course of therapy with IV pamidronate infusion, 1 mg/kg in normal saline to be infused at a rate of 50 mL/hour over 4 hours. He had received an initial infusion (0.5 mg/kg in normal saline infused over 4 hours) 3 months earlier without incident. His oxygen saturation (O2sat) following the second infusion was 100% on room air. His laboratory values were normal. Following discontinuation of the infusion, his symptoms resolved and the infusion was restarted 1.5 hours later, at a rate of one-half the original rate of 50 mL/hour and gradually increased to three-quarters the original rate, with recurrence of symptoms. Following discontinuation of the infusion and administration of acetaminophen and diphenhydramine, his symptoms again resolved and the infusion was restarted. Forty-five minutes later, the patient was pale and mottled with shallow respirations. His O2sat was 75% on room air. He became tachycardic (161 bpm), hypertensive (158/111 mmHg), and pyrexic (37.8 degrees C), and arterial blood gas analysis revealed a pH of 7.1 and a pCO2 of 80. A chest x-ray demonstrated patchy atelectasis or infiltrates bilaterally in his lungs. Following initial bag-mask ventilation and subsequent intubation, the patient began breathing on his own approximately 1.5 hours later and was extubated to nasal cannula oxygen. He continued to improve with normalization of blood pressure, temperature, and O2sat on room air, and was discharged the next day despite continued tachycardia (114 to 126 bpm) (Olson, 2014).
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Neurologic |
3.7.2) CLINICAL EFFECTS
A) HEADACHE 1) WITH THERAPEUTIC USE a) In clinical trials, headache was reported in up to 27% of patients treated with either an oral or parenteral bisphosphonate (Prod Info FOSAMAX(R) oral tablets, oral solution, 2015; Prod Info BONIVA(R) oral tablets, 2015; Prod Info pamidronate disodium intravenous injection, 2015; Prod Info Reclast(R) intravenous injection, 2015; Reginster, 1992) .
B) MALAISE 1) WITH THERAPEUTIC USE a) PAMIDRONATE 1) Generalized malaise has been a relatively frequent adverse effect of pamidronate, occurring in 7 of 95 patients in 1 series. This complication lasted for several weeks following treatment and recurred upon subsequent infusions (Gallacher et al, 1989).
C) SEIZURE 1) PAMIDRONATE a) During clinical trials, seizures occurred in 5 of 231 patients who received pamidronate for the management of hypercalcemia. Two of the five patients had a history of preexisting seizure disorder (Prod Info pamidronate disodium intravenous injection, 2015).
D) PARESTHESIA 1) WITH THERAPEUTIC USE a) Several case reports of paresthesia have occurred following etidronate and pamidronate therapy in which patients developed symptomatic hypocalcemia (Prod Info Didronel(R) oral tablets, 2009; McIntyre & Bruera, 1996; Jodrell et al, 1987).
2) WITH POISONING/EXPOSURE a) ETIDRONATE/CASE REPORT: Hypocalcemia and paresthesia of the fingers were reported in an 18-year-old woman who ingested 4000 to 6000 mg (67 to 100 mg/kg) of etidronate as a single dose (Prod Info Didronel(R) oral tablets, 2015).
b) ZOLEDRONIC ACID/CASE REPORT: A patient with non-Hodgkin's lymphoma developed paresthesia and an increase in liver enzymes (GGT approximately 100 units/L) after receiving zoledronic acid 4 mg daily for 4 days (total dose 16 mg) (Prod Info ZOMETA(R) intravenous injection concentrate, 2016).
E) CRANIAL NERVE DISORDER 1) WITH THERAPEUTIC USE a) PAMIDRONATE 1) CASE REPORT : A 70-year-old man developed partial 3rd and 4th nerve palsy following a total dose of 65 mg of intravenous pamidronate. Symptoms developed within 24 hours along with bilateral uveitis; improvement occurred after a course of oral steroids (Ghose et al, 1994).
F) INSOMNIA 1) WITH THERAPEUTIC USE a) PAMIDRONATE 1) Insomnia was a commonly reported adverse event experienced by patients during three US controlled trials (Prod Info pamidronate disodium intravenous injection, 2015).
G) DIZZINESS 1) WITH THERAPEUTIC USE a) SUMMARY : Transient dizziness has been reported following rapid infusions of bisphosphonates (Adami & Zamberlan, 1996). b) ALENDRONATE 1) In post-marketing experience, dizziness has been associated with alendronate sodium treatment (Prod Info FOSAMAX(R) oral tablets, oral solution, 2015).
c) TILUDRONATE 1) Reginister et al (1992) reported dose dependent (800 mg/day orally) dizziness following therapeutic tiludronate use (Reginster et al, 1992).
H) ASTHENIA 1) WITH THERAPEUTIC USE a) ALENDRONATE 1) In post-marketing experience, asthenia has been reported, usually during the initiation of alendronate sodium treatment (Prod Info FOSAMAX(R) oral tablets, oral solution, 2015).
b) RISEDRONATE 1) During a study which compared risedronate 30 mg (mg) daily for 2 months (n=61) with etidronate 400 mg daily for 6 months (n=61) in patients with Paget's disease, the incidence of asthenia was 4.9% and 0.0%, respectively (Prod Info ACTONEL(R) oral tablets, 2009a).
I) VERTIGO 1) WITH THERAPEUTIC USE a) ALENDRONATE 1) In post-marketing experience, vertigo has been associated with alendronate sodium treatment (Prod Info FOSAMAX(R) oral tablets, oral solution, 2015).
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Gastrointestinal |
3.8.2) CLINICAL EFFECTS
A) NAUSEA AND VOMITING 1) WITH THERAPEUTIC USE a) SUMMARY 1) Nausea and vomiting have been frequently reported with oral and parenteral bisphosphonate therapy during clinical trials (Prod Info FOSAMAX(R) oral tablets, oral solution, 2015; Prod Info pamidronate disodium intravenous injection, 2015; Prod Info ATELVIA(R) oral delayed release tablets, 2015; Prod Info ZOMETA(R) intravenous injection concentrate, 2016; Prod Info SKELID(R) oral tablets, 2006).
b) CLODRONATE 1) Gastrointestinal symptoms have included nausea, dyspepsia, and diarrhea (Luzzani et al, 1990; Yates et al, 1985; Percival et al, 1985) which have been mild in some patients (Bonjour & Rizzoli, 1990) or have necessitated treatment withdrawal (Ziegler & Scharla, 1989; Jacobs et al, 1981).
c) ETIDRONATE 1) INCIDENCE : Nausea and diarrhea have occurred in 20% to 30% of patients treated with high doses of etidronate (20 mg/kg/day) (Prod Info Didronel(R) oral tablets, 2015; Rosen & Kessenich, 1996).
d) PAMIDRONATE 1) Nausea and abdominal pain were reported at daily doses of 450 and 600 mg (Dodwell et al, 1990).
e) TILUDRONATE 1) INCIDENCE : Abdominal pain and nausea occurred in up to 25% of patients at therapeutic dose. Up to 50% of patients in one study experienced diarrhea and vomiting with high doses of tiludronate (1200 mg daily) (Reginster et al, 1994; Reginster, 1992; Reginster, 1992).
B) DIARRHEA 1) WITH THERAPEUTIC USE a) Diarrhea has been frequently reported with bisphosphonate therapy during clinical trials (Prod Info ZOMETA(R) intravenous injection concentrate, 2016; Prod Info FOSAMAX(R) oral tablets, oral solution, 2015; Prod Info Didronel(R) oral tablets, 2015; Prod Info BONIVA(R) oral tablets, 2015; Prod Info ACTONEL(R) oral tablets, 2015).
2) WITH POISONING/EXPOSURE a) ETIDRONATE/CASE REPORT: Diarrhea was reported in a 92-year-old woman who inadvertently received 1600 mg of etidronate per day for 3.5 days. The patient also developed electrolyte imbalance, requiring treatment (Prod Info Didronel(R) oral tablets, 2015).
C) ABDOMINAL PAIN 1) WITH THERAPEUTIC USE a) Abdominal pain has developed in 5% to 25% of patients following therapeutic dosing with oral or parenteral bisphosphonates (Prod Info ZOMETA(R) intravenous injection concentrate, 2016; Prod Info FOSAMAX(R) oral tablets, oral solution, 2015; Prod Info BONIVA(R) oral tablets, 2015; Prod Info BONIVA(R) intravenous injection, 2015; Prod Info pamidronate disodium intravenous injection, 2015; Prod Info ACTONEL(R) oral tablets, 2015; Liberman et al, 1995; Reginster et al, 1994; Reginster, 1992; Reginster, 1992) . b) PAMIDRONATE 1) Nausea and abdominal pain were reported at daily doses of 450 and 600 mg (Dodwell et al, 1990).
c) RISEDRONATE 1) Epigastric pain has been infrequently reported following risedronate therapy (Brown et al, 1994; Roux et al, 1994). Incidence in one series was estimated to be 2% (Brown et al, 1994).
D) INDIGESTION 1) WITH THERAPEUTIC USE a) Dyspepsia has been frequently reported with oral bisphosphonate therapy (Prod Info FOSAMAX(R) oral tablets, oral solution, 2015; Prod Info BONIVA(R) oral tablets, 2015; Prod Info ACTONEL(R) oral tablets, 2015).
E) ULCER OF ESOPHAGUS 1) WITH THERAPEUTIC USE a) SUMMARY : Esophagitis, esophageal ulcers and esophageal erosions, with occasional bleeding, have been reported during therapeutic use with oral bisphosphonate therapy (Prod Info FOSAMAX(R) oral tablets, oral solution, 2015; Abdelmalek & Douglas, 1996; Rosen & Kessenich, 1996; Maconi & Porro, 1995; Lufkin et al, 1994; Saunders, 1977).
b) In a review of adverse effects reported following bisphosphonate use, the incidence of corrosive esophagitis is low; however, when complications occur, they tend to be severe(Lanza, 1998).
c) ALENDRONATE: Of the approximately 475,000 patients currently taking alendronate, the manufacturer has been notified of 36 patients with esophagitis severe enough to require hospital admission (Anon, 1996).
d) PAMIDRONATE: Of 49 women receiving a gelatin capsule (150 mg daily) formulation of pamidronate, four experienced esophagitis four months after beginning the medication. An additional case of esophagitis was confirmed after receiving a tablet formulation. All cases improved following drug discontinuation and the use of antacids (Lufkin et al, 1994).
e) RISK FACTORS : Patient's with a history of chronic reflux esophagitis, Barrett's mucosa, and patients with motility or stricture disease should avoid therapy with bisphosphonates . Patients that are debilitated or bedridden may be at greatest risk for gastrointestinal complications following therapy. (Lanza, 1998). Patients who did not strictly adhere to dosing guidelines (i.e., taking with a full glass of water) appeared to be at more risk for developing esophageal injury. Advanced age (greater than 70 years) and previous gastrointestinal injury also appeared to be factors in the development of esophageal injury (Abraham et al, 1999).
F) STRICTURE OF ESOPHAGUS 1) WITH THERAPEUTIC USE a) Esophageal stricture or perforation are rare complications that may occur with oral bisphosphonate therapy (Prod Info FOSAMAX(R) oral tablets, oral solution, 2015; Prod Info Didronel(R) oral tablets, 2015; Prod Info BONIVA(R) oral tablets, 2015; Prod Info ACTONEL(R) oral tablets, 2015).
b) CASE REPORTS : Dysphagia with evidence of esophageal stricture has been reported in two patients within several weeks of starting alendronate therapy. Both women required esophageal dilatation with one patient requiring repeat dilatation for the same clinical signs and symptoms after restarting alendronate (Levine & Nelson, 1997).
G) GASTRIC ULCER 1) WITH THERAPEUTIC USE a) ETIDRONATE 1) CASE REPORT : A 46-year-old woman treated with etidronate (20 mg/kg/day, orally) to reduce dystrophic calcification developed bloody diarrhea, epigastric burning, and weight loss and was diagnosed with a gastric ulcer after 18 months of therapy. Symptoms resolved with medical intervention (Saunders, 1977).
H) LOSS OF TASTE 1) WITH THERAPEUTIC USE a) ETIDRONATE: Jones et al (1987) reported that 52% (n=23) of patients experienced taste loss following the first or second dose of intravenous etidronate. Symptoms resolved within 4 to 8 hours in all cases; this effect was not observed with other bisphosphonates (Jones et al, 1987).
2) WITH POISONING/EXPOSURE a) PAMIDRONATE/CASE REPORT: Hypotension (from 170/90 mmHg to 90/60 mmHg) , high fever, and transient taste perversion were reported in an obese woman, weighing 95 kg, who was treated with 285 mg pamidronate daily for 3 days. Symptom onset occurred approximately 6 hours after the first infusion, and resolved with corticosteroids (Prod Info pamidronate disodium intravenous injection, 2015).
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Hepatic |
3.9.2) CLINICAL EFFECTS
A) INCREASED LIVER ENZYMES 1) WITH POISONING/EXPOSURE a) ZOLEDRONIC ACID/CASE REPORT: A patient with non-Hodgkin's lymphoma developed paresthesia and an increase in liver enzymes (GGT approximately 100 units/L) after receiving zoledronic acid 4 mg daily for 4 days (total dose 16 mg) (Prod Info ZOMETA(R) intravenous injection concentrate, 2016).
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Genitourinary |
3.10.2) CLINICAL EFFECTS
A) RENAL FUNCTION TESTS ABNORMAL 1) WITH THERAPEUTIC USE a) ETIDRONATE 1) INCIDENCE : Mild to moderate increases of serum creatinine greater than 0.5 mg/dL have developed in 10% of patients (Prod Info Didronel(R) oral tablets, 2015) In one study, creatinine levels returned to baseline with drug cessation (Kanis et al, 1983).
b) PAMIDRONATE 1) Worsening renal function, including focal segmental glomerulosclerosis and nephritic syndrome, was associated with pamidronate therapy, with improved renal function in some patients following pamidronate discontinuation (Prod Info pamidronate disodium intravenous injection, 2015).
2) Elevations in BUN and creatinine have been reported following therapeutic use of pamidronate (Tyrrell et al, 1995).
3) CASE SERIES: A retrospective study of cancer patients receiving pamidronate showed several patients experienced a transient decline in renal function which could not be directly related to drug administration (Machado & Flombaum, 1996).
4) CHRONIC THERAPY: One patient developed an unexplained rise in urea and creatinine following a total of 20 infusions (Ford, 1996).
c) TILUDRONATE 1) Transient increases in creatinine have been observed with tiludronate therapy; levels returned to baseline when drug therapy was completed (Reginster et al, 1994).
d) ZOLEDRONIC ACID 1) Renal toxicity has also been associated with rapid (5-minute) IV administration of zoledronic acid. The incidence of renal toxicity was reduced following administration of zoledronic acid as a 15-minute IV infusion (Prod Info ZOMETA(R) intravenous injection concentrate, 2016).
2) During controlled clinical trials, an increased risk of renal toxicity occurred following administration of zoledronic acid 8 mg compared to administration of zoledronic acid 4 mg, given as a 15-minute IV infusion (Prod Info ZOMETA(R) intravenous injection concentrate, 2016).
B) ACUTE RENAL FAILURE SYNDROME 1) WITH THERAPEUTIC USE a) Acute renal failure has been associated with rapid intravenous infusions of etidronate. (Bounameaux et al, 1983), following a single IV dose of pamidronate (Prod Info pamidronate disodium intravenous injection, 2015), and with oral alendronate therapy (Zazgornik et al, 1997). b) CASE REPORTS 1) ALENDRONATE : A 57-year-old woman with diffuse osteoporosis and skeletal pain who was later diagnosed with multiple myeloma began alendronate 10 mg daily. Within one month of therapy, acute renal failure developed (BUN 13.6 mmol/L and serum creatinine 388 micromoles/L). Symptoms improved following drug cessation. The authors suggested that alendronate may have exaggerated or had a synergistic effect on the underlying disease present (Zazgornik et al, 1997).
2) CLODRONATE: One patient developed fatal oliguric renal failure during the third week of clodronate therapy. The authors suggested that the patient's underlying disease processes contributed to the development of acute renal failure (Jacobs et al, 1981).
3) ETIDRONATE : A 78-year-old woman developed oliguria following one intravenous dose of etidronate (1 gram); the patient died 12 days later. Upon necropsy, severe tubulointerstitial damage was found (Bounameaux et al, 1983).
4) ZOLEDRONIC ACID: A 62-year-old man with a history of recurrent stage IIIB multiple myeloma who received two months of zoledronic acid, at 8 mg per dose monthly, developed renal insufficiency which recovered when the medication was discontinued (Prommer, 2009).
5) PAMIDRONATE: A 62-year-old man with a history of recurrent stage IIIB multiple myeloma who received two years of pamidronate maintenance therapy developed renal insufficiency necessitating dialysis (Prommer, 2009).
3.10.3) ANIMAL EFFECTS
A) ANIMAL STUDIES 1) RENAL FUNCTION TESTS ABNORMAL a) SUMMARY : Bolus intravenous injections of large doses of bisphosphonates have resulted in renal tubular damage and oliguria in dogs (Bonjour & Rizzoli, 1990). b) DOGS 1) PAMIDRONATE a) No renal findings were reported with administration of 3 mg/kg (1.7 times the highest recommended human dose) infused over 4 or 24 hours (Prod Info AREDIA(R) IV injection, 2008).
b) Elevated BUN, creatinine and renal necrosis were reported when 3 mg/kg was infused over 1 hour and at doses of 10 mg/kg (Prod Info AREDIA(R) IV injection, 2008).
c) Several treated animals had elevated BUN and creatinine levels, renal tubular dilation and/or inflammation at 1 mg/kg after each infusion time (Prod Info AREDIA(R) IV injection, 2008).
d) Moribundity/death and renal toxicity occurred at 20 mg/kg (Prod Info AREDIA(R) IV injection, 2008).
e) The dose level that produced no adverse renal effects was 2 mg/kg (Prod Info AREDIA(R) IV injection, 2008).
2) NEPHROPATHY a) RATS 1) PAMIDRONATE a) Nephrotoxicity was observed at 6 mg/kg. Symptoms resolved one month after drug cessation (Prod Info AREDIA(R) IV injection, 2008).
3) LACK OF EFFECT a) DOGS 1) ALENDRONATE a) No clinical or laboratory evidence has been reported of renal impairment when oral doses were administered at 0.25 (low), 0.5 (medium) and 1.0 (high) mg/kg/day for 3 years to beagle dogs (Peter et al, 1996).
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Hematologic |
3.13.2) CLINICAL EFFECTS
A) HEMATOLOGY FINDING 1) WITH THERAPEUTIC USE a) PAMIDRONATE 1) Hypercalcemia of Malignancy : Anemia was reported in 6% of clinical subjects (90 mg over 24 hours), while leukopenia occurred in 4% of subjects (60 mg over 4 hours) (Prod Info pamidronate disodium intravenous injection, 2015).
2) Osteolytic Metastases and Osteolytic Lesions of Multiple Myeloma : During clinical trials, there was a trend at higher doses (90 mg given over 4 hours) towards increased incidences of anemia and granulocytopenia in the treatment group (Prod Info pamidronate disodium intravenous injection, 2015).
3) CHRONIC : Mild leukopenia was reported in 7.7% of patients treated for over 8 months with oral therapy. The white blood cell count returned to normal after interruption of therapy or lowering of the dose (Mautalen et al, 1984).
B) THROMBOCYTOPENIC PURPURA 1) WITH THERAPEUTIC USE a) PAMIDRONATE 1) Thrombocytopenic purpura occurred in one adult following one month of oral therapy; ongoing prednisone therapy was required to maintain an adequate platelet count. The authors concluded that the ongoing effects were due to an idiopathic response, although sensitivity to pamidronate could not be excluded (Mautalen et al, 1984).
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Dermatologic |
3.14.2) CLINICAL EFFECTS
A) ERUPTION 1) WITH THERAPEUTIC USE a) SUMMARY : Rash has been reported infrequently following bisphosphonate therapy (Prod Info FOSAMAX(R) oral tablets, oral solution, 2015; Prod Info BONIVA(R) oral tablets, 2015; Prod Info ACTONEL(R) oral tablets, 2015; Prod Info Reclast(R) intravenous injection, 2015; Pajus et al, 1993; Roux et al, 1992; Mautalen et al, 1984) . b) CASE REPORTS 1) CLODRONATE: A 70-year-old man developed a rash 2 weeks after a single infusion of clodronate (300 mg). Following a second treatment with oral and IV clodronate, the patient developed a generalized erythematous macular and papular rash and a fever (40 degrees Celsius). Symptoms resolved without sequelae following supportive care (Pajus et al, 1993).
2) TILUDRONATE : A 54-year-old woman was treated with tiludronate (200 mg/day orally) for 1 month for the prevention of postmenopausal bone loss and developed eosinophilia and epidermal necrosis confirmed by biopsy. Despite steroid therapy and discontinuation of therapy, the patient had ongoing lesions up to one year later (Roux et al, 1992).
B) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE 1) WITH THERAPEUTIC USE a) SUMMARY: Toxic epidermal necrolysis has been observed during post-marketing surveillance of bisphosphonate therapy; causality has not been established (Prod Info ZOMETA(R) intravenous injection concentrate, 2016; Prod Info FOSAMAX(R) oral tablets, oral solution, 2015; Prod Info Didronel(R) oral tablets, 2015; Prod Info ACTONEL(R) oral tablets, 2015). b) ETIDRONATE 1) CASE REPORT: A 47-year-old woman developed fatal toxic epidermal necrolysis, pancytopenia, and ARDS, 7 days after starting etidronate therapy for osteoporosis (Coakley & Isenberg, 1995).
C) STEVENS-JOHNSON SYNDROME 1) WITH THERAPEUTIC USE a) Stevens-Johnson syndrome has been observed during post-marketing surveillance of bisphosphonate therapy; causality has not been established (Prod Info ZOMETA(R) intravenous injection concentrate, 2016; Prod Info FOSAMAX(R) oral tablets, oral solution, 2015; Prod Info Didronel(R) oral tablets, 2015; Prod Info BONIVA(R) oral tablets, 2015; Prod Info ACTONEL(R) oral tablets, 2015; Prod Info SKELID(R) oral tablets, 2006) .
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Musculoskeletal |
3.15.2) CLINICAL EFFECTS
A) ASEPTIC NECROSIS OF BONE OF JAW 1) WITH THERAPEUTIC USE a) SUMMARY: Osteonecrosis of the jaw has been reported with bisphosphonate use (Prod Info ZOMETA(R) intravenous injection concentrate, 2016; Prod Info FOSAMAX(R) oral tablets, oral solution, 2015; Prod Info Didronel(R) oral tablets, 2015; Prod Info BONIVA(R) oral tablets, 2015; Prod Info pamidronate disodium intravenous injection, 2015; Prod Info ACTONEL(R) oral tablets, 2015).
b) RISK FACTORS: Invasive dental procedures (eg, tooth extraction, dental implants, boney surgery), cancer diagnosis, poor oral hygiene, concurrent therapies (eg, chemotherapy, corticosteroids, angiogenesis inhibitors), and co-morbidities (eg, pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures) are considered known risk factors for the development of osteonecrosis of the jaw with bisphosphonate therapy (Prod Info FOSAMAX(R) oral tablets, oral solution, 2015; Prod Info Didronel(R) oral tablets, 2015; Prod Info BONIVA(R) oral tablets, 2015; Prod Info ACTONEL(R) oral tablets, 2015).
c) PAMIDRONATE/CASE REPORT: A 62-year-old man with a history of recurrent stage IIIB multiple myeloma who received pamidronate maintenance for two years developed osteonecrosis of the jaw. Pamidronate was discontinued after diagnosis, and patient was started on oral opiates, chlorhexidine mouthwash and antibiotics. Two months after presentation, radiographic images of the jaw showed evidence of initial bone healing and the patient had decreased jaw pain and trismus (Prommer, 2009)
B) JOINT PAIN 1) WITH THERAPEUTIC USE a) RISEDRONATE 1) During a study which compared risedronate 5 mg daily (n=1619) with placebo (n=1613) for the treatment of osteoporosis in postmenopausal women, the incidence of arthralgia was 23.7% and 21.1%, respectively (Prod Info ACTONEL(R) oral tablets, 2015) .
2) During a study which compared risedronate 35 mg weekly with placebo for the prevention of osteoporosis in postmenopausal women (n=278), the incidence of arthralgia was 13.9% and 7.8%, respectively (Prod Info ACTONEL(R) oral tablets, 2015).
3) During the postmarketing use of risedronate, rare cases of severe or incapacitating joint pain have been reported. Onset of symptoms occurred from one day to several months after beginning therapy, and in most cases symptoms resolved following discontinuation of the drug. When rechallenged with risedronate or another bisphosphonate, a subset of patients experienced a recurrence of symptoms (Prod Info ACTONEL(R) oral tablets, 2015).
C) BONE PAIN 1) WITH THERAPEUTIC USE a) ALENDRONATE 1) Musculoskeletal pain has been reported in approximately 6% of patients treated with alendronate 40 mg/day, versus 1% of patients treated in the placebo group, but rarely resulted in discontinuation of therapy(Prod Info FOSAMAX(R) oral tablets, oral solution, 2015) .
b) ETIDRONATE 1) INCIDENCE : Bone pain has been reported at doses of 5 mg/kg/day in approximately 10% of patients and increases to about 20% at higher doses (Prod Info Didronel(R) oral tablets, 2015; Metzger et al, 1974) .
c) PAMIDRONATE 1) Transient increases in bone pain have been reported in at least 10% of patients with Paget's disease following intravenous pamidronate (Prod Info pamidronate disodium intravenous injection, 2015; Tyrrell et al, 1995; Gallacher et al, 1989), which have resulted in pain severe enough to discontinue therapy (Hortobagyi et al, 1996).
2) CASE REPORTS : In a small study in adults (n=12) with cystic fibrosis, intravenous pamidronate was given for the treatment of low bone density. Nine patients developed bone pain with seven patients complaining of severe pain requiring them to be bed bound; bone biochemistry results were inconclusive. The exact cause of bone pain remains uncertain, but the authors suggested that the high incidence of bone pain may be a novel reaction that is specific to cystic fibrosis (Haworth et al, 1998).
d) RISEDRONATE 1) During the postmarketing use of risedronate, rare cases of severe or incapacitating bone pain have been reported. Onset of symptoms occurred from one day to several months after beginning therapy, and in most cases symptoms resolved following discontinuation of the drug. When rechallenged with risedronate or another bisphosphonate, a subset of patients experienced a recurrence of symptoms(Prod Info ACTONEL(R) oral tablets, 2015) .
D) MUSCLE PAIN 1) WITH THERAPEUTIC USE a) RISEDRONATE 1) During the postmarketing use of risedronate, rare cases of severe or incapacitating muscle pain have been reported. Onset of symptoms occurred from one day to several months after beginning therapy, and in most cases symptoms resolved following discontinuation of the drug. When rechallenged with risedronate or another bisphosphonate, a subset of patients experienced a recurrence of symptoms (Prod Info ACTONEL(R) oral tablets, 2015).
2) During a study which compared risedronate 35 mg weekly with placebo for the prevention of osteoporosis in postmenopausal women (n=278), the incidence of myalgia was 5.1% and 2.1%, respectively (Prod Info ACTONEL(R) oral tablets, 2015).
E) ARTHRITIS 1) WITH THERAPEUTIC USE a) Pseudogout has been reported infrequently in patients receiving therapeutic doses of etidronate and pamidronate (Gallacher et al, 1991; Malnick et al, 1997).
F) OSTEOMALACIA 1) WITH THERAPEUTIC USE a) ETIDRONATE 1) Osteomalacia has been reported following oral doses above 800 mg/day of etidronate (a first generation bisphosphonate) over several months. The clinical effects reported have included bone pain and an increased risk of fracture despite ongoing therapy (Rosen & Kessenich, 1996).
2) Second or third generation (e.g., alendronate, pamidronate, tiludronate) bisphosphonates do not appear to have this tendency, but long term experience is limited (Rosen & Kessenich, 1996; Devogelaer et al, 1997).
3) RISK : The risk of fractures may increase following the use of etidronate at doses of 20 mg/kg/day for greater than 6 months (Prod Info Didronel(R) oral tablets, 2015).
4) CASE REPORT : A 68-year-old woman with osteoporosis received cyclic etidronate therapy (400 mg/day) for 14 days repeated approximately every 70 days. After 2 years of therapy, the patient developed increased osteoid volume and a mineralization defect indicative of an atypical osteomalacia. No clinical symptoms were observed (Thomas et al, 1995).
5) LACK OF EFFECT : Miller et al (1997) reported no generalized osteomalacia or clinically significant symptoms of abnormal bone remodeling in patients receiving cyclical etidronate (400 mg/day for 14 days) who were followed for up to 7 years(Miller et al, 1997).
G) FRACTURE OF SHAFT OF FEMUR 1) WITH THERAPEUTIC USE a) Low-energy femoral shaft fractures have been reported in patients receiving bisphosphonates for the treatment of osteoporosis, commonly occurring with minimal trauma to the affected area, and may be bilateral. Patients reported a dull, aching thigh pain that may occur weeks to months prior to the complete fracture. Fractures have also been reported in osteoporosis patients not receiving bisphosphonates; therefore, causality has not been definitively established (Prod Info FOSAMAX(R) oral tablets, oral solution, 2015; Prod Info BONIVA(R) oral tablets, 2015; Prod Info ACTONEL(R) oral tablets, 2015).
H) ABNORMAL GAIT 1) WITH THERAPEUTIC USE a) PAMIDRONATE 1) CASE REPORT: Two elderly women with intact neurological functioning experienced sudden onsets of gait disturbance and unsteadiness after receiving one 60 mg dose of intravenous pamidronate. Unsteadiness resolved within 3 to 10 days with one woman requiring physical therapy and rehabilitation. Subsequently, one patient was able to tolerate pamidronate at a slower infusion rate (Karapetis et al, 1997).
I) BACKACHE 1) WITH THERAPEUTIC USE a) RISEDRONATE 1) During a study which compared risedronate 5 mg daily (n=1619) with placebo (n=1613) for the treatment of osteoporosis in postmenopausal women, the incidence of back pain was 28% and 26.1%, respectively (Prod Info ACTONEL(R) oral tablets, 2015).
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Immunologic |
3.19.2) CLINICAL EFFECTS
A) ANAPHYLAXIS 1) WITH THERAPEUTIC USE a) IBANDRONATE: Anaphylaxis with fatalities has been reported following therapy with IV ibandronate (Prod Info BONIVA(R) intravenous injection, 2015).
b) ZOLEDRONIC ACID: Hypersensitivity reactions, including angioedema and bronchoconstriction, as well as anaphylactic reactions or shock have been rarely reported during post-marketing surveillance of IV zoledronic acid therapy (Prod Info ZOMETA(R) intravenous injection concentrate, 2016)
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Reproductive |
3.20.1) SUMMARY
A) Pamidronate and zoledronic acid are classified as FDA pregnancy category D. Alendronate, alendronate/cholecalciferol, etidronate, risedronate, and tiludronate are classified as FDA pregnancy category C. In animal studies involving various bisphosphonates, fetal skeletal, visceral, and external abnormalities have been reported. Dose-related scoliosis has been attributable to tiludronate in rabbit studies.
3.20.2) TERATOGENICITY
A) ANIMAL STUDIES 1) ALENDRONATE/CHOLECALCIFEROL a) RATS, RABBITS: Cases of incomplete fetal ossification of the vertebral, skull, and sternebral bones were statistically significantly increased in rats administered alendronate at does approximately 3 times the clinical dose. The same effects were not reported when rabbits were treated at doses up to 10 times the recommended clinical dose (Prod Info FOSAMAX(R) PLUS D oral tablets, 2013).
2) ETIDRONATE a) RATS, RABBITS: Teratology and toxicity studies conducted in rats and rabbits reported no adverse or teratogenic effects. Skeletal abnormalities in rats have been reported (Prod Info DIDRONEL(R) tablets, 2005).
3) RISEDRONATE a) RATS, RABBITS: In animal studies, significant increases were seen in the number of fetuses exhibiting incomplete ossification of skull or sternebrae from dams treated with approximately 2.5 times the human dose when compared to the controls. Rats treated with oral doses approximately 5 times the human dose resulted in increased incomplete ossification and unossified sternebrae. Fetuses from female rats treated with oral doses approximately equal to the human dose resulted in a low incidence of cleft palate. Rabbits treated with oral doses approximately 7 times the human dose (the highest dose tested) showed no significant fetal ossification effects (Prod Info ATELVIA(TM) delayed-release oral tablets, 2010; Prod Info ACTONEL(R) oral tablets, 2009).
4) TILUDRONATE a) RABBITS: Dose-related scoliosis has been attributable to tiludronate in rabbit studies (Prod Info SKELID(R) oral tablets, 2006).
5) ZOLEDRONIC ACID a) Fetal skeletal, visceral, and external malformations were observed following mid- and high-dose zoledronic acid (0.1 to 0.4 mg/kg) administration. Lower doses (about 1.2 times the human systemic exposure) resulted in fetal skeletal variations, while higher doses (about 4 times the human systemic exposure) resulted in unossified or incompletely ossified bones, thickened, curved or shortened bones, wavy ribs, shortened jaw, reduced lens, rudimentary cerebellum, reduction or absence of liver lobes, reduction of lung lobes, vessel dilation, cleft palate, and edema (Prod Info RECLAST(R) IV injection, 2008).
3.20.3) EFFECTS IN PREGNANCY
A) LACK OF INFORMATION 1) At the time of this review, no data were available to assess the potential effects of exposure to risedronate during pregnancy in humans (Prod Info ATELVIA(TM) delayed-release oral tablets, 2010).
B) ALENDRONATE/CHOLECALCIFEROL 1) There is no data on fetal risk in humans with alendronate, and no data are available for the safety of cholecalciferol use during pregnancy. Animal data suggest that bisphosphonate uptake in fetal bone is greater than that into maternal bone; theoretically, fetal risk may exist after completing a course of treatment. Alendronate with cholecalciferol should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus (Prod Info FOSAMAX(R) PLUS D oral tablets, 2013).
C) PAMIDRONATE 1) Use of IV pamidronate for treatment of malignant hypercalcemia during pregnancy has resulted in transient, mild hypocalcemia in the infant at birth. Total plasma concentration levels normalized within 5 days and both growth and development appeared normal. In a second case, the neonate was born on gestation week 28 and had normal birth weight, normal ionized calcium and parathyroid hormone levels. There were no reports of physical abnormalities. In a third case, an infant was delivered via cesarean section on gestation week 29. Birth weight was appropriate for the gestation age. Respiratory distress and hypercalcemia were reported. Calcium levels normalized after 10 days and remained normal thereafter. Multiple other cases of healthy infants exposed to pamidronate during pregnancy have also been reported (Green & Pappas, 2014).
D) PREGNANCY CATEGORY 1) Pamidronate and zoledronic acid have been classified as FDA pregnancy category D (Prod Info Aredia(R) intravenous injection, 2012; Prod Info RECLAST(R) IV injection, 2008; Prod Info ZOMETA(R) IV injection, 2008).
2) Alendronate, etidronate, risedronate, and tiludronate have been classified as FDA pregnancy category C (Prod Info ATELVIA(TM) delayed-release oral tablets, 2010; Prod Info FOSAMAX(R) oral tablets, solution, 2007; Prod Info SKELID(R) oral tablets, 2006; Prod Info DIDRONEL(R) tablets, 2005).
3) The combination product alendronate/cholecalciferol has been classified as FDA pregnancy category C (Prod Info FOSAMAX(R) PLUS D oral tablets, 2013).
E) LACK OF EFFECT 1) ALENDRONATE a) No adverse effects were reported in an infant inadvertently exposed to alendronate in utero. The 49-year-old mother was believed to be postmenopausal when she was treated with alendronate 10 mg/day and later discovered she was pregnant. The total cumulative dose of alendronate was unclear. At birth, the infant's laboratory values were all within normal limits and there were no reports of abnormal calcifications or variations in bone structure. At a 1 year of age, there were no signs of congenital abnormalities or psychomotor developmental disorders. The child's weight was reported to only be in the tenth-percentile (Green & Pappas, 2014).
b) In an observational cohort study, use of alendronate prior to conception (1 case) and during the first trimester of pregnancy (1 case) had no adverse effects on the newborn infants. However, in a retrospective case-control study, alendronate exposure during pregnancy resulted in significantly lower median birth weights and decreased gestational age compared with infants not exposed to bisphosphonates. The incidence of spontaneous abortion was also significantly higher in the alendronate group compared with the control group (Green & Pappas, 2014).
2) ETIDRONATE a) No neonatal complications, skeletal deformities, or hypocalcemia were reported in infants born to a woman receiving several years of IV etidronate treatment for pregnancy-associated spinal osteoporosis. The patient began cyclic treatment with etidronate after the birth of her first child and continued treatment for 1.5 years before discontinuing for her second pregnancy. After delivery, the patient resumed treatment with etidronate and continued treatment for 2 years. Treatment was discontinued 3 months prior to her third pregnancy. No adverse effects were reported in either infant at birth; however, at 6.8 years of age, low bone mineral density was reported in the third child (Green & Pappas, 2014).
3) RISEDRONATE a) No significant differences in spontaneous abortion or major birth defects were reported in infants exposed to a bisphosphonate, such as risedronate, during pregnancy compared with infants not exposed to bisphosphonates or known teratogens. Non-significant decreases in mean gestational age and birth weight were reported in the bisphosphonate-exposed group (Green & Pappas, 2014).
4) ZOLEDRONIC ACID a) No abnormal hematologic or biochemical parameters were observed at birth in an infant exposed to zoledronic acid during pregnancy. The patient received 2 doses of IV zoledronic acid concurrently with chemotherapy and radiation for metastatic breast cancer during the second trimester of pregnancy. At a 12 month follow-up, no congenital abnormalities or disease were observed in the child (Green & Pappas, 2014).
F) ANIMAL STUDIES 1) ALENDRONATE a) RATS: Animal studies in rats have shown decreased postimplantation survival (at 2 mg/kg/day), decreased body weight gain in normal pups (at 1mg/kg/day), and incomplete fetal ossification in vertebral, skull and sternebral bones. In pregnant rats, decreased total and ionized calcium resulted in delays and failures of delivery (Prod Info FOSAMAX(R) oral tablets, solution, 2007).
b) RATS: A study reported physical signs of toxicity at parturition in female rats while being given alendronate. Tremors, dystonia and death in the dams and associated neonatal deaths due to protracted deliveries were seen (Minsker et al, 1993).
c) RATS: In rats, fetal skeletal ossification is at its greatest in late gestation. To meet this demand females mobilize calcium via increased bone resorption. Maternotoxicity of rats was based on the pharmacologic actions of alendronate to prevent bone resorption and the alendronate-induced hypocalcemia adversely affected parturition (uterine muscle contraction is a calcium-dependent process) (Minsker et al, 1993).
2) ALENDRONATE/CHOLECALCIFEROL a) In animal studies, decreased post-implantation survival and decreased weight gain in normal pups occurred when rats were given alendronate sodium at doses less than half of the recommended clinical dose during reproduction studies. At doses approximately 4 times the recommended clinical dose, both total and ionized calcium decreased in pregnant rats, resulting in delays and failures of delivery. Maternotoxicity occurred at times ranging from treatment only during pre-mating to treatment only during early, middle, or late gestation; these deaths decreased, but were not eliminated, when treatment stopped (Prod Info FOSAMAX(R) PLUS D oral tablets, 2013).
3) PAMIDRONATE a) RATS, RABBITS: Maternal toxicity and nonteratogenic embryo/fetal harm were reported in rats and rabbits administered a single IV dose of pamidronate equivalent to 0.6 to 8.3 times the highest recommended human dose during organogenesis. Animal studies have also shown that pamidronate can cross the placenta in rats (Prod Info Aredia(R) intravenous injection, 2012).
4) RISEDRONATE a) RATS, RABBITS: In animal studies, neonate survival was decreased in rats treated during gestation with oral doses of approximately 5 times the human dose. Additionally, body weight was decreased in neonates from dams treated with approximately 26 times the human dose. Similar to other bisphosphonates, treatment during mating and gestation with doses approximately the same as the human dose resulted in periparturient hypocalcemia and mortality in pregnant rats allowed to deliver. In rabbits treated with oral doses approximately 7 times the human dose (the highest dose tested), 1 of 14 litters were delivered prematurely and 1 of 14 litters were spontaneously aborted (Prod Info ATELVIA(TM) delayed-release oral tablets, 2010; Prod Info ACTONEL(R) oral tablets, 2009).
5) TILUDRONATE a) RATS: Maternal death, presumably from decreased calcium, occurred at 75mg/kg/day (two times the 400 mg/day human dose) when rats were treated from day 15 of gestation to day 25 postpartum (Prod Info SKELID(R) oral tablets, 2006).
6) ZOLEDRONIC ACID a) RATS: Increased stillbirths and decreased pup survival occurred when pregnant rats were given zoledronic acid 0.01 to 0.1 mg/kg/day (greater than or equal to 0.3 times the human systemic exposure following a 5 mg IV dose) beginning 15 days before mating and continuing through gestation. Adverse maternal effects included dystocia and periparturient mortality, which may have been related to periparturient hypocalcemia (Prod Info RECLAST(R) IV injection, 2008).
b) Increased pre- and post-implantation losses and decreased viable fetuses were observed following mid- and high-dose zoledronic acid (0.1 to 0.4 mg/kg) administration. Maternal toxicity was evident with high doses and included reduced body weights and food consumption (Prod Info RECLAST(R) IV injection, 2008).
3.20.4) EFFECTS DURING BREAST-FEEDING
A) LACK OF INFORMATION 1) At the time of this review, no data were available to assess the potential effects of exposure to alendronate, alendronate/cholecalciferol, etidronate, pamidronate, risedronate, tiludronate, or zoledronic acid during lactation in humans (Prod Info FOSAMAX(R) PLUS D oral tablets, 2013; Prod Info Aredia(R) intravenous injection, 2012; Prod Info ATELVIA(TM) delayed-release oral tablets, 2010; Prod Info RECLAST(R) IV injection, 2008; Prod Info ZOMETA(R) IV injection, 2008; Prod Info FOSAMAX(R) oral tablets, solution, 2007; Prod Info SKELID(R) oral tablets, 2006; Prod Info DIDRONEL(R) tablets, 2005).
B) ALENDRONATE/CHOLECALCIFEROL 1) Cholecalciferol and some of its active metabolites are excreted into breast milk. It is not known whether alendronate sodium is excreted into human breast milk, and the potential for adverse effects in the breastfeeding infant has not been determined. Use caution when administering alendronate sodium/cholecalciferol to a nursing woman (Prod Info FOSAMAX(R) PLUS D oral tablets, 2013).
C) PAMIDRONATE 1) In a case study, milk expressed and assayed over a 48-hour period after a single infusion of pamidronate 30 mg did not exhibit detectable levels of pamidronate (Siminoski et al, 2000).
D) ANIMAL STUDIES 1) RISEDRONATE a) RATS: In animal studies, risedronate was detected in rat pups of lactating dams at 24 hours after maternal dosing (Prod Info ATELVIA(TM) delayed-release oral tablets, 2010; Prod Info ACTONEL(R) oral tablets, 2009).
3.20.5) FERTILITY
A) LACK OF INFORMATION 1) RISEDRONATE a) At the time of this review, no data were available to assess the potential effects on fertility from exposure to this agent (Prod Info ATELVIA(TM) delayed-release oral tablets, 2010).
B) ANIMAL STUDIES 1) ALENDRONATE a) RATS: Alendronate has no effect on fertility (male or female) in rats at oral doses up to 5 mg/kg/day (1.3 times a 40 mg human daily dose based on surface area) (Prod Info FOSAMAX(R) oral tablets, solution, 2007).
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Carcinogenicity |
3.21.2) SUMMARY/HUMAN
A) In a review of published studies, oral bisphosphonate use may be associated with an increased risk of esophageal cancer.
3.21.3) HUMAN STUDIES
A) ESOPHAGEAL CANCER 1) In data from 2 large epidemiologic studies, which used the same database, 1 study found no increased risk of esophageal cancer, while the second study found a doubling of the risk of esophageal cancer in patients with 10 or more prescriptions of bisphosphonates, or who had taken the drug for over 3 years. Other studies which employed different databases have reported no increase in risk or a reduced risk. Methodologies of the studies may have contributed to the disparate findings. At this time, there is not enough information to make a definitive conclusion about a possible association (U.S. Food and Drug Administration (FDA), 2011).
3.21.4) ANIMAL STUDIES
A) ENDOCRINE DISORDER 1) ALENDRONATE a) In a comparison 92-week carcinogenicity study between male and female mice, an increased incidence of Harderian gland (a retro-orbital gland not present in humans) adenomas were observed only in the female group receiving high-dose alendronate at doses of 1, 2, and 5 mg/kg/day; male mice received doses of 1, 3, and 10 mg/kg/day (0.12 to 1.2 times the 40 mg human dose based on body surface area) (Prod Info FOSAMAX(R) oral tablets, solution, 2010).
2) ZOLEDRONIC ACID a) In standard lifetime carcinogenicity bioassays conducted in male and female mice, an increased incidence of Harderian gland adenomas were observed in all treatment groups when given doses of zoledronic acid 0.1, 0.5, or 2 mg/kg/day (doses were greater than 0.002 times the human IV dose of 5 mg, based on body surface area). Carcinogenicity was also evaluated in rats; however, at treatment doses of 0.1, 0.5, or 2 mg/kg/day (doses were 0.1 times or less the human IV dose of 5 mg, based on body surface area), no evidence of carcinogenicity was observed (Prod Info Reclast(R) IV injection, 2009).
B) THYROID ADENOMA 1) ALENDRONATE a) In a 2-year carcinogenicity study, Parafollicular cell (thyroid) adenomas were increased in high-dose male rats (p=0.003) ingesting doses of 1 and 3.75 mg/kg (doses are approximately 0.26 and 1 times, respectively, the 40-mg human daily dose) (Prod Info FOSAMAX(R) oral tablets, solution, 2010).
C) LACK OF DATA 1) TILUDRONATE: At the time of this review, no studies were found on the possible carcinogenic activity of tiludronate (Prod Info SKELID(R) oral tablets, 2006).
D) LACK OF EFFECT 1) ETIDRONATE: No evidence of carcinogenicity has been found in long-term studies involving rats (Prod Info Didronel(R) oral tablets, 2009).
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Genotoxicity |
A) ALENDRONATE: Genotoxicity was not seen with alendronate in the following assays: in vitro microbial mutagenesis assay, with and without metabolic activation; in vitro mammalian cell mutagenesis assay; in vitro alkaline elution assay in rat hepatocytes; and in vivo chromosomal aberration assay in mice. Alendronate gave equivocal results in Chinese hamster ovary cells (Prod Info FOSAMAX(R) oral tablets, solution, 2010).
B) TILUDRONATE: Genotoxicity was not found with tiludronate in the following assays: in vitro microbial mutagenesis assay, with and without metabolic activation; a human lymphocyte assay; a yeast cell assay for forward mutation and mitotic crossing over; or the in vivo mouse micronucleus test (Prod Info SKELID(R) oral tablets, 2006).
C) ZOLEDRONIC ACID: Genotoxicity was not observed with zoledronic acid in the following assays: Ames bacterial mutagenicity assay; the Chinese hamster ovary cell assay; the Chinese hamster gene mutation assay, with or without metabolic activation; or the in vivo rat micronucleus assay (Prod Info Reclast(R) IV injection, 2009).
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