Reclast Information
Reclast ()
Reclast () Dosage And Administration
A 5 mg dose of Reclast () administered intravenously is recommended for patients with creatinine clearance ≥35 mL/min [].
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Patients must be appropriately hydrated prior to administration of Reclast () [ ].
Administration of acetaminophen following Reclast () administration may reduce the incidence of acute-phase reaction symptoms.
Reclast () Dosage Forms And Strengths
5 mg in a 100 mL ready to infuse solution.
Reclast ()
Reclast () Warnings And Precautions
Pre-existing hypocalcemia and disturbances of mineral metabolism (e.g., hypoparathyroidism, thyroid surgery, parathyroid surgery; malabsorption syndromes, excision of small intestine) must be effectively treated before initiating therapy with Reclast () . Clinical monitoring of calcium and mineral levels (phosphorus and magnesium) is highly recommended for these patients [].
Hypocalcemia following Reclast () administration is a significant risk in Paget’s disease. All patients should be instructed about the symptoms of hypocalcemia and the importance of calcium and vitamin D supplementation in maintaining serum calcium levels [].
All osteoporosis patients should be instructed on the importance of calcium and vitamin D supplementation in maintaining serum calcium levels [].
A single dose of Reclast () should not exceed 5 mg and the duration of infusion should be no less than 15 minutes [].
Osteonecrosis of the jaw (ONJ) has been reported in patients treated with bisphosphonates, including zoledronic acid. Most cases have been in cancer patients treated with intravenous bisphosphonates undergoing dental procedures. Some cases have occurred in patients with postmenopausal osteoporosis treated with either oral or intravenous bisphosphonates. A routine oral examination should be performed by the prescriber prior to initiation of bisphosphonate treatment. A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with a history of concomitant risk factors (e.g., cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene, pre-existing dental disease or infection, anemia, coagulopathy).
While on treatment, patients with concomitant risk factors should avoid invasive dental procedures if possible. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. The clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment [].
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 transverse 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 femur 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.
Reclast () SHOULD NOT BE USED DURING PREGNANCY
see Use in Specific Populations (8.1)
Reclast () Adverse Reactions
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 Osteoporosis in Postmenopausal Women
The safety of Reclast () in the treatment of postmenopausal osteoporosis was assessed in Study 1, a large, randomized, double-blind, placebo-controlled, multinational study of 7736 postmenopausal women aged 65-89 years with osteoporosis, diagnosed by bone mineral density or the presence of a prevalent vertebral fracture. The duration of the trial was three years with 3862 patients exposed to Reclast () and 3852 patients exposed to placebo administered once annually as a single 5 mg dose in 100 mL solution infused over at least 15 minutes, for a total of three doses. All women received 1000 to 1500 mg of elemental calcium plus 400 to 1200 IU of vitamin D supplementation per day.
The incidence of all-cause mortality was similar between groups: 3.4% in the Reclast () group and 2.9% in the placebo group. The incidence of serious adverse events was 29.2% in the Reclast () group and 30.1% in the placebo group. The percentage of patients who withdrew from the study due to adverse events was 5.4% and 4.8% for the Reclast () and placebo groups, respectively.
The safety of Reclast () in the treatment of osteoporosis patients with a recent (within 90 days) low-trauma hip fracture was assessed in Study 2, a randomized, double-blind, placebo-controlled, multinational endpoint-driven study of 2127 men and women aged 50-95 years; 1065 patients were randomized to Reclast () and 1062 patients were randomized to placebo. Reclast () was administered once annually as a single 5 mg dose in 100 mL solution infused over at least 15 minutes. The study continued until at least 211 patients had a confirmed clinical fracture in the study population who were followed for an average of approximately 2 years on study drug. Vitamin D levels were not routinely measured but a loading dose of vitamin D (50,000 to 125,000 IU orally or IM) was given to patients and they were started on 1000 to 1500 mg of elemental calcium plus 800 to 1200 IU of vitamin D supplementation per day for at least 14 days prior to the study drug infusions.
The incidence of all-cause mortality was 9.6% in the Reclast () group and 13.3% in the placebo group. The incidence of serious adverse events was 38.3% in the Reclast () group and 41.3% in the placebo group. The percentage of patients who withdrew from the study due to adverse events was 5.3% and 4.7% for the Reclast () and placebo groups, respectively.
Adverse reactions reported in at least 2% of patients with osteoporosis and more frequently in the Reclast () -treated patients than placebo-treated patients in either osteoporosis trial are shown below in Table 1.
Renal Impairment
Treatment with intravenous bisphosphonates, including zoledronic acid, has been associated with renal impairment manifested as deterioration in renal function (i.e., increased serum creatinine) and in rare cases, acute renal failure. In the clinical trial for postmenopausal osteoporosis, patients with baseline creatinine clearance 0.5 mg/dL during the screening visits were excluded. The change in creatinine clearance (measured annually prior to dosing) and the incidence of renal failure and impairment was comparable for both the Reclast () and placebo treatment groups over 3 years, including patients with creatinine clearance between 30-60 mL/min at baseline. Overall, there was a transient increase in serum creatinine observed within 10 days of dosing in 1.8% of Reclast () -treated patients versus 0.8% of placebo-treated patients which resolved without specific therapy [ ].
Acute Phase Reaction
The signs and symptoms of acute phase reaction occurred in Study 1 following Reclast () infusion including fever (18%), myalgia (9%), flu-like symptoms (8%), headache (7%), and arthralgia (7%). The majority of these symptoms occurred within the first 3 days following the dose of Reclast () and usually resolved within 3 days of onset but resolution could take up to 7-14 days. In Study 2, patients without a contraindication to acetaminophen were provided with a standard oral dose at the time of the IV infusion and instructed to use additional acetaminophen at home for the next 72 hours as needed. Reclast () was associated with fewer signs and symptoms of a transient acute phase reaction in this trial: fever (7%) and arthralgia (3%). The incidence of these symptoms decreased with subsequent doses of Reclast () .
Laboratory Findings
In Study 1, in women with postmenopausal osteoporosis, approximately 0.2% of patients had notable declines of serum calcium levels (less than 7.5 mg/dL) following Reclast () administration. No symptomatic cases of hypocalcemia were observed. In Study 2, following pre-treatment with vitamin D, no patients had treatment emergent serum calcium levels below 7.5 mg/dL.
Injection Site Reactions
In the osteoporosis trials, local reactions at the infusion site such as itching, redness and/or pain have been reported in 0% to 0.7% of patients following the administration of Reclast () and 0% to 0.5% of patients following administration of placebo.
Osteonecrosis of the Jaw
In the postmenopausal osteoporosis trial, Study 1, in 7736 patients, after initiation of therapy, symptoms consistent with ONJ occurred in one patient treated with placebo and one patient treated with Reclast () . Both cases resolved after appropriate treatment [ ]. No reports of osteonecrosis of the jaw were reported in either treatment group in Study 2.
Atrial Fibrillation
In the postmenopausal osteoporosis trial, Study 1, adjudicated serious adverse events of atrial fibrillation in the zoledronic acid treatment group occurred in 1.3% of patients (50 out of 3862) compared to 0.4% (17 out of 3852) in the placebo group. The overall incidence of all atrial fibrillation adverse events in the zoledronic acid treatment group was reported in 2.5% of patients (96 out of 3862) in the Reclast () group vs. 1.9% of patients (75 out of 3852) in the placebo group. Over 90% of these events in both treatment groups occurred more than a month after the infusion. In an ECG sub-study, ECG measurements were performed on a subset of 559 patients before and 9 to 11 days after treatment. There was no difference in the incidence of atrial fibrillation between treatment groups suggesting these events were not related to the acute infusions. In Study 2, adjudicated serious adverse events of atrial fibrillation in the zoledronic acid treatment group occurred in 1.0% of patients (11 out of 1054) compared to 1.2% (13 out of 1057) in the placebo group demonstrating no difference between treatment groups.
Ocular Adverse Events
Cases of iritis/uveitis/episcleritis/conjunctivitis have been reported in patients treated with bisphosphonates, including zoledronic acid. In the osteoporosis trials, 1 (
Prevention of Osteoporosis in Postmenopausal Women
The safety of Reclast () in postmenopausal women with osteopenia (low bone mass) was assessed in a 2-year randomized, multi-center, double-blind, placebo-controlled study of 581 postmenopausal women aged 45 years. Patients were randomized to one of three treatment groups: (1) Reclast () given at randomization and Month 12 (n=198); (2) Reclast () given at randomization and placebo at Month 12 (n=181); and (3) placebo given at randomization and Month 12 (n=202). Reclast () was administered as a single 5 mg dose in 100 mL solution infused over at least 15 minutes. All women received 500 to 1200 mg elemental calcium plus 400 to 800 IU vitamin D supplementation per day.
The incidence of serious adverse events was similar for subjects given (1) Reclast () at randomization and at Month 12 (10.6%), (2) Reclast () at randomization and placebo given at Month 12 (9.4%), and (3) placebo at randomization and at Month 12 (11.4%). The percentages of patients who withdrew from the study due to adverse events were 7.1%, 7.2%, and 3.0% in the two Reclast () groups and placebo group, respectively. Adverse reactions reported in at least 2% of patients with osteopenia and more frequently in the Reclast () -treated patients than placebo-treated patients are shown in Table 2.
* Combined abdominal pain, abdominal pain upper, and abdominal pain lower as one ADR
** Combined musculoskeletal pain and musculoskeletal chest pain as one ADR
Ocular Adverse Events
Cases of iritis/uveitis/episcleritis/conjunctivitis have been reported in patients treated with bisphosphonates, including zoledronic acid. In the osteoporosis prevention trial, 4 (1.1%) patients treated with Reclast () and 0 (0%) patients treated with placebo developed iritis/uveitis.
Acute Phase Reaction
In patients given Reclast () at randomization and placebo at Month 12, Reclast () was associated with signs and symptoms of an acute phase reaction: myalgia (20.4%), fever (19.3%), chills (18.2%), pain (13.8%), headache (13.3%), fatigue (8.3%), arthralgia (6.1%), pain in extremity (3.9%), influenza-like illness (3.3%), and back pain (1.7%), which occurred within the first 3 days following the dose of Reclast () . The majority of these symptoms were mild to moderate and resolved within 3 days of the event onset but resolution could take up to 7-14 days.
Osteoporosis in Men
The safety of Reclast () in men with osteoporosis or osteoporosis secondary to hypogonadism was assessed in a two year randomized, multicenter, double-blind, active controlled group study of 302 men aged 25-86 years. One hundred fifty three (153) patients were exposed to Reclast () administered once annually with a 5 mg dose in 100 mL infused over 15 minutes for up to a total of two doses, and 148 patients were exposed to a commercially-available oral weekly bisphosphonate (active control) for up to two years. All participants received 1000 mg of elemental calcium plus 800 to 1000 IU of vitamin D supplementation per day.
The incidence of all-cause mortality (one in each group) and serious adverse events were similar between the Reclast () and active control treatment groups. The percentage of patients experiencing at least one adverse event was comparable between the Reclast () and active control groups, with the exception of a higher incidence of post-dose symptoms in the Reclast () group that occurred within 3 days after infusion. The overall safety and tolerability of Reclast () was similar to the active control.
Adverse reactions reported in at least 2% of men with osteoporosis and more frequently in the Reclast () -treated patients than the active control-treated patients and either (1) not reported in the postmenopausal osteoporosis treatment trial or (2) reported more frequently in the trial of osteoporosis in men are presented in Table 3. Therefore, Table 3 should be viewed in conjunction with Table 1.
* Combined abdominal pain, abdominal pain upper, and abdominal pain lower as one ADR
** Combined musculoskeletal pain and musculoskeletal chest pain as one ADR
Creatinine clearance was measured annually prior to dosing and changes in long-term renal function over 24 months were comparable in the Reclast () and active control groups [ ].
Acute Phase Reaction
Reclast () was associated with signs and symptoms of an acute phase reaction: myalgia (17.1%), fever (15.7%), fatigue (12.4%), arthralgia (11.1%), pain (10.5%), chills (9.8%), headache (9.8%), influenza-like illness (8.5%), malaise (5.2%), and back pain (3.3%), which occurred within the first 3 days following the dose of Reclast () . The majority of these symptoms were mild to moderate and resolved within 3 days of the event onset but resolution could take up to 7-14 days. The incidence of these symptoms decreased with subsequent doses of Reclast () .
Atrial Fibrillation
The incidence of all atrial fibrillation adverse events in the Reclast () treatment group was 3.3% (5 out of 153) compared to 2.0% (3 out of 148) in the active control group. However, there were no patients with adjudicated serious adverse events of atrial fibrillation in the Reclast () treatment group.
Laboratory Findings
There were no patients who had treatment emergent serum calcium levels below 7.5 mg/dL.
Injection Site Reactions
There were 4 patients (2.6%) on Reclast () vs. 2 patients (1.4%) on active control with local site reactions.
Osteonecrosis of the Jaw
In this trial there were no cases of osteonecrosis of the jaw [ ].
Glucocorticoid-Induced Osteoporosis
The safety of Reclast () in men and women in the treatment and prevention of glucocorticoid-induced osteoporosis was assessed in a randomized, multicenter, double-blind, active controlled, stratified study of 833 men and women aged 18-85 years treated with 7.5 mg/day oral prednisone (or equivalent). Patients were stratified according to the duration of their pre-study corticosteroid therapy: 3 months prior to randomization (prevention subpopulation), and > 3 months prior to randomization (treatment subpopulation).
The duration of the trial was one year with 416 patients exposed to Reclast () administered once as a single 5 mg dose in 100 mL infused over 15 minutes, and 417 patients exposed to a commercially-available oral daily bisphosphonate (active control)for one year. All participants received 1000 mg of elemental calcium plus 400 to 1000 IU of vitamin D supplementation per day.
The incidence of all–cause mortality was similar between treatment groups: 0.9% in the Reclast () group and 0.7% in the active control group. The incidence of serious adverse events was similar between the Reclast () treatment and prevention groups, 18.4% and 18.1%, respectively, andthe active control treatment and prevention groups, 19.8% and 16.0%, respectively. The percentage of subjects who withdrew from the study due to adverse events was 2.2% in the Reclast () group vs. 1.4% in the active control group. The overall safety and tolerability were similar between Reclast () and active control groups with the exception of a higher incidence of post-dose symptoms in the Reclast () group that occurred within 3 days after infusion. The overall safety and tolerability profile of Reclast () in glucocorticoid-induced osteoporosis was similar to the adverse events reported in the Reclast () postmenopausal osteoporosis clinical trial.
Adverse reactions reported in at least 2% of patients that were either not reported in the postmenopausal osteoporosis treatment trial or reported more frequently in the treatment and prevention of glucocorticoid-induced osteoporosis trial included the following: abdominal pain (Reclast () 7.5%; active control 5.0%), and musculoskeletal pain (Reclast () 3.1%; active control 1.7%).Other musculoskeletal events included back pain (Reclast () 4.3%, active control 6.2%), bone pain (Reclast () 3.1%, active control 2.2%), and pain in the extremity (Reclast () 3.1%, active control 1.2%).In addition, the following adverse events occurred more frequently than in the postmenopausal osteoporosis trial: nausea (Reclast () 9.6%; active control 8.4%), and dyspepsia (Reclast () 5.5%; active control 4.3%).
Renal Impairment
Renal function measured prior to dosing and at the end of the 12 month study was comparable in the Reclast () and active control groups [ ].
Acute Phase Reaction
Reclast () was associated with signs and symptoms of a transient acute phase reaction that was similar to that seen in the Reclast () postmenopausal osteoporosis clinical trial.
The incidence of atrial fibrillation adverse events was 0.7% (3 of 416) in the Reclast () group compared to no adverse events in the active control group. All subjects had a prior history of atrial fibrillation and no cases were adjudicated as serious adverse events. One patient had atrial flutter in the active control group.
Laboratory Findings
There were no patients who had treatment emergent serum calcium levels below 7.5 mg/dL.
There were no local reactions at the infusion site.
Osteonecrosis of the Jaw
In this trial there were no cases of osteonecrosis of the jaw [ ].
Paget’s Disease of Bone
In the Paget’s disease trials, two 6-month, double-blind, comparative, multinational studies of 349 men and women aged > 30 years with moderate to severe disease and with confirmed Paget’s disease of bone, 177 patients were exposed to Reclast () and 172 patients exposed to risedronate. Reclast () was administered once as a single 5 mg dose in 100 mL solution infused over at least 15 minutes. Risedronate was given as an oral daily dose of 30 mg for 2 months.
The incidence of serious adverse events was 5.1% in the Reclast () group and 6.4% in the risedronate group. The percentage of patients who withdrew from the study due to adverse events was 1.7% and 1.2% for the Reclast () and risedronate groups, respectively.
Adverse reactions occurring in at least 2% of the Paget’s patients receiving Reclast () (single 5 mg IV infusion) or risedronate (30 mg oral daily dose for 2 months) over a 6-month study period are listed by system organ class in Table 4.
Laboratory Findings
In the Paget’s disease trials, early, transient decreases in serum calcium and phosphate levels were observed. Approximately 21% of patients had serum calcium levels
Renal Impairment
In clinical trials in Paget’s disease there were no cases of renal deterioration following a single 5 mg 15-minute infusion [ ].
Acute Phase Reaction
The signs and symptoms of acute phase reaction (influenza-like illness, pyrexia, myalgia, arthralgia, and bone pain) were reported in 25% of patients in the Reclast () -treated group compared to 8% in the risedronate-treated group. Symptoms usually occur within the first 3 days following Reclast () administration. The majority of these symptoms resolved within 4 days of onset.
Osteonecrosis of the Jaw
Osteonecrosis of the jaw has been reported with zoledronic acid [].
Because these 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.
The following adverse reactions have been identified during post approval use of Reclast () :
Acute Phase Reactions
Fever, headache, flu-like symptoms, nausea, vomiting, diarrhea, arthralgia, and myalgia. Symptoms may be significant and lead to dehydration.
Acute Renal Failure
Cases of acute renal failure requiring hospitalization and/or dialysis or with a fatal outcome have been rarely reported. Increased serum creatinine was reported in patients with 1) underlying renal disease, 2) dehydration secondary to fever, sepsis, gastrointestinal losses, or diuretic therapy, or 3) other risk factors such as advanced age, or concomitant nephrotoxic drugs in the post-infusion period. Transient rise in serum creatinine can be correctable with intravenous fluids.
Allergic Reactions
There have been rare reports of allergic reaction with intravenous zoledronic acid including urticaria, angioedema, and bronchoconstriction. Rare cases of anaphylactic reaction/shock have also been reported.
Hypocalcemia
Rare cases of hypocalcemia have been reported.
Osteonecrosis of the Jaw
Rare cases of osteonecrosis of the jaw have been reported.
Ocular Adverse Events
Rare cases of the following events have been reported: conjunctivitis, iritis, iridocyclitis, uveitis, episcleritis, scleritis and orbital inflammation/edema.
Other
Rare cases of hypotension in patients with underlying risk factors have been reported.
Reclast () Drug Interactions
No drug interaction studies have been performed for Reclast () . and studies showed low affinity of zoledronic acid for the cellular components of human blood. mean zoledronic acid protein binding in human plasma ranged from 28% at 200 ng/mL to 53% at 50 ng/mL. studies showed that zoledronic acid is not metabolized, and is excreted into the urine as the intact drug.
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Reclast () Patient Counseling Information
Patients should be made aware that Reclast () contains the same active ingredient (zoledronic acid) found in Zometa, and that patients being treated with Zometa should not be treated with Reclast () .
Reclast () is contraindicated in patients with creatinine clearance
Before being given Reclast () , patients should tell their doctor if they have kidney problems and what medications they are taking.
Reclast () should not be given if the patient is pregnant or plans to become pregnant, or if she is breast-feeding [ ].
There have been reports of bronchoconstriction in aspirin-sensitive patients receiving bisphosphonates, including Reclast () . Before being given Reclast () , patients should tell their doctor if they are aspirin-sensitive.
If the patient had surgery to remove some or all of the parathyroid glands in their neck, or had sections of their intestine removed, or are unable to take calcium supplements they should tell their doctor.
Reclast () is given as an infusion into a vein by a nurse or a doctor, and the infusion time must not be less than 15 minutes.
On the day of treatment the patient should eat and drink normally, which includes drinking at least 2 glasses of fluid such as water within a few hours prior to the infusion, as directed by their doctor, before receiving Reclast () .
After getting Reclast () it is strongly recommended patients with Paget’s disease take calcium in divided doses (for example, 2 to 4 times a day) for a total of 1500 mg calcium a day to prevent low blood calcium levels. This is especially important for the two weeks after getting Reclast () [].
Adequate calcium and vitamin D intake is important in patients with osteoporosis and the current recommended daily intake of calcium is 1200 mg and vitamin D is 800 IU – 1000 IU daily. All patients should be instructed on the importance of calcium and vitamin D supplementation in maintaining serum calcium levels.
Patients should be aware of the most commonly associated side effects of therapy. Patients may experience one or more side effects that could include: fever, flu-like symptoms, myalgia, arthralgia, and headache. Most of these side effects occur within the first 3 days following the dose of Reclast () . They usually resolve within 3 days of onset but may last for up to 7 to 14 days. Patients should consult their physician if they have questions or if these symptoms persist. The incidence of these symptoms decreased markedly with subsequent doses of Reclast () .
Administration of acetaminophen following Reclast () administrationmay reduce the incidence of these symptoms
Physicians should inform their patients that there have been reports of persistent pain and/or a non-healing sore of the mouth or jaw, primarily in patients treated with bisphosphonates for other illnesses. If they experience these symptoms, they should inform their physician or dentist.
Severe and occasionally incapacitating bone, joint, and/or muscle pain have been infrequently reported in patients taking bisphosphonates, including Reclast () . Consider withholding future Reclast () treatment if severe symptoms develop.
Atypical femur fractures in patients on bisphosphonate therapy have been reported; patients with thigh or groin pain should be evaluated to rule out a femoral fracture.
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