Source: FDA, National Drug Code (US) Revision Year: 2024
Pre-existing hypocalcemia must be corrected prior to initiating therapy with Wyost [see Warnings and Precautions (5.3)].
Wyost is contraindicated in patients with known clinically significant hypersensitivity to denosumab products [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)].
The active ingredient in Wyost is denosumab-bbdz. Patients receiving Wyost should not receive other denosumab products concomitantly.
Clinically significant hypersensitivity including anaphylaxis has been reported with use of denosumab products. Reactions may include hypotension, dyspnea, upper airway edema, lip swelling, rash, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue Wyost therapy permanently [see Contraindications (4.2) and Adverse Reactions (6.2)].
Denosumab products can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Correct pre-existing hypocalcemia prior to Wyost treatment. Monitor calcium levels, throughout Wyost therapy, especially in the first weeks of initiating therapy, and administer calcium, magnesium, and vitamin D as necessary. Concomitant use of calcimimetics and other drugs that can lower calcium levels may worsen hypocalcemia risk and serum calcium should be closely monitored. Advise patients to contact a healthcare provider for symptoms of hypocalcemia [see Contraindications (4.1), Adverse Reactions (6.1, 6.2), and Patient Counseling Information (17)].
An increased risk of hypocalcemia has been observed in clinical trials of patients with increasing renal dysfunction, most commonly with severe dysfunction (creatinine clearance less than 30 mL/min and/or on dialysis), and with inadequate/no calcium supplementation. Monitor calcium levels and calcium and vitamin D intake [see Adverse Reactions (6.1), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
Osteonecrosis of the jaw (ONJ) has been reported in patients receiving denosumab products, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials in patients with cancer, the incidence of ONJ was higher with longer duration of exposure [see Adverse Reactions (6.1)]. Seventy-nine percent of patients with ONJ had a history of tooth extraction, poor oral hygiene, or use of a dental appliance as a predisposing factor. Other risk factors for the development of ONJ include immunosuppressive therapy, treatment with angiogenesis inhibitors, systemic corticosteroids, diabetes, and gingival infections. Similarly, for denosumab-treated patients with multiple myeloma that developed ONJ, 58% had a history of invasive dental procedures as a predisposing factor.
Perform an oral examination and appropriate preventive dentistry prior to the initiation of Wyost and periodically during Wyost therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with Wyost. Consider temporary discontinuation of Wyost therapy if an invasive dental procedure must be performed. There are no data available to suggest the optimal duration of treatment interruption.
Patients who are suspected of having or who develop ONJ while on Wyost should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Clinical judgment of the treating healthcare provider should guide the management plan of each patient based on individual risk/benefit assessment.
Atypical femoral fracture has been reported with denosumab products [see Adverse Reactions (6.1)]. 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.
Atypical femoral 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.
During Wyost treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient 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. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of Wyost therapy should be considered, pending a risk/benefit assessment, on an individual basis.
Clinically significant hypercalcemia requiring hospitalization and complicated by acute renal injury has been reported in denosumab product-treated patients with giant cell tumor of bone and patients with growing skeletons. Hypercalcemia has been reported within the first year after treatment discontinuation. After treatment is discontinued, monitor patients for signs and symptoms of hypercalcemia, assess serum calcium periodically, reevaluate the patient’s calcium and vitamin D supplementation requirements and manage patients as clinically appropriate [see Adverse Reactions (6) and Use in Specific Populations (8.4)].
Multiple vertebral fractures (MVF) have been reported following discontinuation of treatment with denosumab products. Patients at higher risk for MVF include those with risk factors for or a history of osteoporosis or prior fractures.
When Wyost treatment is discontinued, evaluate the individual patient’s risk for vertebral fractures [see Patient Counseling Information (17)].
Based on data from animal studies and its mechanism of action, denosumab products can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of denosumab to cynomolgus monkeys throughout pregnancy at a dose 25-fold higher than the recommended human dose of denosumab based on body weight resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent peripheral lymph nodes, abnormal bone growth and decreased neonatal growth.
Verify the pregnancy status of females of reproductive potential prior to the initiation of Wyost. Advise pregnant women and females of reproductive potential that exposure to Wyost during pregnancy or within 5 months prior to conception can result in fetal harm. Advise females of reproductive potential to use effective contraception during therapy, and for at least 5 months after the last dose of Wyost [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].
The following adverse reactions are discussed below and elsewhere in the labeling:
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.
The safety of denosumab was evaluated in three randomized, double-blind, double-dummy trials [see Clinical Trials (14.1)] in which a total of 2841 patients with bone metastasis from prostate cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple myeloma received at least one dose of denosumab. In Studies 20050136, 20050244, and 20050103, patients were randomized to receive either 120 mg of denosumab every 4 weeks as a subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater. Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required.
The median duration of exposure to denosumab was 12 months (range: 0.1-41) and median duration on-study was 13 months (range: 0.1-41). Of patients who received denosumab, 46% were female. Eighty-five percent were White, 5% Hispanic/Latino, 6% Asian, and 3% Black. The median age was 63 years (range: 18-93). Seventy-five percent of patients who received denosumab received concomitant chemotherapy.
The most common adverse reactions in patients (incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, and nausea (see Table 1). The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation of denosumab were osteonecrosis and hypocalcemia.
Table 1. Selected^a^ Adverse Reactions of Any Severity (Studies 20050136, 20050244, and 20050103):
| Body System | Denosumab n = 2841 % | Zoledronic Acid n = 2836 % |
|---|---|---|
| GASTROINTESTINAL | ||
| Nausea | 31 | 32 |
| Diarrhea | 20 | 19 |
| GENERAL | ||
| Fatigue/Asthenia | 45 | 46 |
| INVESTIGATIONS | ||
| Hypocalcemia^b^ | 18 | 9 |
| Hypophosphatemia^b^ | 32 | 20 |
| NEUROLOGICAL | ||
| Headache | 13 | 14 |
| RESPIRATORY | ||
| Dyspnea | 21 | 18 |
| Cough | 15 | 15 |
a Adverse reactions reported in at least 10% of patients receiving denosumab in Studies 20050136, 20050244, and 20050103, and meeting one of the following criteria:
b Laboratory-derived and below the central laboratory lower limit of normal [8.3-8.5 mg/dL (2.075- 2.125 mmol/L) for calcium and 2.2-2.8 mg/dL (0.71-0.9 mmol/L) for phosphorus]
In the primary treatment phases of Studies 20050136, 20050244, and 20050103, ONJ was confirmed in 1.8% of patients in the denosumab group (median exposure of 12.0 months; range: 0.1-40.5) and 1.3% of patients in the zoledronic acid group. The trials in patients with breast (Study 20050136) or prostate (Study 20050103) cancer included an open-label extension treatment phase where patients were offered denosumab 120 mg once every 4 weeks (median overall exposure of 14.9 months; range: 0.1-67.2). The patient-year adjusted incidence (number of events per 100 patient years) of confirmed ONJ was 1.1% during the first year of treatment, 3.7% in the second year, and 4.6% per year thereafter. The median time to ONJ was 20.6 months (range: 4-53) [see Warnings and Precautions (5.4)].
In a placebo-controlled clinical trial with an extension treatment phase evaluating denosumab for the prevention of bone metastases in patients with non-metastatic prostate cancer (a patient population for which denosumab is not indicated), with longer treatment exposure of up to 7 years, the patient-year adjusted incidence (number of events per 100 patient years) of confirmed ONJ was 1.1% during the first year of treatment, 3.0% in the second year, and 7.1% per year thereafter.
In the clinical trial program, atypical femoral fracture has been reported in patients treated with denosumab and the risk increased with longer duration of treatment. Events have occurred during treatment and after treatment was discontinued [see Warnings and Precautions (5.5)].
The safety of denosumab was evaluated in an international, randomized (1:1), double-blind, active-controlled trial of patients with newly diagnosed multiple myeloma with treatment through disease progression [see Clinical Trials (14.2)]. In this trial, patients received denosumab 120 mg every 4 weeks as a subcutaneous injection (n = 850) or 4 mg (dose adjusted for renal function) of zoledronic acid intravenously (IV) every 4 weeks by IV infusion (n = 852). Entry criteria included serum calcium (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater. Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required.
The median duration of exposure to denosumab was 16 months (range: 1-50) and median duration on-study was 17 months (range: 0-49). Of patients who received denosumab, 46% were female, 83% percent were White, 13% Asian, 3% Black or African American, and 4% Hispanic/Latino. The median age of the patients randomized to denosumab was 63 years (range: 29-91) and all patients who received denosumab received concomitant anti-myeloma chemotherapy.
The adverse reaction profile of denosumab in patients with multiple myeloma, Study 20090482, was similar to that observed in Studies 20050136, 20050244, and 20050103. The most common adverse reactions (incidence ≥ 10%) were diarrhea (34%), nausea (32%), anemia (22%), back pain (21%), thrombocytopenia (19%), peripheral edema (17%), hypocalcemia (16%), upper respiratory tract infection (15%), rash (14%), and headache (11%). The most common serious adverse reaction (incidence ≥ 5%) was pneumonia (8%). The most common adverse reaction resulting in discontinuation of denosumab (≥ 1.0%) was osteonecrosis of the jaw.
Severe hypocalcemia (corrected serum calcium less than 7 mg/dL or less than 1.75 mmol/L) and severe hypophosphatemia (serum phosphorus less than 2 mg/dL or less than 0.6 mmol/L) occurred in 2% and 21% patients treated with denosumab, respectively.
In the primary treatment phase of Study 20090482, ONJ was confirmed in 4.1% of patients in the denosumab group (median exposure of 16 months; range: 1-50) and 2.8% of patients in the zoledronic acid group (median 15 months, range: 1-45 months). At the completion of the double-blind treatment phase of Study 20090482, the patient-year adjusted incidence (number of events per 100 patient years) of confirmed ONJ in the denosumab group (median exposure of 19.4 months; range 1-52) was 2.0% during the first year of treatment, 5.0% in the second year, and 4.5% per year thereafter. The median time to ONJ was 18.7 months (range: 1-44) [see Warnings and Precautions (5.4)].
The safety of denosumab was evaluated in two single-arm trials (Study 20062004 and Study 20040215) [see Clinical Trials (14.3)] in which a total of 548 adult or skeletally mature adolescent patients with giant cell tumor of bone received at least 1 dose of denosumab. Patients received denosumab 120 mg subcutaneously every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy. Patients receiving concurrent bisphosphonate therapy were excluded from enrollment in both studies. Patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure were excluded from enrollment in Study 20040215. During the trial, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required.
Of the 548 patients who received denosumab, 467 patients were treated with denosumab for ≥ 1 year, 323 patients for ≥ 2 years, and 255 patients for ≥ 3 years. The median number of doses received was 33 (range: 4-138 doses) and the median number of months on-study was 60 (range: 0-140 months). Fifty-seven percent of the enrolled patients were women and 82% were White. The median age was 33 years (range: 13-83 years); a total of 19 patients were skeletally mature adolescents (12 to < 17 years of age).
The common adverse reaction profile of denosumab in patients with giant cell tumor of bone was generally similar to that reported in Studies 20050136, 20050244, and 20050103. The most common adverse reactions in patients (incidence ≥ 10%) were arthralgia, back pain, pain in extremity, fatigue, headache, nausea, nasopharyngitis, musculoskeletal pain, toothache, vomiting, hypophosphatemia, constipation, diarrhea, and cough. The most frequent serious adverse reactions were osteonecrosis of the jaw (3.6%), bone giant cell tumor (1.5%), anemia (1.1%), pneumonia (0.9%), and back pain (0.9%). The most frequent adverse reactions resulting in discontinuation of denosumab was osteonecrosis of the jaw (incidence of 3.6%). The adverse reaction profile appeared similar in skeletally mature adolescents and adults.
In Study 20062004 and Study 20040215, ONJ was confirmed in 6.6% of patients who received denosumab. [see Warnings and Precautions (5.4)].
Atypical femoral fracture has been reported with denosumab and was observed in 0.9% of patients in the pooled safety population [see Warnings and Precautions (5.5)].
In the pooled safety population, 0.7% of patients experienced serious adverse events of hypercalcemia > 30 days following treatment discontinuation that was recurrent in some patients [see Warnings and Precautions (5.6)].
Denosumab was evaluated in an open-label, single-arm trial (Study 20070315) in which 33 patients with hypercalcemia of malignancy (with or without bone metastases) refractory to treatment with intravenous bisphosphonate therapy were enrolled [see Clinical Trials (14.4)].
The adverse reaction profile of denosumab in patients with hypercalcemia of malignancy was similar to that reported in Studies 20050136, 20050244, 20050103, 20062004, and 20040215. Adverse reactions occurring in greater than 20% of patients were nausea (30%), dyspnea (27%), decreased appetite (24%), headache (24%), peripheral edema (24%), vomiting (24%), anemia (21%), constipation (21%), and diarrhea (21%). The following adverse reactions of Grade 3 or greater severity related to study therapy were reported on-study: fatigue (3%) and infection (6%). Grade 3 laboratory abnormalities included hypomagnesemia (3%), hypokalemia (3%), and hypophosphatemia (76%) of patients. No deaths on-study were related to denosumab therapy.
The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of denosumab or of other denosumab products.
Using an electrochemiluminescent bridging immunoassay, less than 1% (7/2758) of patients with osseous metastases treated with denosumab doses ranging from 30-180 mg every 4 weeks or every 12 weeks for up to 3 years tested positive for binding antibodies against denosumab. None of the 37 patients with giant cell tumor of bone in Study 20040215 tested positive for binding antibodies against denosumab. Three of the 506 patients with giant cell tumor of bone in Study 20062004 tested positive for transient binding antibodies following treatment with denosumab. In multiple myeloma patients in Study 20090482, 1 out of 199 patients with a postbaseline result, tested positive for binding antibodies against denosumab. No patient with positive binding antibodies tested positive for neutralizing antibodies as assessed using a chemiluminescent cell-based in vitro biological assay. There was no evidence of altered pharmacokinetic profile, toxicity profile, or clinical response to denosumab associated with binding antibody development.
The following adverse reactions have been identified during post-approval use of denosumab products. 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.
Based on findings in animals and its mechanism of action, denosumab products can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are insufficient data with denosumab products use in pregnant women to inform any drug associated risks for adverse developmental outcomes. In utero denosumab exposure from cynomolgus monkeys dosed monthly with denosumab throughout pregnancy at a dose 25-fold higher than the recommended human dose of denosumab based on body weight resulted in increased fetal loss, stillbirths, and postnatal mortality; and absent lymph nodes, abnormal bone growth, and decreased neonatal growth [see Data].
Apprise pregnant women of the potential risk to the fetus.
The background rate of major birth defects and miscarriage is unknown for the indicated population. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
The effects of denosumab on prenatal development have been studied in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a “knockout mouse”). In cynomolgus monkeys dosed subcutaneously with denosumab throughout pregnancy starting at gestational day 20 and at a pharmacologically active dose 25-fold higher than the recommended human dose of denosumab based on body weight, there was increased fetal loss during gestation, stillbirths, and postnatal mortality. Other findings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal bone growth, reduced bone strength, reduced hematopoiesis, dental dysplasia, and tooth malalignment; and decreased neonatal growth. At birth out to one month of age, infants had measurable blood levels of denosumab (22-621% of maternal levels).
Following a recovery period from birth out to 6 months of age, the effects on bone quality and strength returned to normal; there were no adverse effects on tooth eruption, though dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes were present, though small; and minimal to moderate mineralization in multiple tissues was seen in one recovery animal. There was no evidence of maternal harm prior to labor; adverse maternal effects occurred infrequently during labor. Maternal mammary gland development was normal. There was no fetal NOAEL (no observable adverse effect level) established for this study because only one dose of 50 mg/kg was evaluated. Mammary gland histopathology at 6 months of age was normal in female offspring exposed to denosumab in utero; however, development and lactation have not been fully evaluated.
In RANKL knockout mice, absence of RANKL (the target of denosumab) also caused fetal lymph node agenesis and led to postnatal impairment of dentition and bone growth. Pregnant RANKL knockout mice showed altered maturation of the maternal mammary gland, leading to impaired lactation [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.2)].
There is no information regarding the presence of denosumab products in human milk, the effects on the breastfed child, or the effects on milk production. Denosumab was detected in the maternal milk of cynomolgus monkeys up to 1 month after the last dose of denosumab (≤ 0.5% milk:serum ratio) and maternal mammary gland development was normal, with no impaired lactation. However, pregnant RANKL knockout mice showed altered maturation of the maternal mammary gland, leading to impaired lactation [see Use in Specific Populations (8.1) and Nonclinical Toxicology (13.2)]. Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for Wyost treatment and any potential adverse effects on the breastfed child from Wyost or from the underlying maternal condition.
Based on findings in animals and its mechanism of action, denosumab products can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
Verify the pregnancy status of females of reproductive potential prior to initiating Wyost treatment.
Advise females of reproductive potential to use effective contraception during therapy, and for at least 5 months after the last dose of Wyost.
The safety and efficacy of Wyost have not been established in pediatric patients except in skeletally mature adolescents (aged 12–16 years) with giant cell tumor of bone. Wyost is recommended only for treatment of skeletally mature adolescents (aged 12–16 years) with giant cell tumor of bone [see Indications and Usage (1.2)]. Clinically significant hypercalcemia after treatment discontinuation has been reported in pediatric patients with growing skeletons who received denosumab products for giant cell tumor of bone or for unapproved indications [see Adverse Reactions (6.2) and Warnings and Precautions (5.6)].
Denosumab was studied in an open-label trial that enrolled a subset of 19 adolescent patients (aged 12-16 years) with giant cell tumor of bone who had reached skeletal maturity, defined by at least 1 mature long bone (e.g., closed epiphyseal growth plate of the humerus), and had a body weight ≥ 45 kg [see Indications and Usage (1.2) and Clinical Trials (14.3)]. A total of one of five (20%) evaluable adolescent patients had an objective response by retrospective independent assessment of radiographic response according to modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1). The adverse reaction profile and efficacy results appeared to be similar in skeletally mature adolescents and adults [see Adverse Reactions (6.1) and Clinical Trials (14.3)].
Treatment with denosumab products may impair bone growth in children with open growth plates and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target of denosumab therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) at doses ≤ 10 mg/kg was associated with inhibition of bone growth and tooth eruption. Adolescent primates treated with denosumab at doses 5 and 25 times (10 and 50 mg/kg dose) higher than the recommended human dose of 120 mg administered once every 4 weeks, based on body weight (mg/kg), had abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab.
Cynomolgus monkeys exposed in utero to denosumab exhibited bone abnormalities, reduced hematopoiesis, tooth malalignment, decreased neonatal growth, and an absence of axillary, inguinal, mandibular, and mesenteric lymph nodes. Some bone abnormalities recovered once exposure was ceased following birth; however, axillary and inguinal lymph nodes remained absent 6 months post-birth [see Use in Specific Populations (8.1)].
Of the total number of patients in clinical studies that received denosumab (n = 2841) in Studies 20050136, 20050244, and 20050103, 1271 (44%) were ≥ 65 years old, while 473 patients (17%) were ≥ 75 years old. Of the 859 patients in Study 20090482 that received denosumab, 387 patients (45%) were ≥ 65 years old, while 141 patients (16%) were ≥ 75 years old. No overall differences in safety or efficacy were observed between older and younger patients.
Two clinical trials were conducted in patients without cancer and with varying degrees of renal function.
In one study, patients (N = 55) with varying degrees of renal function (ranging from normal through end-stage renal disease requiring dialysis) received a single 60 mg subcutaneous dose of denosumab. In a second study, patients (N = 32) with severe renal dysfunction (creatinine clearance less than 30 mL/min and/or on dialysis) were given two 120 mg subcutaneous doses of denosumab. In both studies, greater risk of developing hypocalcemia was observed with increasing renal impairment, and with inadequate/no calcium supplementation. Hypocalcemia was mild to moderate in severity in 96% of patients. Monitor calcium levels and calcium and vitamin D intake [see Warnings and Precautions (5.3), Adverse Reactions (6.1), and Clinical Pharmacology (12.3)].
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