DOXERCALCIFEROL- doxercalciferol injection
Dr.Reddy's Laboratories Inc
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to useDOXERCALCIFEROL INJECTION safely and effectively.
See full prescribing information for DOXERCALCIFEROL INJECTION.
Doxercalciferol Injection, for intravenous use
Initial U.S. Approval: 1999
INDICATIONS AND USAGE
Doxercalciferol is a synthetic vitamin D2 analog:
DOSAGE AND ADMINISTRATION
Before initiating treatment, ensure serum calcium is not above the upper limit of normal. (2.1)
DOSAGE FORMS AND STRENGTHS
WARNINGS AND PRECAUTIONS
The most common adverse reactions in patients with Stage 3 or 4 CKD (incidence >5%) were infection, urinary tract infection, chest pain, angina pectoris, constipation, dyspepsia, anemia, leucopenia, dehydration, edema, depression, hypertonia, insomnia, asthenia, paresthesia, cough increased, dyspnea, pruritus, sinusitis, and rhinitis. (6.1)
The most common adverse reactions in patients with CKD on dialysis (incidence >5%) were headache, malaise, edema, nausea/vomiting, dyspnea, dizziness, pruritus, and bradycardia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Dr. REDDY’S LABORATORIES Inc., at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION.
FULL PRESCRIBING INFORMATION: CONTENTS*
- discard unused portion of the single-dose vial;
- store opened multiple-dose vial for up to 3 days at 2°C to 8°C (36°F to 46°F). Discard unused portion of multiple-dose vial after 3 days [see How Supplied/Storage and Handling (16)].
Injection: clear and colorless solution available as follows:
Doxercalciferol Injection is contraindicated in patients with:
Hypercalcemia may occur during Doxercalciferol Injection treatment. Acute hypercalcemia may increase the risk of cardiac arrhythmias and seizures and may potentiate the effect of digitalis on the heart [see Warnings and Precautions (5.2)]. Chronic hypercalcemia can lead to generalized vascular calcification and other soft-tissue calcification. Severe hypercalcemia may require emergency attention.
Hypercalcemia may be exacerbated by concomitant administration of high doses of calcium-containing preparations, thiazide diuretics, or other vitamin D compounds [see Drug Interactions (7)]. In addition, high intake of calcium and phosphate concomitantly with vitamin D compounds may lead to hypercalciuria and hyperphosphatemia. Patients with a history of hypercalcemia prior to initiating therapy may be at increased risk for development of hypercalcemia with Doxercalciferol Injection. In these circumstances, frequent serum calcium monitoring and Doxercalciferol Injection dose adjustments may be required.
When initiating Doxercalciferol Injection or adjusting Doxercalciferol Injection dose, measure serum calcium frequently (weekly in patients with CKD on dialysis or every 2 weeks for patients with stage 3 or 4 CKD). Once a maintenance dose has been established, measure serum calcium monthly for 3 months and then every 3 months. If hypercalcemia occurs, reduce the dose or discontinue Doxercalciferol Injection until serum calcium is normal [see Dosage and Administration (2)].
Inform patients about the symptoms of elevated calcium (feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination and weight loss) and instruct them to report new or worsening symptoms when they occur.
Doxercalciferol Injection can cause hypercalcemia [see Warnings and Precautions (5.1)] which increases the risk of digitalis toxicity. In patients using Doxercalciferol Injection concomitantly with digitalis compounds, monitor both serum calcium and patients for signs and symptoms of digitalis toxicity. Increase the frequency of monitoring when initiating or adjusting the dose of Doxercalciferol Injection [see Drug Interactions (7)].
Serious hypersensitivity reactions, including fatal outcome, have been reported post marketing in patients on hemodialysis following administration of Doxercalciferol Injection. Hypersensitivity reactions include anaphylaxis with symptoms of angioedema (involving face, lips, tongue and airways), hypotension, unresponsiveness, chest discomfort, shortness of breath, and cardiopulmonary arrest. These reactions may occur separately or together.
Monitor patients receiving Doxercalciferol Injection upon initiation of treatment for hypersensitivity reactions. Should a hypersensitivity reaction occur, discontinue Doxercalciferol Injection, monitor and treat if indicated [see Contraindications (4)].
Adynamic bone disease with subsequent increased risk of fractures may develop if intact PTH levels are suppressed by Doxercalciferol Injection to abnormally low levels. Monitor intact PTH levels to avoid oversuppression and adjust the Doxercalciferol Injection dose, if needed [see Dosage and Administration (2)].
The following adverse reactions are discussed in greater detail in another section of the label:
Hypercalcemia [see Warnings and Precautions (5.1)]
Serious Hypersensitivity Reactions [see Warnings and Precautions (5.3)]
Adynamic Bone Disease [see Warnings and Precautions (5.4)]
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.
Adverse reactions in patients with CKD on hemodialysis
Doxercalciferol Injection has been studied in 70 patients with CKD on hemodialysis in two 12-week, open-label, single-arm, multicenter studies [see Clinical Studies (14.3)]. The incidence of hypercalcemia and hyperphosphatemia increased during therapy with Doxercalciferol Injection. Patients with higher pretreatment serum levels of calcium (>10.5 mg/dL) or phosphorus (>6.9 mg/dL) were more likely to experience hypercalcemia or hyperphosphatemia.
There was no placebo group included in the studies of Doxercalciferol Injection. Adverse reactions in patients with CKD on hemodialysis receiving Doxercalciferol Injection are expected to be similar to those reported in placebo-controlled studies of Doxercalciferol capsules presented in Table 1.
Table 1: Adverse Reactions Occurring in ≥2% Doxercalciferol Capsule-Treated Patients with CKD on Dialysis and Greater than Placebo in Two Double-Blind Clinical Studies
|Adverse Reaction*||Doxercalciferol (n=61)%||Placebo (n=61)%|
* A patient who reported the same medical term more than once was counted only once for that medical term.
The following adverse reactions have been identified during postapproval use of Doxercalciferol Injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or to establish a causal relationship to drug exposure.
Hypersensitivity reactions, including fatal outcome, have been reported in patients on hemodialysis following administration of Doxercalciferol Injection. Hypersensitivity reactions include anaphylaxis with symptoms of angioedema (involving face, lips, tongue and airways), hypotension, unresponsiveness, chest discomfort, shortness of breath, cardiopulmonary arrest, pruritus, and skin burning sensation.
Table 2: Clinically Significant Drug Interactions with Doxercalciferol Injection
|Drugs that May Increase the Risk of Hypercalcemia|
|Clinical Impact||Concomitant administration of high doses of calcium-containing preparations or other vitamin D compounds may increase the risk of hypercalcemia. Thiazide diuretics are known to induce hypercalcemia by reducing excretion of calcium in the urine.|
|Examples||Calcium-containing products, other vitamin D compounds or thiazide diuretics|
|Intervention||Monitor serum calcium concentrations more frequently and adjust Doxercalciferol Injection dose as needed [see Warnings and Precautions (5.1)].|
|Clinical Impact||Doxercalciferol can cause hypercalcemia which can potentiate the risk of digitalis toxicity.|
|Intervention||Monitor patients for signs and symptoms of digitalis toxicity and increase frequency of serum calcium monitoring when initiating or adjusting the dose of Doxercalciferol Injection in patients receiving digitalis compounds [see Warnings and Precautions (5.2)].|
|Cytochrome P450 Inhibitors|
|Clinical Impact||Doxercalciferol is activated by CYP 27 in the liver. Cytochrome P450 inhibitors may inhibit the 25-hydroxylation of doxercalciferol and thus reduce the formation of active doxercalciferol moiety [see Clinical Pharmacology (12.3)].|
|Examples||Ketoconazole and erythromycin|
|Intervention||If a patient initiates or discontinues therapy with a cytochrome P450 inhibitor, dose adjustment of Doxercalciferol Injection may be necessary. Monitor intact PTH and serum calcium concentrations closely.|
|Clinical Impact||Doxercalciferol is activated by CYP 27 in the liver. Enzyme inducers may affect the 25-hydroxylation of doxercalciferol [see Clinical Pharmacology (12.3)].|
|Examples||Glutethimide and phenobarbital|
|Intervention||If a patient initiates or discontinues therapy with an enzyme inducer, dose adjustment of Doxercalciferol Injection may be necessary. Monitor intact PTH and serum calcium concentrations closely.|
|Clinical Impact||Concomitant administration of Doxercalciferol Injection and high doses of magnesium-containing products may increase the risk of hypermagnesemia.|
|Examples||Magnesium-containing products such as antacids|
|Intervention||Avoid use of magnesium-containing products and Doxercalciferol Injection in patients on chronic renal dialysis.|
The limited available data with Doxercalciferol Injection in pregnant women are insufficient to identify a drug-associated risk for major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with chronic kidney disease in pregnancy [see Clinical Considerations]. In reproduction studies in rats and rabbits administered doxercalciferol during organogenesis at up to 20 mcg/kg/day and 0.1 mcg/kg/day, respectively (approximately 25 times (rats) and less than (rabbits) the maximum recommended human oral dose of 60 mcg/week based on mcg/m2 body surface area), no adverse developmental effects were observed [see Data].
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Disease-associated maternal and/or embryo/fetal risk
Chronic kidney disease in pregnancy increases the risk for maternal hypertension and preeclampsia, miscarriage, preterm delivery polyhydramnios, stillbirth, and low-birth-weight infants.
There were no adverse effects on fetal development when doxercalciferol was administered at doses up to 20 mcg/kg/day in pregnant rats or doses up to 0.1 mcg/kg/day in pregnant rabbits during the period of organogenesis.
There is no information available on the presence of doxercalciferol in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Infants exposed to Doxercalciferol Injection through breast milk should be monitored for signs and symptoms of hypercalcemia [see Clinical Considerations].
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Doxercalciferol Injection and any potential adverse effects on the breastfed child from Doxercalciferol Injection or from the underlying maternal condition.
Infants exposed to Doxercalciferol Injection through breast milk should be monitored for signs and symptoms of hypercalcemia, including seizures, vomiting, constipation and weight loss. Monitoring of serum calcium in the infant should be considered.
Safety and efficacy of Doxercalciferol Injection in pediatric patients have not been established.
Clinical studies of Doxercalciferol Injection did not include sufficient numbers of patients 65 years or over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic or cardiac function, and of concomitant disease or other drug therapy.
Overdosage of Doxercalciferol Injection may lead to hypercalcemia, hypercalciuria, and hyperphosphatemia [see Warnings and Precautions (5.1)]. The treatment of acute overdosage should consist of supportive measures and discontinuation of Doxercalciferol Injection administration. Serum calcium levels should be measured until normal.
Based on similarities between doxercalciferol and its active metabolite, 1α,25-(OH)2D2, it is expected that doxercalciferol is not removed from the blood by dialysis.
Doxercalciferol Injection contains doxercalciferol, which is a synthetic vitamin D2 analog. Doxercalciferol undergoes metabolic activation in vivo to form 1α,25-dihydroxyvitamin D2 (1α,25-(OH)2D2), a naturally occurring, biologically active form of vitamin D2.
Doxercalciferol is a colorless crystalline compound with a calculated molecular weight of 412.66 and a molecular formula of C28H44O2. It is soluble in oils and organic solvents, but is relatively insoluble in water. Chemically, doxercalciferol is (1α,3β,5Z,7E,22E)-9,10-secoergosta-5,7,10(19),22-tetraene-1,3-diol. The structural formula is:
Doxercalciferol Injection 2 mL single-dose vials contain 4 mcg/2 mL (2 mcg/mL) of doxercalciferol. Each milliliter (mL) of solution contains 2 mcg doxercalciferol and the following inactive ingredients: butylated hydroxytoluene (0.02 mg); disodium edetate (1.1 mg); ethanol (0.05 mL); polysorbate 20 (10 mg); sodium chloride (1.5 mg); sodium phosphate dibasic, heptahydrate (14.4 mg); and sodium phosphate monobasic, monohydrate (1.8 mg).
Doxercalciferol Injection 2 mL multiple-dose vials contain 4 mcg/2 mL (2 mcg/mL) of doxercalciferol. Each milliliter (mL) of solution contains 2 mcg doxercalciferol and the following inactive ingredients: butylated hydroxytoluene (0.02 mg); disodium edetate (1.1 mg); ethanol (0.075 mL); polysorbate 20 (10 mg); sodium chloride (1.5 mg); sodium phosphate dibasic, heptahydrate (14.4 mg); and sodium phosphate monobasic, monohydrate (1.8 mg).
Doxercalciferol is a synthetic vitamin D2 analog that requires metabolic activation to form the active 1α,25-(OH)2D2 metabolite, which binds to the vitamin D receptor (VDR) to result in the selective activation of vitamin D responsive pathways. Vitamin D and doxercalciferol have been shown to reduce PTH levels by inhibiting PTH synthesis and secretion.
In healthy volunteers, peak blood levels of 1α,25-(OH)2D2, the major metabolite of doxercalciferol, are attained at 8 hours after a single intravenous dose of Doxercalciferol Injection.
The mean elimination half-life of 1α,25-(OH)2D2 after an oral dose is approximately 32 to 37 hours with a range of up to 96 hours.
Doxercalciferol is activated by CYP 27 in the liver to form 1α,25-(OH)2D2 (major metabolite) and 1α,24- dihydroxyvitamin D2 (minor metabolite). Activation of doxercalciferol does not require the involvement of the kidneys.
Patients with renal impairment
The mean elimination half-life of 1α,25-(OH)2D2 in patients with end-stage renal disease (ESRD) and in healthy volunteers appears to be similar following an oral dose. Hemodialysis causes a temporary increase in 1α,25- (OH)2D2 mean concentrations, presumably due to volume contraction. 1α,25-(OH)2D2 is not removed from blood during hemodialysis.
In a 104-week carcinogenicity study in rats, there was an increased incidence of benign and malignant adrenal pheochromocytomas in both males and females at oral doses of 0.04, 0.13, and 0.39 mcg/kg/day (less than the maximum recommended human oral dose of 60 mcg/week based on mcg/m2 body surface area). This increased incidence of pheochromocytomas in rats may be due to altered calcium homeostasis by doxercalciferol. No evidence of genetic toxicity was observed in an in vitro bacterial mutagenicity assay (Ames test) or a mouse lymphoma gene mutation assay. Doxercalciferol caused structural chromatid and chromosome aberrations in an in vitro human lymphocyte clastogenicity assay with metabolic activation. However, doxercalciferol was negative in an in vivo mouse micronucleus clastogenicity assay.
Doxercalciferol had no effect on male or female fertility in rats at oral doses up to 2.5 mcg/kg/day (approximately 3 times the maximum recommended human oral dose of 60 mcg/week based on mcg/m2 body surface area).
The safety and effectiveness of Doxercalciferol Injection were evaluated in two open-label, single-arm, multicenter clinical studies (Study C and Study D) in a total of 70 patients with CKD on hemodialysis. Patients in Study C were an average age of 54 years (range: 23 to 73), were 50% male, and were 61% African-American, 25% Caucasian, and 14% Hispanic, and had been on hemodialysis for an average of 65 months.
Patients in Study D were an average age of 51 years (range: 28 to 76), were 48% male, and 100% African-American and had been on hemodialysis for an average of 61 months. This group of 70 of the 138 patients who had been treated with Doxercalciferol capsules in prior clinical studies received Doxercalciferol Injection in an open-label fashion for 12 weeks following an 8-week washout (control) period.
Dosing of Doxercalciferol Injection was initiated at the rate of 4 mcg administered at the end of each dialysis session (3 times weekly) for a total of 12 mcg per week. The dosage of Doxercalciferol Injection was adjusted to achieve intact PTH levels (measured weekly) within a targeted range of 150 pg/mL to 300 pg/mL. The dosage was increased by 2 mcg per dialysis session after 8 weeks of treatment if the intact PTH levels remained above 300 pg/mL and were greater than 50% of baseline levels. The maximum dosage was limited to 18 mcg per week. If at any time during the study intact PTH fell below 150 pg/mL, Doxercalciferol Injection was immediately suspended and restarted at a lower dosage the following week. Mean weekly doses ranged from ranged from 9 mcg to 13 mcg in Study C and ranged from 9 mcg to 12 mcg in Study D.
Fifty-two (74%) of the 70 patients who were treated with Doxercalciferol Injection achieved intact PTH levels ≤300 pg/mL. Forty-one (59%) of these patients exhibited plasma intact PTH levels ≤300 pg/mL on at least 3 occasions. Thirty-six (51%) patients had plasma intact PTH levels <150 pg/mL on at least one occasion during study participation. Decreases in plasma intact PTH from baseline values were calculated using as baseline the average of the last 3 values obtained during the 8-week washout period and are displayed in Table 3.
Table 3: Intact PTH Summary Data for Patients with CKD on Dialysis Receiving Doxercalciferol Injection in Studies C and D
|Intact PTH Level||Study C(n=28)||Study D(n=42)||Combined Protocols(n=70)|
|Baseline (Mean of Weeks -2, -1, and 0)|
|Mean (SE)||698 (60)||762 (65)||736 (46)|
|On-treatment (Week 12 ⃰ )|
|Mean (SE)||406 (63)||426 (60)||418 (43)|
|Change from Baseline†|
|Mean (SE)||-292 (55)||-336 (41)||-318 (33)|
* Values were carried forward for the two patients on study for 10 weeks
†Treatment intact PTH minus baseline intact PTH
‡Wilcoxon one-sample test
Doxercalciferol Injection treatment resulted in at least 30% reduction from baseline in mean intact PTH levels during the 12-week open-label treatment period in more than 92% of the 70 treated patients.
Doxercalciferol Injection is a clear, colorless solution supplied in 2 mL amber glass vials as follows.
|Total Strengthper Total Volume||Strength
|Vial Count per Carton × Total
Vial Volume and Vial Type
|Carton NDC||Vial NDC|
|4 mcg/2 mL||2 mcg/mL||50 × 2 mL multiple-dose vials||43598-850-50||43598-850-11|
Storage and Handling
|Dosage Form||Storage temperature||Excursions permitted to||In-use storage|
|Single-dose vial*||20º to 25°C (68º to 77°F)||[see USP controlled room temperature]||Discard unused portion|
|Multiple-dose vial*||25°C (77°F)||15°C to 30°C (59°F to 86°F)[see USP controlled room temperature]||2°C to 8°C (36°F to 46°F),Discard 3 days after opening|
*Protect from light. Store unopened vial in original carton.
Advise patients to contact a health care provider if they develop symptoms of elevated calcium (e.g. feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination and weight loss) [see Warnings and Precautions (5.1)].
Inform patients that hypersensitivity reactions can occur with Doxercalciferol Injection [see Warnings and Precautions (5.3)].
Inform patients that they will need routine monitoring of laboratory parameters such as calcium and intact PTH while receiving Doxercalciferol Injection. Inform patients that more frequent monitoring is necessary during the initiation of therapy, following dose changes or when potentially interacting medications are started or discontinued [see Dosage and Administration (2), Drug Interactions (7)].
Advise patients to inform their physician of all medications, including prescription and nonprescription drugs, and supplements they are taking. Advise patients to also inform their physician that they are receiving Doxercalciferol Injection if a new medication is prescribed [see Drug Interactions (7)].
|Labeler - Dr.Reddy's Laboratories Inc (802315887)|
|GLAND PHARMA LIMITED||918601238||analysis(43598-850) , manufacture(43598-850)|