Zemplar™
(paricalcitol injection)
Fliptop Vial
DESCRIPTION
Zemplar™ (paricalcitol injection) is a synthetically manufactured vitamin D analog. It is available as a sterile, clear, colorless, aqueous solution for intravenous injection. Each mL contains paricalcitol, 5 mcg; propylene glycol, 30% (v/v); and alcohol, 20% (v/v).
Paricalcitol is a white powder chemically designated as
19-nor-1a,3ß,25-trihydroxy-9,10-coergosta-5(Z),7(E),22(E)-triene and has the following structural formula:
Molecular weight is 416.65.
CLINICAL PHARMACOLOGY
Mechanism of Action
Paricalcitol is a synthetic vitamin D analog. Vitamin D and paricalcitol have been shown to reduce parathyroid hormone (PTH) levels.
Pharmacokinetics
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Distribution
The pharmacokinetics of paricalcitol have been studied in patients with chronic renal failure (CRF) requiring hemodialysis.Zemplar™ is administered as an intravenous bolus injection. Within two hours after administering dos ranging from 0.04 to 0.24 mcg/kg, concentrations of paricalcitol decread rapidly; thereafter, concentrations of paricalcitol declined log-linearly with a mean half-life of about 15 hours. No accumulation of paricalcitol was obrved with multiple dosing.
Elimination
In healthy subjects, plasma radioactivity after a single 0.16 mcg/kg intravenous bolus do of3H-paricalcitol (n=4) was attributed to parent drug. Paricalcitol was eliminated primarily by hepatobiliary excretion, as 74% of the radioactive do was recovered in feces and only 16%was found in urine.
Metabolism
Several unknown metabolites were detected in both the urine and feces, with no detectable paricalcitol in the urine. The metabolites have not been characterized and have not been identified. Together, the metabolites contributed 51% of the urinary radioactivity and 59%
of the fecal radioactivity.In vitro plasma protein binding of paricalcitol was extensive (>99.9%) and nonsaturable over the concentration range of 1 to 100 ng/mL.
Paricalcitol Pharmacokinetic Characteristics in CRF Patients (0.24 mcg/kg do) Parameter n Values (Mean ± SD) .
C max (5 min. after bolus)6 1850 ± 664 (pg/mL)ware
AUC0- 527382 ± 8230 (pg•hr/mL)
CL5 0.72 ± 0.24 (L/hr)
V ss5 6 ± 2 (L)
Laboratory Tests
In placebo-controlled studies, paricalcitol reduced rum total alkaline phosphata levels. Special Populations
Paricalcitol pharmacokinetics have not been investigated in special populations (geriatric, pediatric, hepatic insufficiency), or for drug-drug interactions. Pharmacokinetics were not gender-dependent.
Clinical Studies
In three 12-week, placebo-controlled, pha 3 studies in chronic renal failure patients on dialysis, the do of Zemplar™ was started at 0.04 mcg/kg 3 times per week. The do was incread by 0.04 mcg/kg every 2 weeks until intact parathyroid hormone (iPTH) levels were decread at least 30% from baline or a fifth escalation brought the do to 0.24 mcg/kg, or iPTH fell to less than 100 pg/mL, or the Ca x P product was greater than 75 within any 2 week period, or rum calcium became greater than 11.5 mg/dL at any time.
Patients treated with Zemplar™ achieved a mean iPTH reduction of 30% within 6 weeks. In the studies, there was no significant difference in the incidence of hypercalcemia or hyperphosphatemia between Zemplar™ and placebo-treated patients. The results from the studies are as follows:
Mean (SE) Change Group Baline Mean From Baline to (No. of Pts.) (Range)Final Evaluation PTH (pg/mL)Zemplar™ (n=40)783 (291 – 2076)-379 (43.7) .
placebo (n=38)745 (320 – 1671) -69.6 (44.8) . Alkaline Zemplar™ (n=31)150 (40 – 600) -41.5 (10.6) . Phosphata (U/L)placebo (n=34)169 (56 – 911) +2.6 (10.1) . Calcium (mg/dL)Zemplar
™ (n=40) 9.3 (7.2 – 10.4) +0.47 (0.1) .
placebo (n=38) 9.1 (7.8 – 10.7) +0.02 (0.1) . Phosphorus (mg/dL)Zemplar™ (n=40) 5.8 (3.7 – 10.2) +0.47 (0.3) .
英文简历怎么写
placebo (n=38) 6.0 (2.8 – 8.8) -0.47 (0.3) . Calcium x Zemplar™ (n=40) 54 (32 – 106) +7.9 (2.2) . Phosphorus Product placebo (n=38) 54 (26 – 77) -3.9 (2.3) .
A long-term, open-label safety study of 164 CRF patients (mean do of 7.5 mcg three times per week), demonstrated that mean rum Ca, P, and Ca x P remained within clinically appropriate ranges with PTH reduction (mean decrea of 323 pg/mL at 13 months).
INDICATIONS AND USAGE
betrothZemplar™ is indicated for the prevention and treatment of condary hyperparathyroidism associated with chronic renal failure. Studies in patients with chronic renal failure show that Zemplar™ suppress PTH levels with no significant difference in the incidence of hypercalcemia or hyperphosphatemia when compared to placebo. However, the rum phosphorus, calcium and calcium x phosphorus product (Ca x P) may increa when Zemplar™ is administered.
CONTRAINDICATIONS
Zemplar™ should not be given to patients with evidence of vitamin D toxicity, hypercalcemia, or hypernsitivity to any ingredient in this product (e PRECAUTIONS, General).
WARNINGS
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Acute overdo of Zemplar™ may cau hypercalcemia, and require emergency attention. During do adjustment, rum calcium and phosphorus levels should be monitored cloly (e.g., twice weekly). If clinically significant hypercalcemia develops, the do should be reduced or interrupted. Chronic administration of Zemplar™ may place patients at risk of
hypercalcemia, elevated Ca x P product, and metastatic calcification. Signs and symptoms of vitamin D intoxication associated with hypercalcemia include:
Early
Weakness, headache, somnolence, naua, vomiting, dry mouth, constipation, muscle pain, bone pain, and metallic taste.
Late
Anorexia, weight loss, conjunctivitis (calcific),pancreatitis, photophobia, rhinorrhea, pruritus,hyperthermia, decread libido, elevated BUN, hypercholesterolemia, elevated AST and ALT, ectopic calcification, hypertension, cardiac arrhythmias, somnolence, death, and, rarely, overt psychosis.
cnn向港警道歉Treatment of patients with clinically significant hypercalcemia consists of immediate do reduction or interruption of Zemplar™ therapy and includes a low calcium diet, withdrawal of calcium supplements, patient mobilization, attention to fluid and electrolyte imbalances, asssment of electrocardiographic abnormalities (critical in patients receiving digitalis), and hemodialysis or periton
eal dialysis against a calcium-free dialysate, as warranted. Serum calcium levels should be monitored frequently until normocalcemia ensues.
Phosphate or vitamin D-related compounds should not be taken concomitantly with Zemplar™.
PRECAUTIONS
General: Digitalis toxicity is potentiated by hypercalcemia of any cau, so caution should be applied when digitalis compounds are prescribed concomitantly with Zemplar™. Adynamic bone lesions may develop if PTH levels are suppresd to abnormal levels. Information for the Patient: The patient should be instructed that, to ensure effectiveness of Zemplar™ therapy, it is important to adhere to a dietary regimen of calcium supplementation and phosphorus restriction. Appropriate types of phosphate-binding compounds may be needed to control rum phosphorus levels in patients with chronic renal failure (CRF), but excessive u of aluminum containing compounds should be avoided. Patients should also be carefully informed about the symptoms of elevated calcium.
Esntial Laboratory Tests:During the initial pha of medication, rum calcium and phosphorus should be determined frequently (e.g., twice weekly). Once dosage has been established, rum calcium and phosphorus should be measured at least monthly. Measurements of rum or plasma P
TH are recommended every 3 months. An intact PTH (iPTH) assay is recommended for reliable detection of biologically active PTH in patients with CRF. During do adjustment of Zemplar™, laboratory tests may be required more frequently.
Drug Interactions:Specific interaction studies were not performed. Digitalis toxicity is potentiated by hypercalcemia of any cau, so caution should be applied when digitalis compounds are prescribed concomitantly with Zemplar™.
Carcinogenesis,Mutagenesis, Impairment of Fertility:Long-term studies in animals to evaluate the carcinogenic potential of paricalcitol have not been completed. Paricalcitol did not exhibit genetic toxicity in vitro with or without metabolic activation in the microbial mutagenesis assay (Ames Assay), mou lymphoma mutagenesis assay (L5178Y), or a human lymphocyte cell chromosomal aberration assay. There was also no evidence of genetic toxicity in an in vivo mou micronucleus assay. Zemplar™ had no effect on fertility (male or female) in rats at intravenous dos up to 20 mcg/kg/do [equivalent to 13 times the highest recommended human do (0.24 mcg/kg) bad on surface area, mg/m2]. Pregnancy:Pregnancy Category C.Paricalcitol has been shown to cau minimal decreas in fetal viability (5%) when administered daily to rabbits at a do 0.5 times the
0.24mcg/kg human do (bad on surface area, mg/m2) and when administered to rats at
a do 2 times the 0.24 mcg/kg human do (bad on plasma levels of exposure). At the highest do tested (20 mcg/kg 3 times per week in rats,
韩国的英文怎么写13 times the 0.24 mcg/kg human do bad on surface area), there was a significant increa of the mortality of newborn rats at dos that were maternally toxic (hypercalcemia). No other effects on offspring development were obrved. Paricalcitol was not teratogenic at the dos tested.
There are no adequate and well-controlled studies in pregnant women. Zemplar™ should be ud during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: It is not known whether paricalcitol is excreted in human milk. Becau many drugs are excreted in human milk, caution should be exercid when Zemplar™ is administered to a nursing woman.
Pediatric U:Safety and efficacy of Zemplar™ in pediatric patients have not been established.
Geriatric U:Of the 40 patients receiving Zemplar™ in the three pha 3 placebo-controlled CRF studies, 10 patients were 65 years or over. In the studies, no overall differences in efficacy or safety were obrved between patients 65 years or older and younger patients.
ADVERSE REACTIONS
Zemplar™ has been evaluated for safety in clinical studies in 454 CRF patients.
In four, placebo-controlled, double-blind, multicenter studies, discontinuation of therapy due to any adver event occurred in 6.5% of 62 patients treated with Zemplar™ (dosage titrated as tolerated, e CLINICAL PHARMACOLOGY, Clinical Studies) and 2.0% of 51 patients treated with placebo for one to three months. Adver events occurring with greater frequency in the Zemplar™ group at a frequency of 2% or greater, regardless of causality, are prented in the following table:
Adver Event Incidence Rates for All Treated Patients
In All Placebo-Controlled Studies
Zemplar™ (n=62)Placebo (n=51)
Adver Event number of events, %number of events, % Overall7178 .
断章取义英文Body as a Whole
Chills5 0
Feeling unwell3 0
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Fever5 2
Flu5 4
Sepsis5 2
Cardiovascular System
Palpitation3 0
Digestive System
Dry mouth3 2
Gastrointestinal bleeding5 2
Naua 13 8
Vomiting8 4
Metabolic and Nutritional Disorders
Edema7 0
Nervous System
Light-headedness5 2
Respiratory System
Pneumonia5 0
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