Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1769
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ZEMPLAR (Injection, Solution)
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The currently accepted target range for iPTH levels
in CKD Stage 5 patients is no more than 1.5 to 3 times the non-uremic
upper limit of normal. The recommended initial
dose of Zemplar is 0.04 mcg/kg to 0.1 mcg/kg (2.8���7 mcg) administered
as a bolus dose no more frequently than every other day at any time during
dialysis. If a satisfactory response is not observed,
the dose may be increased by 2 to 4 mcg at 2- to 4-week intervals. During
any dose adjustment period, serum calcium and phosphorus levels should be
monitored more frequently, and if an elevated calcium level or a Ca��P product greater than 75 is noted, the drug dosage should be immediately
reduced or interrupted until these parameters are normalized. Then, Zemplar
should be reinitiated at a lower dose. If a patient is on a calcium-based
phosphate binder, the dose may be decreased or withheld, or the patient may
be switched to a non-calcium-based phosphate binder. Zemplar doses may need
to be decreased as the PTH levels decrease in response to therapy. Thus,
incremental dosing must be individualized. The
following table is a suggested approach in dose titration: The influence of mild to moderately impaired hepatic
function on paricalcitol pharmacokinetics is sufficiently small that no dosing
adjustment is required. Parenteral drug products
should be inspected visually for particulate matter and discoloration prior
to administration whenever solution and container permit. Discard unused portion.
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Paricalcitol, USP, the active ingredient in Zemplar
Injection, is a synthetically manufactured analog of calcitriol, the metabolically
active form of vitamin D indicated for the prevention and treatment of secondary
hyperparathyroidism associated with chronic kidney disease(CKD) Stage 5.
Zemplar is available as a sterile, clear, colorless, aqueous solution for
intravenous injection. Each mL contains paricalcitol, 2 mcg or 5 mcg; propylene
glycol, 30% (v/v); and alcohol, 20% (v/v). Paricalcitol
is a white powder chemically designated as 19-nor-1��,3��,25-trihydroxy-9,10-secoergosta-5(Z),7(E),22(E)-triene
and has the following structural formula: Molecular formula is CHO. Molecular weight is 416.64.
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Secondary hyperparathyroidism is characterized by
an elevation in parathyroid hormone (PTH) associated with inadequate levels
of active vitamin D hormone. The source of vitamin D in the body is from
synthesis in the skin and from dietary intake. Vitamin D requires two sequential
hydroxylations in the liver and the kidney to bind to and to activate the
vitamin D receptor (VDR). The endogenous VDR activator, calcitriol [1,25(OH)D],
is a hormone that binds to VDRs that are present in the parathyroid gland,
intestine, kidney, and bone to maintain parathyroid function and calcium and
phosphorus homeostasis, and to VDRs found in many other tissues, including
prostate, endothelium and immune cells. VDR activation is essential for the
proper formation and maintenance of normal bone. In the diseased kidney,
the activation of vitamin D is diminished, resulting in a rise of PTH, subsequently
leading to secondary hyperparathyroidism, and disturbances in the calcium
and phosphorus homeostasis.The decreased levels of 1,25(OH)Dand resultant elevated PTH levels, both of which often precede abnormalities
in serum calcium and phosphorus, affect bone turnover rate and may result
in renal osteodystrophy.<br/>Mechanism of Action: Paricalcitol is a synthetic, biologically active
vitamin D analog of calcitriol with modifications to the side chain (D)
and the A (19-nor) ring. Preclinical and in
vitro studies have demonstrated that paricalcitol's biological
actions are mediated through binding of the VDR, which results in the selective
activation of vitamin D responsive pathways. Vitamin D and paricalcitol have
been shown to reduce parathyroid hormone levels by inhibiting PTH synthesis
and secretion.<br/>Pharmacokinetics: Within two hours after administering Zemplar intravenous
doses ranging from 0.04 to 0.24 mcg/kg, concentrations of paricalcitol decreased
rapidly; thereafter, concentrations of paricalcitol declined log-linearly.
No accumulation of paricalcitol was observed with multiple dosing.<br/>Distribution: Paricalcitol is extensively bound to plasma proteins
(���99.8%). In healthy subjects, the steady state volume of distribution
is approximately 23.8 L. The mean apparent volume of distribution following
a 0.24 mcg/kg dose of paricalcitol in CKD Stage 5 subjects requiring hemodialysis
(HD) and peritoneal dialysis (PD) is between 31 and 35 L.<br/>Metabolism: After IV administration of a 0.48 mcg/kg dose
ofH-paricalcitol, parent drug was extensively metabolized, with
only about 2% of the dose eliminated unchanged in the feces and no parent
drug found in the urine. Several metabolites were detected in both the urine
and feces. Most of the systemic exposure was from the parent drug. Two
minor metabolites, relative to paricalcitol, were detected in human plasma.
One metabolite was identified as 24(R)-hydroxy paricalcitol, while the other
metabolite was unidentified. The 24(R)-hydroxy paricalcitol is less active
than paricalcitol in an in vivo rat
model of PTH suppression. In vitro data suggest that paricalcitol is metabolized
by multiple hepatic and non-hepatic enzymes, including mitochondrial CYP24,
as well as CYP3A4 and UGT1A4. The identified metabolites include the product
of 24(R)-hydroxylation (present at low levels in plasma), as well as 24,26-
and 24,28-dihydroxylation and direct glucuronidation.<br/>Elimination: Paricalcitol is excreted primarily by hepatobiliary
excretion. Approximately 63% of the radioactivity was eliminated in the feces
and 19% was recovered in the urine in healthy subjects. In healthy subjects,
the mean elimination half-life of paricalcitol is about five to seven hours
over the studied dose range of 0.04 to 0.16 mcg/kg. The pharmacokinetics
of paricalcitol has been studied in CKD Stage 5 subjects requiring hemodialysis
(HD) and peritoneal dialysis (PD). The mean elimination half-life of paricalcitol
after administration of 0.24 mcg/kg paricalcitol IV bolus dose in CKD Stage
5 HD and PD patients is 13.9 and 15.4 hours, respectively (Table 1). The degree of accumulation was consistent with
the half-life and dosing frequency.<br/>Special Populations:<br/>Drug Interactions: An in vitro study
indicates that paricalcitol is not an inhibitor of CYP1A2, CYP2A6, CYP2B6,
CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A at concentrations up to
50 nM (21 ng/mL) (approximately 20-fold greater than that obtained after highest
tested dose). In fresh primary cultured hepatocytes, the induction observed
at paricalcitol concentrations up to 50 nM was less than two-fold for CYP2B6,
CYP2C9 or CYP3A, where the positive controls rendered a six- to nineteen-fold
induction. Hence, paricalcitol is not expected to inhibit or induce the clearance
of drugs metabolized by these enzymes. Drug
interactions with paricalcitol injection have not been studied.<br/>Omeprazole: The pharmacokinetic interaction between paricalcitol
capsule (16 mcg) and omeprazole (40 mg; oral) was investigated in a single
dose, crossover study in healthy subjects. The pharmacokinetics of paricalcitol
were unaffected when omeprazole was administrated approximately 2 hours prior
to the paricalcitol dose.<br/>Ketoconazole: Although no data are available for the drug interaction
between paricalcitol injection and ketoconazole, the effect of multiple doses
of ketoconazole administered as 200 mg BID for 5 days on the pharmacokinetics
of paricalcitol capsule has been studied in healthy subjects. The Cof
paricalcitol was minimally affected, but AUCapproximately
doubled in the presence of ketoconazole. The mean half-life of paricalcitol
was 17.0 hours in the presence of ketoconazole as compared to 9.8 hours, when
paricalcitol was administered alone (See PRECAUTIONS).
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Zemplar should not be given to patients with evidence
of vitamin D toxicity, hypercalcemia, or hypersensitivity to any ingredient
in this product (see WARNINGS).
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Zemplar Injection is available as 2 mcg/mL (NDC 0074-4637-01) and 5 mcg/mL (NDC 0074-1658-01 and NDC 0074-1658-02). Store at 25��C (77��F). Excursions permitted
between 15��- 30��C (59��- 86��F). U.S.
patents: 5,246,925; 5,587,497; 6,136,799; 6,361,758
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Overdosage of Zemplar may lead to hypercalcemia, hypercalciuria,
hyperphosphatemia, and over suppression of PTH. (see WARNINGS).<br/>Treatment of Overdosage and Hypercalcemia: The treatment of acute overdosage should consist
of general supportive measures. Serial serum electrolyte determinations (especially
calcium), rate of urinary calcium excretion, and assessment of electrocardiographic
abnormalities due to hypercalcemia should be obtained. Such monitoring is
critical in patients receiving digitalis. Discontinuation of supplemental
calciumand institution of a low calcium diet are also indicated in acute
overdosage. General treatment of hypercalcemia
due to overdosage consists of immediate suspension of Zemplar therapy, institution
of a low calcium diet, and withdrawal of calcium supplements. Serum calcium
levels should be determined at least weekly until normocalcemia ensues. When
serum calcium levels have returned to within normal limits, Zemplar may be
reinitiated at a lower dose. If persistent and markedly elevated serum calcium
levels occur, there are a variety of therapeutic alternatives that may be
considered. These include the use of drugs such as phosphates and corticosteroids
as well as measures to induce diuresis. Also, one may consider dialysis against
a calcium-free dialysate.
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paricalcitol
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ZEMPLAR (Injection, Solution)
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Zemplar has been evaluated for safety in clinical
studies in 454 CKD Stage 5 patients. In four, placebo-controlled, double-blind,
multicenter studies, discontinuation of therapy due to any adverse event occurred
in 6.5% of 62 patients treated with Zemplar (dosage titrated as tolerated,
see CLINICAL PHARMACOLOGY - Clinical Studies)
and 2.0% of 51 patients treated with placebo for 1to 3 months. Adverse
events occurring with greater frequency in the Zemplar group at a frequency
of 2% or greater, regardless of causality, are presented in the following
table: A patient who reported the same medical term more
than once was counted only once for that medical term. Safety
parameters (changes in mean Ca, P, Ca��P) in an open-label safety study
up to 13 months in duration support the long-term safety of Zemplar in
this patient population. Potential adverse events
of Zemplar Injection are, in general, similar to those encountered with excessive
vitamin D intake. Signs and symptoms of vitamin D intoxication associated
with hypercalcemia include:<br/>Early: Weakness, headache, somnolence, nausea, vomiting,
dry mouth, constipation, muscle pain, bone pain, and metallic taste.<br/>Late: Anorexia, weight loss, conjunctivitis (calcific),
pancreatitis, photophobia, rhinorrhea, pruritus, hyperthermia, decreased libido,
elevated BUN, hypercholesterolemia, elevated AST and ALT, ectopic calcification,
hypertension, cardiac arrhythmias, somnolence, death, and rarely, overt psychosis.<br/>Adverse Events During Post-marketing Experience: Taste perversion, such as metallic taste, and allergic
reactions, such as rash, urticaria, pruritus, facial and oral edema rarely
have been reported.
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Acute overdose of Zemplar may cause hypercalcemia,
and require emergency attention. During dose adjustment, serum calcium and
phosphorus levels should be monitored closely (e.g., twice weekly). If clinically
significant hypercalcemia develops, the dose should be reduced or interrupted.
Chronic administration of Zemplar may place patients at risk of hypercalcemia,
elevated Ca��P product, and metastatic calcification. Treatment of patients with clinically significant hypercalcemia
consists of immediate dose reduction or interruption of Zemplar therapy and
includes a low calcium diet, withdrawal of calcium supplements, patient mobilization,
attention to fluid and electrolyte imbalances, assessment of electrocardiographic
abnormalities (critical in patients receiving digitalis), hemodialysis or
peritoneal 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.
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| dailymed-instance:indicatio... |
Zemplar is indicated for the prevention and treatment
of secondary hyperparathyroidism associated with chronic kidney disease Stage
5.
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ZEMPLAR
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