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Calcitriol
Overview
What is Calcitriol?
Calcitriol is a synthetic vitamin D analog which is active in the
regulation of the absorption of calcium from the gastrointestinal tract and its
utilization in the body. It is available as capsules containing 0.25 mcg or 0.5
mcg calcitriol. Each capsule also contains the following inactive ingredients:
butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) as
antioxidants, and triglycerides (medium chain). Gelatin capsule shell contains
gelatin, glycerol, mannitol, red iron oxide, sorbitanhydrides, sorbitol,
superior polyols, titanium dioxide and yellow iron oxide. Imprinting ink
contains ammonium hydroxide, isopropyl alcohol, propylene glycol, shellac and
titanium dioxide.
CHOM.W. 416.65
The other names frequently used for calcitriol are
1α,25-dihydroxycholecalciferol, 1,25- dihydroxyvitamin D, 1,25-DHCC, 1,25(OH)D and 1,25-diOHC.
What does Calcitriol look like?
What are the available doses of Calcitriol?
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What should I talk to my health care provider before I take Calcitriol?
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How should I use Calcitriol?
Calcitriol is indicated in the management of secondary
hyperparathyroidism and resultant metabolic bone disease in patients with
moderate to severe chronic renal failure (C 15 to 55
mL/min) not yet on dialysis. In children, the creatinine clearance value must be
corrected for a surface area of 1.73 square meters. A serum iPTH level of ≥ 100
pg/mL is strongly suggestive of secondary hyperparathyroidism.
Calcitriol is indicated in the management of hypocalcemia and the
resultant metabolic bone disease in patients undergoing chronic renal dialysis.
In these patients, calcitriol administration enhances calcium absorption,
reduces serum alkaline phosphatase levels, and may reduce elevated parathyroid
hormone levels and the histological manifestations of osteitis fibrosa cystica
and defective mineralization.
Calcitriol is also indicated in the management of hypocalcemia
and its clinical manifestations in patients with postsurgical
hypoparathyroidism, idiopathic hypoparathyroidism, and pseudohypoparathyroidism.
The optimal daily dose of calcitriol capsules must be carefully
determined for each patient. Calcitriol can be administered orally as a capsule
(0.25 mcg or 0.50 mcg). Calcitriol therapy should always be started at the
lowest possible dose and should not be increased without careful monitoring of
serum calcium.
The effectiveness of calcitriol capsule therapy is predicated on the
assumption that each patient is receiving an adequate but not excessive daily
intake of calcium. Patients are advised to have a dietary intake of calcium at a
minimum of 600 mg daily. The U.S. RDA for calcium in adults is 800 mg to 1200
mg. To ensure that each patient receives an adequate daily intake of calcium,
the physician should either prescribe a calcium supplement or instruct the
patient in proper dietary measures.
Because of improved calcium absorption from the gastrointestinal tract, some
patients on calcitriol may be maintained on a lower calcium intake. Patients who
tend to develop hypercalcemia may require only low doses of calcium or no
supplementation at all.
During the titration period of treatment with calcitriol, serum calcium
levels should be checked at least twice weekly. When the optimal dosage of
calcitriol has been determined, serum calcium levels should be checked every
month (or as given below for individual indications). Samples for serum calcium
estimation should be taken without a tourniquet.
The recommended initial dose of calcitriol capsules is 0.25
mcg/day. If a satisfactory response in the biochemical parameters and clinical
manifestations of the disease state is not observed, dosage may be increased by
0.25 mcg/day at 4 to 8 week intervals. During this titration period, serum
calcium levels should be obtained at least twice weekly, and if hypercalcemia is
noted, the drug should be immediately discontinued until normocalcemia ensues
(see , ).
Phosphorus, magnesium, and alkaline phosphatase should be determined
periodically.
Patients with normal or only slightly reduced serum calcium levels may
respond to calcitriol capsule doses of 0.25 mcg every other day. Most patients
undergoing hemodialysis respond to doses between 0.5 and 1 mcg/day.
Oral calcitriol capsules may normalize plasma ionized calcium in some uremic
patients, yet fail to suppress parathyroid hyperfunction. In these individuals
with autonomous parathyroid hyperfunction, oral calcitriol capsules may be
useful to maintain normocalcemia, but have not been shown to be adequate
treatment for hyperparathyroidism.
The recommended initial dosage of calcitriol capsules is 0.25
mcg/day given in the morning. If a satisfactory response in the biochemical
parameters and clinical manifestations of the disease is not observed, the dose
may be increased at 2 to 4 week intervals. During the dosage titration period,
serum calcium levels should be obtained at least twice weekly and, if
hypercalcemia is noted, calcitriol capsules should be immediately discontinued
until normocalcemia ensues (see , ). Careful consideration should also be given to
lowering the dietary calcium intake. Serum calcium, phosphorus, and 24 hour
urinary calcium should be determined periodically.
Most adult patients and pediatric patients age 6 years and older have
responded to dosages in the range of 0.5 mcg to 2 mcg daily. Pediatric patients
in the 1 to 5 year age group with hypoparathyroidism have usually been given
0.25 mcg to 0.75 mcg daily. The number of treated patients with
pseudohypoparathyroidism less than 6 years of age is too small to make dosage
recommendations.
Malabsorption is occasionally noted in patients with hypoparathyroidism;
hence, larger doses of calcitriol may be needed.
The recommended initial dosage of calcitriol is 0.25 mcg/day in
adults and pediatric patients 3 years of age and older. This dosage may be
increased if necessary to 0.5 mcg/day.
For pediatric patients less than 3 years of age, the recommended initial
dosage of calcitriol is 10 to 15 ng/kg/day.
What interacts with Calcitriol?
Calcitriol capsules should not be given to patients with hypercalcemia or evidence of vitamin D toxicity. Use of calcitriol capsules in patients with known hypersensitivity to calcitriol (or drugs of the same class) or any of the inactive ingredients is contraindicated.
What are the warnings of Calcitriol?
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Overdosage of any form of vitamin D is dangerous (see ). Progressive hypercalcemia due to overdosage of
vitamin D and its metabolites may be so severe as to require emergency
attention. Chronic hypercalcemia can lead to generalized vascular calcification,
nephrocalcinosis and other soft-tissue calcification. Radiographic
evaluation of suspect anatomical regions may be useful in the early detection of
this condition.
Calcitriol is the most potent metabolite of vitamin D available. The
administration of calcitriol to patients in excess of their daily requirements
can cause hypercalcemia, hypercalciuria, and hyperphosphatemia. Therefore,
pharmacologic doses of vitamin D and its derivatives should be withheld during
calcitriol treatment to avoid possible additive effects and hypercalcemia. If
treatment is switched from ergocalciferol (vitamin D) to
calcitriol, it may take several months for the ergocalciferol level in the blood
to return to the baseline value (see ).
Calcitriol increases inorganic phosphate levels in serum. While this is
desirable in patients with hypophosphatemia, caution is called for in patients
with renal failure because of the danger of ectopic calcification. A
non-aluminum phosphate-binding compound and a low-phosphate diet should be used
to control serum phosphorus levels in patients undergoing dialysis.
Magnesium-containing preparations (e.g., antacids) and calcitriol should not
be used concomitantly in patients on chronic renal dialysis because such use may
lead to the development of hypermagnesemia.
Studies in dogs and rats given calcitriol for up to 26 weeks have shown that
small increases of calcitriol above endogenous levels can lead to abnormalities
of calcium metabolism with the potential for calcification of many tissues in
the body.
What are the precautions of Calcitriol?
Excessive dosage of calcitriol induces hypercalcemia and in some
instances hypercalciuria; therefore, early in treatment during dosage
adjustment, serum calcium should be determined twice weekly. In dialysis
patients, a fall in serum alkaline phosphatase levels usually antedates the
appearance of hypercalcemia and may be an indication of impending hypercalcemia.
An abrupt increase in calcium intake as a result of changes in diet (e.g.,
increased consumption of dairy products) or uncontrolled intake of calcium
preparations may trigger hypercalcemia.
Should hypercalcemia develop, treatment with calcitriol should be stopped
immediately. During periods of hypercalcemia, serum calcium and phosphate levels
must be determined daily. When normal levels have been attained, treatment with
calcitriol can be continued, at a daily dose 0.25 mcg lower than that previously
used. An estimate of daily dietary calcium intake should be made and the intake
adjusted when indicated. Calcitriol should be given cautiously to patients on
digitalis, because hypercalcemia in such patients may precipitate cardiac
arrhythmias.
Immobilized patients, e.g., those who have undergone surgery, are
particularly exposed to the risk of hypercalcemia.
In patients with normal renal function, chronic hypercalcemia may be
associated with an increase in serum creatinine. While this is usually
reversible, it is important in such patients to pay careful attention to those
factors which may lead to hypercalcemia. Calcitriol therapy should always be
started at the lowest possible dose and should not be increased without careful
monitoring of the serum calcium. An estimate of daily dietary calcium intake
should be made and the intake adjusted when indicated.
Patients with normal renal function taking calcitriol should avoid
dehydration. Adequate fluid intake should be maintained.
The patient and his or her caregivers should be informed about
compliance with dosage instructions, adherence to instructions about diet and
calcium supplementation, and avoidance of the use of unapproved nonprescription
drugs. Patients and their caregivers should also be carefully informed about the
symptoms of hypercalcemia (see ).
The effectiveness of calcitriol therapy is predicated on the assumption that
each patient is receiving an adequate daily intake of calcium. Patients are
advised to have a dietary intake of calcium at a minimum of 600 mg daily. The
U.S. RDA for calcium in adults is 800 mg to 1200 mg.
For dialysis patients, serum calcium, phosphorus, magnesium, and
alkaline phosphatase should be determined periodically. For hypoparathyroid
patients, serum calcium, phosphorus, and 24 hour urinary calcium should be
determined periodically. For predialysis patients, serum calcium, phosphorus,
alkaline phosphatase, creatinine, and intact PTH (iPTH) should be determined
initially. Thereafter, serum calcium, phosphorus, alkaline phosphatase, and
creatine should be determined monthly for a 6 month period and then determined
periodically. Intact PTH (iPTH) should be determined periodically every 3 to 4
months at the time of visits. During the titration period of treatment with
calcitriol, serum calcium levels should be checked at least twice weekly (see
).
Cholestyramine has been reported to reduce intestinal absorption
of fat-soluble vitamins; as such it may impair intestinal absorption of
calcitriol. (see and , ).
The coadministration of phenytoin or phenobarbital will not
affect plasma concentrations of calcitriol, but may reduce endogenous plasma
levels of 25(OH)D by accelerating metabolism. Since
blood level of calcitriol will be reduced, higher doses of calcitriol may be
necessary if these drugs are administered simultaneously.
Thiazides are known to induce hypercalcemia by the reduction of
calcium excretion in urine. Some reports have shown that the concomitant
administration of thiazides with calcitriol causes hypercalcemia. Therefore,
precaution should be taken when coadministration is necessary.
Calcitriol dosage must be determined with care in patients
undergoing treatment with digitalis, as hypercalcemia in such patients may
precipitate cardiac arrhythmias (see , ).
Ketoconazole may inhibit both synthetic and catabolic enzymes of
calcitriol. Reductions in serum endogenous calcitriol concentrations have been
observed following the administration of 300 mg/day to 1200 mg/day ketoconazole
for a week to healthy men. However, drug
interaction studies of ketoconazole with calcitriol have not been
investigated.
A relationship of functional antagonism exists between vitamin D
analogues, which promote calcium absorption, and corticosteroids, which inhibit
calcium absorption.
Since calcitriol also has an effect on phosphate transport in the
intestine, kidneys and bones, the dosage of phosphate-binding agents must be
adjusted in accordance with the serum phosphate concentration.
Since calcitriol is the most potent active metabolite of vitamin
D, pharmacological doses of vitamin D and its
derivatives should be withheld during treatment with calcitriol to avoid
possible additive effects and hypercalcemia (see ).
Uncontrolled intake of additional calcium-containing preparations
should be avoided (see ,).
Magnesium-containing preparations (e.g., antacids) may cause
hypermagnesemia and should therefore not be taken during therapy with calcitriol
by patients on chronic renal dialysis.
Long-term studies in animals have not been conducted to evaluate
the carcinogenic potential of calcitriol. Calcitriol is not mutagenic in the Ames Test, nor is it genotoxic in the Mouse Micronucleus Test. No significant
effects of calcitriol on fertility and/or general reproductive performances were
observed in a Segment I study in rats at doses of up to 0.3 mcg/kg
(approximately 3 times the maximum recommended dose based on body surface
area).
Calcitriol has been found to be teratogenic in rabbits when given
at doses of 0.08 and 0.3 mcg/kg (approximately 2 and 6 times the maximum
recommended dose based on mg/m). All 15 fetuses in 3
litters at these doses showed external and skeletal abnormalities. However, none
of the other 23 litters (156 fetuses) showed external and skeletal abnormalities
compared with controls.
Teratogenicity studies in rats at doses up to 0.45 mcg/kg (approximately 5
times maximum recommended dose based on mg/m) showed no
evidence of teratogenic potential. There are no adequate and well-controlled
studies in pregnant women. Calcitriol should be used during pregnancy only if
the potential benefit justifies the potential risk to the fetus.
In the rabbit, dosages of 0.3 mcg/kg/day (approximately 6 times
maximum recommended dose based on surface area) administered on days 7 to 18 of
gestation resulted in 19% maternal mortality, a decrease in mean fetal body
weight and a reduced number of newborn surviving to 24 hours. A study of
perinatal and postnatal development in rats resulted in hypercalcemia in the
offspring of dams given calcitriol at doses of 0.08 or 0.3 mcg/kg/day
(approximately 1 and 3 times the maximum recommended dose based on mg/m), hypercalcemia and hypophosphatemia in dams given calcitriol
at a dose of 0.08 or 0.3 mcg/kg/day, and increased serum urea nitrogen in dams
given calcitriol at a dose of 0.3 mcg/kg/day. In another study in rats, maternal
weight gain was slightly reduced at a dose of 0.3 mcg/kg/day (approximately 3
times the maximum recommended dose based on mg/m)
administered on days 7 to 15 of gestation. The offspring of a woman administered
17 mcg/day to 36 mcg/day of calcitriol (approximately 17 to 36 times the maximum
recommended dose), during pregnancy manifested mild hypercalcemia in the first 2
days of life which returned to normal at day 3.
Calcitriol from ingested calcitriol capsules may be excreted in
human milk. Because many drugs are excreted in human milk and because of the
potential for serious adverse reactions from calcitriol in nursing infants, a
mother should not nurse while taking calcitriol.
Safety and effectiveness of calcitriol in pediatric patients
undergoing dialysis have not been established. The safety and effectiveness of
calcitriol in pediatric predialysis patients is based on evidence from adequate
and well-controlled studies of calcitriol in adults with predialysis chronic
renal failure and additional supportive data from non-placebo controlled studies
in pediatric patients. Dosing guidelines have not been established for pediatric
patients under 1 year of age with hypoparathyroidism or for pediatric patients
less than 6 years of age with pseudohypoparathyroidism (see , ).
Oral doses of calcitriol ranging from 10 to 55 ng/kg/day have been shown to
improve calcium homeostasis and bone disease in pediatric patients with chronic
renal failure for whom hemodialysis is not yet required (predialysis). Long-term
calcitriol therapy is well tolerated by pediatric patients. The most common
safety issues are mild, transient episodes of hypercalcemia, hyperphosphatemia,
and increases in the serum calcium times phosphate (Ca x P) product which are
managed effectively by dosage adjustment or temporary discontinuation of the
vitamin D derivative.
Clinical studies of calcitriol did not include sufficient numbers
of subjects aged 65 and over to determine whether they respond differently from
younger subjects. Other reported clinical experience has not identified
differences in responses between the elderly and younger patients. 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, renal, or cardiac function, and of concomitant disease or other drug
therapy.
What are the side effects of Calcitriol?
Since calcitriol is believed to be the active hormone which
exerts vitamin D activity in the body, adverse effects are, in general, similar
to those encountered with excessive vitamin D intake, i.e., hypercalcemia
syndrome or calcium intoxication (depending on the severity and duration of
hypercalcemia) (see ). Because of the short
biological half-life of calcitriol, pharmacokinetic investigations have shown
normalization of elevated serum calcium within a few days of treatment
withdrawal, i.e., much faster than in treatment with vitamin D preparations.
The early and late signs and symptoms of vitamin D intoxication associated
with hypercalcemia include:
Early:
Late:
In clinical studies on hypoparathyroidism and pseudohypoparathyroidism,
hypercalcemia was noted on at least one occasion in about 1 in 3 patients and
hypercalciuria in about 1 in 7 patients. Elevated serum creatinine levels were
observed in about 1 in 6 patients (approximately one half of whom had normal
levels at baseline).
In concurrent hypercalcemia and hyperphosphatemia, soft-tissue calcification
may occur; this can be seen radiographically (see ).
In patients with normal renal function, chronic hypercalcemia may be
associated with an increase in serum creatinine (see , ).
Hypersensitivity reactions (pruritus, rash, urticaria, and very rarely severe
erythematous skin disorders) may occur in susceptible individuals. One case of
erythema multiforme and one case of allergic reaction (swelling of lips and
hives all over the body) were confirmed by rechallenge.
What should I look out for while using Calcitriol?
Calcitriol capsules should not be given to patients with hypercalcemia or
evidence of vitamin D toxicity. Use of calcitriol capsules in patients with
known hypersensitivity to calcitriol (or drugs of the same class) or any of the
inactive ingredients is contraindicated.
Overdosage of any form of vitamin D is dangerous (see ). Progressive hypercalcemia due to overdosage of
vitamin D and its metabolites may be so severe as to require emergency
attention. Chronic hypercalcemia can lead to generalized vascular calcification,
nephrocalcinosis and other soft-tissue calcification. Radiographic
evaluation of suspect anatomical regions may be useful in the early detection of
this condition.
Calcitriol is the most potent metabolite of vitamin D available. The
administration of calcitriol to patients in excess of their daily requirements
can cause hypercalcemia, hypercalciuria, and hyperphosphatemia. Therefore,
pharmacologic doses of vitamin D and its derivatives should be withheld during
calcitriol treatment to avoid possible additive effects and hypercalcemia. If
treatment is switched from ergocalciferol (vitamin D) to
calcitriol, it may take several months for the ergocalciferol level in the blood
to return to the baseline value (see ).
Calcitriol increases inorganic phosphate levels in serum. While this is
desirable in patients with hypophosphatemia, caution is called for in patients
with renal failure because of the danger of ectopic calcification. A
non-aluminum phosphate-binding compound and a low-phosphate diet should be used
to control serum phosphorus levels in patients undergoing dialysis.
Magnesium-containing preparations (e.g., antacids) and calcitriol should not
be used concomitantly in patients on chronic renal dialysis because such use may
lead to the development of hypermagnesemia.
Studies in dogs and rats given calcitriol for up to 26 weeks have shown that
small increases of calcitriol above endogenous levels can lead to abnormalities
of calcium metabolism with the potential for calcification of many tissues in
the body.
What might happen if I take too much Calcitriol?
Administration of calcitriol to patients in excess of their daily
requirements can cause hypercalcemia, hypercalciuria, and hyperphosphatemia.
Since calcitriol is a derivative of vitamin D, the signs and symptoms of
overdose are the same as for an overdose of vitamin D (see
). High intake of
calcium and phosphate concomitant with calcitriol may lead to similar
abnormalities. The serum calcium times phosphate (Ca x P) product should not be
allowed to exceed 70 mg/dL. High
levels of calcium in the dialysate bath may contribute to the hypercalcemia (see
).
General treatment of hypercalcemia (greater than 1 mg/dL above
the upper limit of the normal range) consists of immediate discontinuation of
calcitriol therapy, institution of a low-calcium diet and withdrawal of calcium
supplements. Serum calcium levels should be determined daily until normocalcemia
ensues. Hypercalcemia frequently resolves in 2 to 7 days. When serum calcium
levels have returned to within normal limits, calcitriol therapy may be
reinstituted at a dose of 0.25 mcg/day less than prior therapy. Serum calcium
levels should be obtained at least twice weekly after all dosage changes and
subsequent dosage titration. In dialysis patients, persistent or markedly
elevated serum calcium levels may be corrected by dialysis against a
calcium-free dialysate.
If hypercalcemia ensues (greater than 1 mg/dL above the upper
limit of the normal range), adjust dosage to achieve normocalcemia by reducing
calcitriol therapy from 0.5 mcg to 0.25 mcg daily. If the patient is receiving a
therapy of 0.25 mcg daily, discontinue calcitriol until patient becomes
normocalcemic. Calcium supplements should also be reduced or discontinued. Serum
calcium levels should be determined 1 week after withdrawal of calcium
supplements. If serum calcium levels have returned to normal, calcitriol therapy
may be reinstituted at a dosage of 0.25 mcg/day if previous therapy was at a
dosage of 0.5 mcg/day. If calcitriol therapy was previously administered at a
dosage of 0.25 mcg/day, calcitriol therapy may be reinstituted at a dosage of
0.25 mcg every other day. If hypercalcemia is persistent at the reduced dosage,
serum PTH should be measured. If serum PTH is normal, discontinue calcitriol
therapy and monitor patient in 3 months’ time.
If serum phosphorus levels exceed 5.0 mg/dL to 5.5 mg/dL, a
calcium-containing phosphate-binding agent (i.e., calcium carbonate or calcium
acetate) should be taken with meals. Serum phosphorus levels should be
determined as described earlier (see , ). Aluminum-containing gels should be used
with caution as phosphate-binding agents because of the risk of slow aluminum
accumulation.
The treatment of acute accidental overdosage of calcitriol should
consist of general supportive measures. If drug ingestion is discovered within a
relatively short time, induction of emesis or gastric lavage may be of benefit
in preventing further absorption. If the drug has passed through the stomach,
the administration of mineral oil may promote its fecal elimination. 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 calcium and a low-calcium
diet are also indicated in accidental overdosage. Due to the relatively short
duration of the pharmacological action of calcitriol, further measures are
probably unnecessary. Should, however, persistent and markedly elevated serum
calcium levels occur, there are a variety of therapeutic alternatives which may
be considered, depending on the patient’s underlying condition. These include
the use of drugs such as phosphates and corticosteroids as well as measures to
induce an appropriate forced diuresis. The use of peritoneal dialysis against a
calcium-free dialysate has also been reported.
How should I store and handle Calcitriol?
Store bottles of 1000 SINGULAIR 5-mg chewable tablets and 8000 SINGULAIR 10-mg film-coated tablets at 25°C (77°F), excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from moisture and light. Store in original container. When product container is subdivided, repackage into a well-closed, light resistant container. Calcitriol capsules are available as follows:0.25 mcg - opaque, red-brown and yellow-brown, two-tone, oval, soft, gelatin capsules, imprinted “93” and “657”, in bottles of 30, NDC 54868-4584-0.0.5 mcg - opaque, brown and pink, two-tone, oblong, soft, gelatin capsules, imprinted “93” and “658”, in bottles of 30,NDC 54868-4582-0.Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Calcitriol capsules are available as follows:0.25 mcg - opaque, red-brown and yellow-brown, two-tone, oval, soft, gelatin capsules, imprinted “93” and “657”, in bottles of 30, NDC 54868-4584-0.0.5 mcg - opaque, brown and pink, two-tone, oblong, soft, gelatin capsules, imprinted “93” and “658”, in bottles of 30,NDC 54868-4582-0.Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Calcitriol capsules are available as follows:0.25 mcg - opaque, red-brown and yellow-brown, two-tone, oval, soft, gelatin capsules, imprinted “93” and “657”, in bottles of 30, NDC 54868-4584-0.0.5 mcg - opaque, brown and pink, two-tone, oblong, soft, gelatin capsules, imprinted “93” and “658”, in bottles of 30,NDC 54868-4582-0.Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Calcitriol capsules are available as follows:0.25 mcg - opaque, red-brown and yellow-brown, two-tone, oval, soft, gelatin capsules, imprinted “93” and “657”, in bottles of 30, NDC 54868-4584-0.0.5 mcg - opaque, brown and pink, two-tone, oblong, soft, gelatin capsules, imprinted “93” and “658”, in bottles of 30,NDC 54868-4582-0.Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Calcitriol capsules are available as follows:0.25 mcg - opaque, red-brown and yellow-brown, two-tone, oval, soft, gelatin capsules, imprinted “93” and “657”, in bottles of 30, NDC 54868-4584-0.0.5 mcg - opaque, brown and pink, two-tone, oblong, soft, gelatin capsules, imprinted “93” and “658”, in bottles of 30,NDC 54868-4582-0.Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
Man’s natural supply of vitamin D depends mainly on exposure to
the ultraviolet rays of the sun for conversion of 7-dehydrocholesterol in the
skin to vitamin D(cholecalciferol). Vitamin D must be metabolically activated in the liver and the kidney
before it is fully active as a regulator of calcium and phosphorus metabolism at
target tissues. The initial transformation of vitamin Dis catalyzed by a vitamin D-25-hydroxylase enzyme
(25-OHase) present in the liver, and the product of this reaction is
25-hydroxyvitamin D [25-(OH)D].
Hydroxylation of 25-(OH)Doccurs in the mitochondria of
kidney tissue, activated by the renal 25-hydroxyvitamin D-1 alpha-hydroxylase (alpha-OHase), to produce 1,25-(OH)D (calcitriol), the active form of
vitamin D. Endogenous synthesis and catabolism of
calcitriol, as well as physiological control mechanisms affecting these
processes, play a critical role regulating the serum level of calcitriol.
Physiological daily production is normally 0.5 to 1.0 mcg and is somewhat higher
during periods of increased bone synthesis (e.g., growth or pregnancy).
The two known sites of action of calcitriol are intestine and
bone. A calcitriol receptor-binding protein appears to exist in the mucosa of
human intestine. Additional evidence suggests that calcitriol may also act on
the kidney and the parathyroid glands. Calcitriol is the most active known form
of vitamin D in stimulating intestinal calcium
transport. In acutely uremic rats calcitriol has been shown to stimulate
intestinal calcium absorption.
The kidneys of uremic patients cannot adequately synthesize calcitriol, the
active hormone formed from precursor vitamin D. Resultant hypocalcemia and
secondary hyperparathyroidism are a major cause of the metabolic bone disease of
renal failure. However, other bone-toxic substances which accumulate in uremia
(e.g., aluminum) may also contribute.
The beneficial effect of calcitriol in renal osteodystrophy appears to result
from correction of hypocalcemia and secondary hyperparathyroidism. It is
uncertain whether calcitriol produces other independent beneficial effects.
Calcitriol treatment is not associated with an accelerated rate of renal
function deterioration. No radiographic evidence of extraskeletal calcification
has been found in predialysis patients following treatment. The duration of
pharmacologic activity of a single dose of calcitriol is about 3 to 5
days.
Calcitriol is rapidly absorbed from the intestine. Peak serum
concentrations (above basal values) were reached within 3 to 6 hours following
oral administration of single doses of 0.25 to 1.0 mcg of calcitriol. Following
a single oral dose of 0.5 mcg, mean serum concentrations of calcitriol rose from
a baseline value of 40.0 ± 4.4 (SD) pg/mL to 60.0 ± 4.4 pg/mL at 2 hours, and
declined to 53.0 ± 6.9 at 4 hours, 50 ± 7.0 at 8 hours, 44 ± 4.6 at 12 hours,
and 41.5 ± 5.1 at 24 hours.
Following multiple-dose administration, serum calcitriol levels reached
steady-state within 7 days.
Calcitriol is approximately 99.9% bound in blood. Calcitriol and
other vitamin D metabolites are transported in blood, by an alpha-globulin
vitamin D binding protein. There is evidence that maternal calcitriol may enter
the fetal circulation. Calcitriol is transferred into human breast milk at low
levels (i.e., 2.2 ± 0.1 pg/mL).
In vivo
in
vitro
Enterohepatic recycling and biliary excretion of calcitriol
occur. The metabolites of calcitriol are excreted primarily in feces. Following
intravenous administration of radiolabeled calcitriol in normal subjects,
approximately 27% and 7% of the radioactivity appeared in the feces and urine,
respectively, within 24 hours. When a 1 mcg oral dose of radiolabeled calcitriol
was administered to normal subjects, approximately 10% of the total
radioactivity appeared in urine within 24 hours. Cumulative excretion of
radioactivity on the sixth day following intravenous administration of
radiolabeled calcitriol averaged 16% in urine and 49% in feces. The elimination
half-life of calcitriol in serum after single oral doses is about 5 to 8 hours
in normal subjects.
The steady-state pharmacokinetics of oral calcitriol were
determined in a small group of pediatric patients (age range: 1.8 to 16 years)
undergoing peritoneal dialysis. Calcitriol was administered for 2 months at an
average dose of 10.2 ng/kg (SD 5.5 ng/kg). In this pediatric population, mean
C was 116 pmol/L, mean serum half-life was 27.4 hours,
and mean clearance was 15.3 mL/hr/kg.
No studies have examined the pharmacokinetics of calcitriol in
geriatric patients.
Controlled studies examining the influence of gender on
calcitriol have not been conducted.
Controlled studies examining the influence of hepatic disease on
calcitriol have not been conducted.
Lower predose and peak calcitriol levels in serum were observed
in patients with nephrotic syndrome and in patients undergoing hemodialysis
compared with healthy subjects. The elimination half-life of calcitriol
increased by at least two-fold in chronic renal failure and hemodialysis
patients compared with healthy subjects. Peak serum levels in patients with
nephrotic syndrome were reached in 4 hours. For patients requiring hemodialysis
peak serum levels were reached in 8 to 12 hours; half-lives were estimated to be
16.2 and 21.9 hours, respectively.
Non-Clinical Toxicology
Calcitriol capsules should not be given to patients with hypercalcemia or evidence of vitamin D toxicity. Use of calcitriol capsules in patients with known hypersensitivity to calcitriol (or drugs of the same class) or any of the inactive ingredients is contraindicated.Overdosage of any form of vitamin D is dangerous (see ). Progressive hypercalcemia due to overdosage of vitamin D and its metabolites may be so severe as to require emergency attention. Chronic hypercalcemia can lead to generalized vascular calcification, nephrocalcinosis and other soft-tissue calcification. Radiographic evaluation of suspect anatomical regions may be useful in the early detection of this condition.
Calcitriol is the most potent metabolite of vitamin D available. The administration of calcitriol to patients in excess of their daily requirements can cause hypercalcemia, hypercalciuria, and hyperphosphatemia. Therefore, pharmacologic doses of vitamin D and its derivatives should be withheld during calcitriol treatment to avoid possible additive effects and hypercalcemia. If treatment is switched from ergocalciferol (vitamin D) to calcitriol, it may take several months for the ergocalciferol level in the blood to return to the baseline value (see ).
Calcitriol increases inorganic phosphate levels in serum. While this is desirable in patients with hypophosphatemia, caution is called for in patients with renal failure because of the danger of ectopic calcification. A non-aluminum phosphate-binding compound and a low-phosphate diet should be used to control serum phosphorus levels in patients undergoing dialysis.
Magnesium-containing preparations (e.g., antacids) and calcitriol should not be used concomitantly in patients on chronic renal dialysis because such use may lead to the development of hypermagnesemia.
Studies in dogs and rats given calcitriol for up to 26 weeks have shown that small increases of calcitriol above endogenous levels can lead to abnormalities of calcium metabolism with the potential for calcification of many tissues in the body.
Few systemic data have been collected on the metabolism of bupropion following concomitant administration with other drugs or, alternatively, the effect of concomitant administration of bupropion on the metabolism of other drugs.
Because bupropion is extensively metabolized, the coadministration of other drugs may affect its clinical activity. studies indicate that bupropion is primarily metabolized to hydroxybupropion by the CYP2B6 isoenzyme. Therefore, the potential exists for a drug interaction between bupropion hydrochloride tablets and drugs that are substrates or inhibitors of the CYP2B6 isoenzyme (e.g., orphenadrine, thiotepa, and cyclophosphamide). In addition, studies suggest that paroxetine, sertraline, norfluoxetine, and fluvoxamine as well as nelfinavir, ritonavir, and efavirenz inhibit the hydroxylation of bupropion. No clinical studies have been performed to evaluate this finding. The threohydrobupropion metabolite of bupropion does not appear to be produced by the cytochrome P450 isoenzymes. The effects of concomitant administration of cimetidine on the pharmacokinetics of bupropion and its active metabolites were studied in 24 healthy young male volunteers. Following oral administration of two 150 mg sustained-release tablets with and without 800 mg of cimetidine, the pharmacokinetics of bupropion and hydroxybupropion were unaffected. However, there were 16% and 32% increases in the AUC and C, respectively, of the combined moieties of threohydrobupropion and erythrohydrobupropion.
While not systematically studied, certain drugs may induce the metabolism of bupropion (e.g., carbamazepine, phenobarbital, phenytoin).
Multiple oral doses of bupropion had no statistically significant effects on the single dose pharmacokinetics of lamotrigine in 12 healthy volunteers.
Animal data indicated that bupropion may be an inducer of drug-metabolizing enzymes in humans. In one study, following chronic administration of bupropion, 100 mg 3 times daily to 8 healthy male volunteers for 14 days, there was no evidence of induction of its own metabolism. Nevertheless, there may be the potential for clinically important alterations of blood levels of coadministered drugs.
Excessive dosage of calcitriol induces hypercalcemia and in some instances hypercalciuria; therefore, early in treatment during dosage adjustment, serum calcium should be determined twice weekly. In dialysis patients, a fall in serum alkaline phosphatase levels usually antedates the appearance of hypercalcemia and may be an indication of impending hypercalcemia. An abrupt increase in calcium intake as a result of changes in diet (e.g., increased consumption of dairy products) or uncontrolled intake of calcium preparations may trigger hypercalcemia.
Should hypercalcemia develop, treatment with calcitriol should be stopped immediately. During periods of hypercalcemia, serum calcium and phosphate levels must be determined daily. When normal levels have been attained, treatment with calcitriol can be continued, at a daily dose 0.25 mcg lower than that previously used. An estimate of daily dietary calcium intake should be made and the intake adjusted when indicated. Calcitriol should be given cautiously to patients on digitalis, because hypercalcemia in such patients may precipitate cardiac arrhythmias.
Immobilized patients, e.g., those who have undergone surgery, are particularly exposed to the risk of hypercalcemia.
In patients with normal renal function, chronic hypercalcemia may be associated with an increase in serum creatinine. While this is usually reversible, it is important in such patients to pay careful attention to those factors which may lead to hypercalcemia. Calcitriol therapy should always be started at the lowest possible dose and should not be increased without careful monitoring of the serum calcium. An estimate of daily dietary calcium intake should be made and the intake adjusted when indicated.
Patients with normal renal function taking calcitriol should avoid dehydration. Adequate fluid intake should be maintained.
The patient and his or her caregivers should be informed about compliance with dosage instructions, adherence to instructions about diet and calcium supplementation, and avoidance of the use of unapproved nonprescription drugs. Patients and their caregivers should also be carefully informed about the symptoms of hypercalcemia (see ).
The effectiveness of calcitriol therapy is predicated on the assumption that each patient is receiving an adequate daily intake of calcium. Patients are advised to have a dietary intake of calcium at a minimum of 600 mg daily. The U.S. RDA for calcium in adults is 800 mg to 1200 mg.
For dialysis patients, serum calcium, phosphorus, magnesium, and alkaline phosphatase should be determined periodically. For hypoparathyroid patients, serum calcium, phosphorus, and 24 hour urinary calcium should be determined periodically. For predialysis patients, serum calcium, phosphorus, alkaline phosphatase, creatinine, and intact PTH (iPTH) should be determined initially. Thereafter, serum calcium, phosphorus, alkaline phosphatase, and creatine should be determined monthly for a 6 month period and then determined periodically. Intact PTH (iPTH) should be determined periodically every 3 to 4 months at the time of visits. During the titration period of treatment with calcitriol, serum calcium levels should be checked at least twice weekly (see ).
Cholestyramine has been reported to reduce intestinal absorption of fat-soluble vitamins; as such it may impair intestinal absorption of calcitriol. (see and , ).
The coadministration of phenytoin or phenobarbital will not affect plasma concentrations of calcitriol, but may reduce endogenous plasma levels of 25(OH)D by accelerating metabolism. Since blood level of calcitriol will be reduced, higher doses of calcitriol may be necessary if these drugs are administered simultaneously.
Thiazides are known to induce hypercalcemia by the reduction of calcium excretion in urine. Some reports have shown that the concomitant administration of thiazides with calcitriol causes hypercalcemia. Therefore, precaution should be taken when coadministration is necessary.
Calcitriol dosage must be determined with care in patients undergoing treatment with digitalis, as hypercalcemia in such patients may precipitate cardiac arrhythmias (see , ).
Ketoconazole may inhibit both synthetic and catabolic enzymes of calcitriol. Reductions in serum endogenous calcitriol concentrations have been observed following the administration of 300 mg/day to 1200 mg/day ketoconazole for a week to healthy men. However, drug interaction studies of ketoconazole with calcitriol have not been investigated.
A relationship of functional antagonism exists between vitamin D analogues, which promote calcium absorption, and corticosteroids, which inhibit calcium absorption.
Since calcitriol also has an effect on phosphate transport in the intestine, kidneys and bones, the dosage of phosphate-binding agents must be adjusted in accordance with the serum phosphate concentration.
Since calcitriol is the most potent active metabolite of vitamin D, pharmacological doses of vitamin D and its derivatives should be withheld during treatment with calcitriol to avoid possible additive effects and hypercalcemia (see ).
Uncontrolled intake of additional calcium-containing preparations should be avoided (see ,).
Magnesium-containing preparations (e.g., antacids) may cause hypermagnesemia and should therefore not be taken during therapy with calcitriol by patients on chronic renal dialysis.
Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of calcitriol. Calcitriol is not mutagenic in the Ames Test, nor is it genotoxic in the Mouse Micronucleus Test. No significant effects of calcitriol on fertility and/or general reproductive performances were observed in a Segment I study in rats at doses of up to 0.3 mcg/kg (approximately 3 times the maximum recommended dose based on body surface area).
Calcitriol has been found to be teratogenic in rabbits when given at doses of 0.08 and 0.3 mcg/kg (approximately 2 and 6 times the maximum recommended dose based on mg/m). All 15 fetuses in 3 litters at these doses showed external and skeletal abnormalities. However, none of the other 23 litters (156 fetuses) showed external and skeletal abnormalities compared with controls.
Teratogenicity studies in rats at doses up to 0.45 mcg/kg (approximately 5 times maximum recommended dose based on mg/m) showed no evidence of teratogenic potential. There are no adequate and well-controlled studies in pregnant women. Calcitriol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In the rabbit, dosages of 0.3 mcg/kg/day (approximately 6 times maximum recommended dose based on surface area) administered on days 7 to 18 of gestation resulted in 19% maternal mortality, a decrease in mean fetal body weight and a reduced number of newborn surviving to 24 hours. A study of perinatal and postnatal development in rats resulted in hypercalcemia in the offspring of dams given calcitriol at doses of 0.08 or 0.3 mcg/kg/day (approximately 1 and 3 times the maximum recommended dose based on mg/m), hypercalcemia and hypophosphatemia in dams given calcitriol at a dose of 0.08 or 0.3 mcg/kg/day, and increased serum urea nitrogen in dams given calcitriol at a dose of 0.3 mcg/kg/day. In another study in rats, maternal weight gain was slightly reduced at a dose of 0.3 mcg/kg/day (approximately 3 times the maximum recommended dose based on mg/m) administered on days 7 to 15 of gestation. The offspring of a woman administered 17 mcg/day to 36 mcg/day of calcitriol (approximately 17 to 36 times the maximum recommended dose), during pregnancy manifested mild hypercalcemia in the first 2 days of life which returned to normal at day 3.
Calcitriol from ingested calcitriol capsules may be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from calcitriol in nursing infants, a mother should not nurse while taking calcitriol.
Safety and effectiveness of calcitriol in pediatric patients undergoing dialysis have not been established. The safety and effectiveness of calcitriol in pediatric predialysis patients is based on evidence from adequate and well-controlled studies of calcitriol in adults with predialysis chronic renal failure and additional supportive data from non-placebo controlled studies in pediatric patients. Dosing guidelines have not been established for pediatric patients under 1 year of age with hypoparathyroidism or for pediatric patients less than 6 years of age with pseudohypoparathyroidism (see , ).
Oral doses of calcitriol ranging from 10 to 55 ng/kg/day have been shown to improve calcium homeostasis and bone disease in pediatric patients with chronic renal failure for whom hemodialysis is not yet required (predialysis). Long-term calcitriol therapy is well tolerated by pediatric patients. The most common safety issues are mild, transient episodes of hypercalcemia, hyperphosphatemia, and increases in the serum calcium times phosphate (Ca x P) product which are managed effectively by dosage adjustment or temporary discontinuation of the vitamin D derivative.
Clinical studies of calcitriol did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. 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, renal, or cardiac function, and of concomitant disease or other drug therapy.
Since calcitriol is believed to be the active hormone which exerts vitamin D activity in the body, adverse effects are, in general, similar to those encountered with excessive vitamin D intake, i.e., hypercalcemia syndrome or calcium intoxication (depending on the severity and duration of hypercalcemia) (see ). Because of the short biological half-life of calcitriol, pharmacokinetic investigations have shown normalization of elevated serum calcium within a few days of treatment withdrawal, i.e., much faster than in treatment with vitamin D preparations.
The early and late signs and symptoms of vitamin D intoxication associated with hypercalcemia include:
Early:
Late:
In clinical studies on hypoparathyroidism and pseudohypoparathyroidism, hypercalcemia was noted on at least one occasion in about 1 in 3 patients and hypercalciuria in about 1 in 7 patients. Elevated serum creatinine levels were observed in about 1 in 6 patients (approximately one half of whom had normal levels at baseline).
In concurrent hypercalcemia and hyperphosphatemia, soft-tissue calcification may occur; this can be seen radiographically (see ).
In patients with normal renal function, chronic hypercalcemia may be associated with an increase in serum creatinine (see , ).
Hypersensitivity reactions (pruritus, rash, urticaria, and very rarely severe erythematous skin disorders) may occur in susceptible individuals. One case of erythema multiforme and one case of allergic reaction (swelling of lips and hives all over the body) were confirmed by rechallenge.
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
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