Calcijex® (calcitriol injection) is synthetically manufactured calcitriol and is available as a sterile, isotonic, clear, colorless to yellow, aqueous solution for intravenous injection. Calcijex® is available in 1 mL ampuls. Each 1 mL contains calcitriol, 1 mcg; Polysorbate 20, 4 mg; sodium ascorbate 2.5 mg added. May contain hydrochloric acid and/or sodium hydroxide for pH adjustment. pH is 6.5 (5.9 to 7.0). Contains no more than 1 mcg/mL of aluminum.

Calcitriol is a crystalline compound which occurs naturally in humans. It is soluble in organic solvents but relatively insoluble in water.

Calcitriol is chemically designated (5Z,7E)-9, 10-secocholesta-5,7,10(19)-triene-1α,3β,25-triol and has the following structural formula:

Molecular Formula: C₂₇H₄₄O₃

The other names frequently used for calcitriol are 1α,25-dihydroxycholecalciferol, 1α,25-dihydroxyvitamin D₃, 1,25-DHCC, 1,25(OH)₂D₃ and 1,25-diOHC.

Calcijex® (calcitriol injection) is indicated in the management of hypocalcemia in patients undergoing chronic renal dialysis. It has been shown to significantly reduce elevated parathyroid hormone levels. Reduction of PTH has been shown to result in an improvement in renal osteodystrophy.

The optimal dose of Calcijex® (calcitriol injection) must be carefully determined for each patient.

The effectiveness of Calcijex® therapy is predicated on the assumption that each patient is receiving an adequate and appropriate daily intake of calcium. The RDA for calcium in adults is 800 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.

The recommended initial dose of Calcijex®, depending on the severity of the hypocalcemia and/or secondary hyperparathyroidism, is 1 mcg (0.02 mcg/kg) to 2 mcg administered three times weekly, approximately every other day. Doses as small as 0.5 mcg and as large as 4 mcg three times weekly have been used as an initial dose. If a satisfactory response is not observed, the dose may be increased by 0.5 to 1 mcg at two to four week intervals. During this titration period, serum calcium and phosphorus levels should be obtained at least twice weekly. If hypercalcemia or a serum calcium times phosphate product greater than 70 is noted, the drug should be immediately discontinued until these parameters are appropriate. Then, the Calcijex® dose should be reinitiated at a lower dose. Doses may need to be reduced as the PTH levels decrease in response to the therapy. Thus, incremental dosing must be individualized and commensurate with PTH, serum calcium and phosphorus levels. The following is a suggested approach in dose titration:

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard unused portion.

Calcijex® (calcitriol injection) is supplied as follows:

Protect from light.

Store at controlled room temperature 15° to 30°C (59° to 86°F). Patent Pending.

Reference: EN-0249 Revised: September, 2004 Mfd. by: Hospira, Inc., Lake Forest, IL 60045 USA For: ABBOTT LABORATORIES, NORTH CHICAGO, IL 60064, U.S.A. FDA Rev date: 07/01/2007

Adverse effects of Calcijex® (calcitriol injection) are, in general, similar to those encountered with excessive vitamin D intake. The early and late signs and symptoms of vitamin D intoxication associated with hypercalcemia include:

Early

Weakness, headache, somnolence, nausea, vomiting, dry mouth, constipation, muscle pain, bone pain and metallic taste.

Late

Polyuria, polydipsia, anorexia, weight loss, nocturia, conjunctivitis (calcific), pancreatitis, photophobia, rhinorrhea, pruritus, hyperthermia, decreased libido, elevated BUN, albuminuria, hypercholesterolemia, elevated SGOT and SGPT, ectopic calcification, hypertension, cardiac arrhythmias and, rarely, overt psychosis. Occasional mild pain on injection has been observed.

Magnesium-containing antacid and Calcijex® should not be used concomitantly, because such use may lead to the development of hypermagnesemia.

Since calcitriol is the most potent metabolite of vitamin D available, vitamin D and its derivatives should be withheld during treatment.

A non-aluminum phosphate-binding compound should be used to control serum phosphorus levels in patients undergoing dialysis.

Overdosage of any form of vitamin D is dangerous (see also OVERDOSAGE). 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. The serum calcium times phosphate (Ca x P) product should not be allowed to exceed 70. Radiographic evaluation of suspect anatomical regions may be useful in the early detection of this condition.

General

Excessive dosage of Calcijex® (calcitriol injection) induces hypercalcemia and in some instances hypercalciuria; therefore, early in treatment during dosage adjustment, serum calcium and phosphorus should be determined at least twice weekly. Should hypercalcemia develop, the drug should be discontinued immediately.

Calcijex® should be given cautiously to patients on digitalis, because hypercalcemia in such patients may precipitate cardiac arrhythmias.

Essential Laboratory Tests

Serum calcium, phosphorus, magnesium and alkaline phosphatase and 24-hour urinary calcium and phosphorus should be determined periodically. During the initial phase of the medication, serum calcium and phosphorus should be determined more frequently (twice weekly).

Adynamic bone disease may develop if PTH levels are suppressed to abnormal levels. If biopsy is not being done for other (diagnostic) reasons, PTH levels may be used to indicate the rate of bone turnover. If PTH levels fall below recommended target range (1.5 to 3 times the upper limit of normal), in patients treated with Calcijex®, the Calcijex® dose should be reduced or therapy discontinued. Discontinuation of Calcijex® therapy may result in rebound effect, therefore, appropriate titration downward to a maintenance dose is recommended.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of Calcijex® (calcitriol injection). Calcitriol was not mutagenic in vitro in the Ames Test nor was oral calcitriol genotoxic in vivo in the Mouse Micronucleus Test. No significant effects on fertility and/or general reproductive performances were observed in a Segment I study in rats using oral calcitriol at doses of up to 0.3 mcg/kg.

Pregnancy: Teratogenic Effects: Pregnancy Category C:

Calcitriol has been found to be teratogenic in rabbits when given orally at doses of 0.08 and 0.3 mcg/kg. 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 orally showed no evidence of teratogenic potential. There are no adequate and well-controlled studies in pregnant women. Calcijex® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects: In the rabbit, oral dosages of 0.3 mcg/kg/day 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 newborns surviving to 24 hours. A study of the effects on orally administered calcitriol on peri-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, 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 an oral dose of 0.3 mcg/kg/day administered on days 7 to 15 of gestation.

The offspring of a woman administered oral calcitriol at 17 to 36 mcg/day during pregnancy manifested mild hypercalcemia in the first 2 days of life which returned to normal at day 3.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from calcitriol, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of Calcijex® were examined in a 12-week randomized, double-blind, placebo-controlled study of 35 pediatric patients, aged 13-18 years, with end-stage renal disease on hemodialysis. Sixty-six percent of the patients were male, 57% were African-American, and nearly all had received some form of vitamin D therapy prior to the study. The initial dose of Calcijex® was 0.5 mcg, 1.0 mcg, or 1.5 mcg, 3 times per week, based on baseline iPTH level of less than 500 pg/mL, 500-1000 pg/mL, or greater than 1000 pg/mL, respectively. The dose of Calcijex® was adjusted in 0.25 mcg increments based on the levels of serum iPTH, calcium, and Ca x P. The mean baseline levels of iPTH were 769 pg/mL for the 16 Calcijex®-treated patients and 897 pg/mL for the 19 placebo-treated subjects. The mean weekly dose of Calcijex® ranged from 1.0 mcg to 1.4 mcg. In the primary efficacy analysis, 7 of 16 (44%) subjects in the Calcijex® group had 2 consecutive 30% decreases from baseline iPTH compared with 3 of 19 (16%) patients in the placebo group (95% CI for the difference between groups -6%, 62%). One Calcijex®-treated patient experienced transient hypercalcemia (>11.0 mg/dL), while 6 of 16 (38%) Calcijex®-treated patients vs. 2 of 19 (11%) placebo-treated patients experienced Ca x P >75.

Geriatric Use

Clinical studies of Calcijex® 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 dosage range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Administration of Calcijex® (calcitriol injection) to patients in excess of their requirements can cause hypercalcemia, hypercalciuria and hyperphosphatemia. High intake of calcium and phosphate concomitant with Calcijex® may lead to similar abnormalities.

Treatment of Hypercalcemia and Overdosage in Patients on Hemodialysis

General treatment of hypercalcemia (greater than 1 mg/dL above the upper limit of normal range) consists of immediate discontinuation of Calcijex® therapy, institution of a low calcium diet and withdrawal of calcium supplements. Serum calcium levels should be determined daily until normocalcemia ensues. Hypercalcemia usually resolves in two to seven days. When serum calcium levels have returned to within normal limits, Calcijex® therapy may be reinstituted at a dose 0.5 mcg less than prior therapy. Serum calcium levels should be obtained at least twice weekly after all dosage changes.

Persistent or markedly elevated serum calcium levels may be corrected by dialysis against a calcium-free dialysate.

Treatment of Accidental Overdosage of Calcitriol Injection

The treatment of acute accidental overdosage of Calcijex® 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 calcium and 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 patients' 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.

Calcijex® (calcitriol injection) should not be given to patients with hypercalcemia or evidence of vitamin D toxicity.

Calcitriol is the active form of vitamin D₃ (cholecalciferol). The natural or endogenous supply of vitamin D in man mainly depends on ultraviolet light for conversion of 7-dehydrocholesterol to vitamin D₃ in the skin. Vitamin D₃ must be metabolically activated in the liver and the kidney before it is fully active on its target tissues. The initial transformation is catalyzed by a vitamin D₃-25-hydroxylase enzyme present in the liver, and the product of this reaction is 25-(OH)D₃ (calcifediol). The latter undergoes hydroxylation in the mitochondria of kidney tissue, and this reaction is activated by the renal 25-hydroxyvitamin D₃-1-α-hydroxylase to produce 1,25-(OH)₂D₃ (calcitriol), the active form of vitamin D₃.

The known sites of action of calcitriol are intestine, bone, kidney and parathyroid gland. Calcitriol is the most active known form of vitamin D₃ in stimulating intestinal calcium transport. In acutely uremic rats, calcitriol has been shown to stimulate intestinal calcium absorption. In bone, calcitriol, in conjunction with parathyroid hormone, stimulates resorption of calcium; and in the kidney, calcitriol increases the tubular reabsorption of calcium. In vitro and in vivo studies have shown that calcitriol directly suppresses secretion and synthesis of PTH. A vitamin D-resistant state may exist in uremic patients because of the failure of the kidney to adequately convert precursors to the active compound, calcitriol.

Calcitriol when administered by bolus injection is rapidly available in the blood stream. Vitamin D metabolites are known to be transported in blood, bound to specific plasma proteins. The pharmacologic activity of an administered dose of calcitriol is about 3 to 5 days. Two metabolic pathways for calcitriol have been identified, conversion to 1,24,25-(OH)₃D₃ and to calcitroic acid.

The patient and his or her parents should be informed about adherence to instructions about diet and calcium supplementation and avoidance of the use of unapproved non-prescription drugs, including magnesium-containing antacids. Patients should also be carefully informed about the symptoms of hypercalcemia (see ADVERSE REACTIONS).

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

CALCITRIOL - INJECTION

(kal-SIT-ree-ole)

COMMON BRAND NAME(S): Calcijex

USES: Calcitriol is a man-made active form of vitamin D (vitamin D3). Vitamin D is a vitamin stored in the body that is needed for building and keeping strong bones. Calcitriol is used to treat or prevent certain problems that can happen with long-term kidney dialysis, such as low levels of calcium or high levels of parathyroid hormone. Calcitriol is usually used along with a certain diet, supplements, and sometimes other medications.

Most people get enough vitamin D from exposure to the sun and from fortified food products (e.g., dairy products, vitamins). Before regular vitamin D can be used by the body, it needs to be changed to the active form by the liver and kidneys. People with kidney disease cannot make enough of the active form of vitamin D. This medication works by affecting parathyroid hormone (PTH) levels and increasing blood calcium levels.

HOW TO USE: Learn all preparation and usage instructions in the product package. If any of the information is unclear, consult your doctor or pharmacist.

Before using, check this product visually for particles or discoloration. If either is present, do not use the liquid.

This medication is given by injection into a vein, usually by a health care professional 3 times a week (every other day), or during dialysis, or as directed by your doctor. The dosage is based on your condition and response to therapy. Your doctor will do blood tests to find the best dose for you.

It is very important to follow the diet recommended by your doctor to get the most benefit from this medication and to prevent serious side effects. Do not take other supplements/vitamins (e.g., calcium, vitamin D) unless directed by your doctor.

Learn how to store and discard needles and medical supplies safely. Consult your pharmacist.

SIDE EFFECTS: Nausea, headache, constipation, or pain/discomfort at the injection site may occur. If any of these effects persist or worsen, notify your doctor promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: back/bone/joint/muscle pain, dry mouth, metallic taste, vomiting, sleepiness, weakness.

Tell your doctor immediately if any of these unlikely but very serious side effects occur: loss of appetite, dizziness, eye pain/redness/sensitivity to light, fever, fast/slow/irregular heartbeat, decreased interest in sex, mental/mood changes (e.g., confusion), stomach/abdominal pain, swelling of the ankles/feet/hands (edema), increased thirst, change in the amount of urine, weight loss.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any of the following symptoms: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using calcitriol, tell your doctor or pharmacist if you are allergic to it; or to other vitamin D products; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: high calcium levels (hypercalcemia).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: heart problems (e.g., irregular heartbeat, coronary artery disease), kidney disease, kidney stones.

Notify your doctor beforehand if you will be having surgery or will be confined to a chair/bed (immobile) for a long time. Being immobile for long periods increases your risk of side effects.

Be sure to drink plenty of fluids unless otherwise directed by your doctor.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Breast-feeding is not recommended while using this drug. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medication because a very serious interaction may occur: other vitamin D products (e.g., ergocalciferol).

If you are currently using the medication listed above, tell your doctor or pharmacist before starting calcitriol.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially: cardiac glycosides (e.g., digoxin, digitalis), corticosteroids (e.g., hydrocortisone, prednisone), magnesium-containing medications (e.g., antacids, milk of magnesia), phosphate binders, "water pills" (e.g., thiazide diuretics such as hydrochlorothiazide), vitamins/nutritional supplements (especially calcium and vitamin D).

Check the labels on all your prescription and nonprescription/herbal products (e.g., antacids, laxatives, vitamins) because they may contain calcium, magnesium, phosphate, and vitamin D. Ask your pharmacist about using those products safely.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: Overdose of any type of vitamin D is dangerous. If overdose is suspected, contact your poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: irregular heartbeat, severe stomach pain, unusually deep sleep.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., calcium, magnesium, phosphorus, parathyroid levels) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

It is important to closely follow your doctor's diet orders while taking this medication. Foods rich in vitamin D include: fortified dairy products, eggs, sardines, cod liver oil, chicken livers, and freshwater fish. Vitamin D is also obtained from short periods of exposure to the sun. Calcium supplements may be recommended in addition to this medication. The usual recommendation for calcium is 600-1200 milligrams per day. Discuss this with your doctor. Do not take supplements unless directed by your doctor.

MISSED DOSE: If you miss a dose, contact your doctor or pharmacist immediately to establish a new dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 59-86 degrees F (15-30 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medications away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.