Paricalcitol

PARICALCITOL- paricalcitol injection
West-Ward Pharmaceutical Corp

1 INDICATIONS AND USAGE

Paricalcitol Injection is an active vitamin D2 analogue indicated for the prevention and treatment of secondary hyperparathyroidism associated with chronic kidney disease (CKD) Stage 5.

2 DOSAGE AND ADMINISTRATION

For intravenous use through hemodialysis vascular access port only.

The recommended starting dose of Paricalcitol Injection is 0.04 mcg/kg to 0.1 mcg/kg (2.8 – 7 mcg) administered through a hemodialysis vascular access port as a bolus dose at any time during dialysis. Dosing should not occur more frequently than every other day. The drug product should not be injected directly into a vein. Dosage should be individualized. If a satisfactory parathyroid hormone (PTH) lowering response is not observed using the recommended starting dose, the dose may be increased by 2 to 4 mcg every 2 to 4 weeks based on PTH levels (refer to Table 1).

Table 1: Suggested Dosage Adjustment
PTH Level at Follow-up Visit Dosage Adjustment
Above target and PTH increased Increase
Above target and PTH decreased by less than 30% Increase
Above target and PTH decreased by 30 to 60% No Change
Above target and PTH decreased by more than 60% Decrease
At target and PTH stable No Change

When initiating Paricalcitol Injection or adjusting Paricalcitol Injection dose, measure serum calcium and phosphorus frequently (e.g., twice weekly) and PTH every 2 to 4 weeks. Once a maintenance dose has been established, serum calcium and phosphorus should be measured at least monthly and plasma PTH every 3 months.

3 DOSAGE FORMS AND STRENGTHS

Paricalcitol Injection is available in the following presentations:

  • 2 mcg per mL single dose vial
  • 5 mcg per mL single dose vial
  • 10 mcg per 2 mL (5 mcg per mL) multiple dose vial

4 CONTRAINDICATIONS

Paricalcitol Injection is contraindicated in patients with evidence of:

  • Hypercalcemia [see Warnings and Precautions (5.1) ]
  • Vitamin D toxicity [see Warnings and Precautions (5.1) ] or
  • Hypersensitivity to paricalcitol or any inactive ingredient in this product [see Adverse Reactions (6.2) ]

5 WARNINGS AND PRECAUTIONS

5.1 Hypercalcemia

Hypercalcemia may occur during Paricalcitol Injection treatment and may be exacerbated by concomitant administration of high doses of calcium containing preparations, thiazide diuretics, or vitamin D (i.e., all forms). Acute hypercalcemia may exacerbate tendencies for cardiac arrhythmias and seizures and may potentiate the effect of digitalis on the heart. Chronic hypercalcemia can lead to generalized vascular calcification and other soft-tissue calcification. Hypercalcemia may be so severe as to require emergency attention.

High intake of calcium and phosphate concomitantly with vitamin D compounds may lead to hypercalcemia, hypercalciuria, and hyperphosphatemia. Prevention of such adverse reactions requires frequent serum calcium monitoring and careful Paricalcitol Injection dose adjustments.

Concomitant use with other active vitamin D analogues should be avoided during Paricalcitol Injection treatment to prevent hypercalcemia.

Patients also should be informed about the symptoms of elevated calcium, which include feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination and weight loss.

5.2 Digitalis Toxicity

Hypercalcemia of any cause increases the risk of digitalis toxicity. In patients using Paricalcitol Injection concomitantly with digitalis compounds, monitor both serum calcium and patients for signs and symptoms of digitalis toxicity and increase frequency of monitoring when initiating or adjusting the dose of Paricalcitol Injection [see Dosage and Administration (2) ].

5.3 Risk of Increased Paricalcitol Levels With Concomitant Use of Strong CYP3A Inhibitors

Concomitant use of Paricalcitol Injection with strong CYP3A inhibitors will increase the levels of paricalcitol in the blood. In patients on Paricalcitol Injection who are initiating or discontinuing therapy with drugs known to be strong CYP3A inhibitors, monitor serum calcium and PTH more frequently and adjust Paricalcitol Injection dose as required [see Drug Interactions (7.1), Clinical Pharmacology (12.3) ].

5.4 Adynamic Bone Disease

Adynamic bone disease with subsequent increased risk of fractures may develop if PTH levels are suppressed to abnormally low levels. Monitor PTH levels and adjust Paricalcitol Injection dose [see Dosage and Administration (2) ].

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Safety has been evaluated in clinical studies conducted with another paricalcitol injection product in 609 patients with CKD Stage 5. 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 paricalcitol injection (dosage titrated as tolerated, [see Clinical Studies (14) ]) and 2% of 51 patients treated with placebo for 1 to 3 months. Adverse reactions occurring with greater frequency in the paricalcitol group and at a frequency of 2% or greater are presented in the following table:

Table 2: Adverse Reactions Occurring at a Rate *of 2% or Greater in CKD Stage 5 Patients in Four Placebo-Controlled Studies
*
A patient who reported the same medical term more than once was counted only once for that medical term.
Adverse Reaction

Placebo (n=51) %

Paricalcitol Injection(n=62) %
Cardiac Disorders
Palpitations 0.0 3.2
Gastrointestinal Disorders
Nausea 7.8 12.9
Vomiting 5.9 8.1
Gastrointestinal Hemorrhage 2.0 4.8
Dry Mouth 2.0 3.2
General Disorders and Administration Site Conditions
Edema 0.0 6.5
Chills 2.0 4.8
Pyrexia 2.0 4.8
Malaise 0.0 3.2
Infections and Infestations
Pneumonia 0.0 4.8
Sepsis 2.0 4.8
Influenza 3.9 4.8
Musculoskeletal and Connective Tissue Disorders
Arthralgia 3.9 4.8

Specific laboratory parameters [i.e., changes in mean Calcium (Ca), Phosphorus (P), and Calcium Phosphorus product (Ca × P)] were followed in an open-label safety study conducted with another paricalcitol injection product for up to 13 months in duration in this patient population and results are shown below [see Clinical Studies (14) ].

Other Adverse Reactions Associated with Paricalcitol Injection Use

The following adverse reactions occurred in less than 2% of the paricalcitol-treated patients in the above mentioned double-blind, placebo-controlled clinical trials and in additional double-blind, active-controlled and open-label studies:

Blood and Lymphatic System Disorders: Anemia, lymphadenopathy

Cardiac Disorders: Arrhythmia, atrial flutter, cardiac arrest

Ear and Labyrinth Disorders: Ear discomfort

Endocrine Disorders: Hypoparathyroidism

Eye Disorders: Conjunctivitis, glaucoma, ocular hyperemia

Gastrointestinal Disorders: Abdominal discomfort, constipation, diarrhea, dysphagia, gastritis, intestinal ischemia, rectal hemorrhage

General Disorders and Administration Site Conditions: Asthenia, chest discomfort, chest pain, condition aggravated, edema peripheral, fatigue, feeling abnormal, gait disturbance, injection site extravasation, injection site pain, pain, swelling, thirst

Infections and Infestations: Nasopharyngitis, upper respiratory tract infection, vaginal infection

Laboratory Investigations and Vital Signs: Increased aspartate aminotransferase, prolonged bleeding time, irregular heart rate, decreased weight

Metabolism and Nutrition Disorders: Decreased appetite, hypercalcemia, hyperkalemia, hyperphosphatemia, hypocalcemia

Musculoskeletal and Connective Tissue Disorders: Joint stiffness, muscle twitching, myalgia

Neoplasms Benign, Malignant and Unspecified : Breast cancer

Nervous System Disorders: Cerebrovascular accident, dizziness, dysgeusia, headache, hypoesthesia, myoclonus, paresthesia, syncope, unresponsive to stimuli

Psychiatric Disorders: Agitation, confusional state, delirium, insomnia, nervousness, restlessness

Reproductive System and Breast Disorders: Breast pain, erectile dysfunction

Respiratory, Thoracic and Mediastinal Disorders: Cough, dyspnea, orthopnea, pulmonary edema, wheezing

Skin and Subcutaneous Tissue Disorders: Alopecia, blister, hirsutism, night sweats, rash pruritic, pruritus, skin burning sensation

Vascular Disorders: Hypertension, hypotension

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