Paricalcitol (Page 2 of 6)

5 WARNINGS AND PRECAUTIONS

5.1 Hypercalcemia

Hypercalcemia may occur during Paricalcitol Injection treatment. Acute hypercalcemia may increase the risk of cardiac arrhythmias and seizures and may potentiate the effect of digitalis on the heart [see Warnings and Precautions (5.2)] . Chronic hypercalcemia can lead to generalized vascular calcification and other soft-tissue calcification. Severe hypercalcemia may require emergency attention.

Hypercalcemia may be exacerbated by concomitant administration of high doses of calcium-containing preparations, thiazide diuretics, or other vitamin D compounds [see Drug Interactions (7)] . In addition, high intake of calcium and phosphate concomitantly with vitamin D compounds may lead to hypercalciuria and hyperphosphatemia. Patients with a history of hypercalcemia prior to initiating therapy may be at increased risk for development of hypercalcemia with Paricalcitol Injection. In these circumstances, frequent serum calcium monitoring and Paricalcitol Injection dose adjustments may be required.

When initiating Paricalcitol Injection or adjusting Paricalcitol Injection dose, measure serum calcium frequently (e.g., twice weekly). Once a maintenance dose has been established, measure serum calcium at least monthly. If hypercalcemia occurs, reduce the dose or discontinue Paricalcitol Injection until serum calcium is normal [see Dosage and Administration (2.2, 2.3)] .

Inform patients about the symptoms of elevated calcium (feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination and weight loss) and instruct them to report new or worsening symptoms when they occur.

5.2 Digitalis Toxicity

Paricalcitol Injection can cause hypercalcemia [see Warnings and Precautions (5.1)] which increases the risk of digitalis toxicity. In patients using Paricalcitol Injection concomitantly with digitalis compounds, monitor serum calcium and patients for signs and symptoms of digitalis toxicity. Increase the frequency of monitoring when initiating or adjusting the dose of Paricalcitol Injection [see Drug Interactions (7)] .

5.3 Adynamic Bone Disease

Adynamic bone disease with subsequent increased risk of fractures may develop if intact PTH levels are suppressed by Paricalcitol Injection to abnormally low levels. Monitor intact PTH levels to avoid over suppression and adjust Paricalcitol Injection dose, if needed [see Dosage and Administration (2.2, 2.3)] .

6 ADVERSE REACTIONS

The following serious adverse reactions are described below and elsewhere in the labeling:

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.

The safety of Paricalcitol Injection has been established from adequate and well-controlled studies of another paricalcitol injection product [see Clinical Studies (14)] . Below is a display of the adverse reactions of paricalcitol injection in these adequate and well-controlled studies.

Four placebo-controlled, double-blind, multicenter studies were conducted in 113 patients (51% male, 10% Caucasian, 81% African-American and 9% Hispanic, ranging in age from 18 to 90 years). Sixty-two patients were exposed to paricalcitol injection and the average dose at the end of treatment was 0.12 mcg/kg/dose with a mean number of 55 days of dosing across the studies. Discontinuation of therapy due to any adverse reaction occurred in 6.5% of patients treated with paricalcitol injection and 2.0% of patients treated with placebo. Adverse reactions occurring with greater frequency in the paricalcitol injection group and at a frequency of 2% or greater are presented in Table 3.

Table 3: Adverse Reactions Occurring at a Rate of 2% or Greater in Patients with CKD on Dialysis in Four Placebo-Controlled Studies

Adverse Reaction

Placebo (n = 51) %

Paricalcitol Injection (n = 62) %

Nausea

8

13

Vomiting

6

8

Edema

0

7

Gastrointestinal Hemorrhage

2

5

Chills

2

5

Pyrexia

2

5

Pneumonia

0

5

Sepsis

2

5

Influenza

4

5

Arthralgia

4

5

Palpitations

0

3

Dry Mouth

2

3

Malaise

0

3

Other Adverse Reactions

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

Blood and Lymphatic System Disorders: Anemia, lymphadenopathy

Cardiac Disorders: Arrhythmia, atrial flutter, irregular heart rate, cardiac arrest, chest discomfort, chest pain, edema peripheral

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: Asthenia, condition aggravated, fatigue, feeling abnormal, pain, swelling

Infections: Nasopharyngitis, upper respiratory tract infection, vaginal infection

Injection site reactions: Injection site extravasation, injection site pain

Laboratory abnormalities: Hypercalcemia, hyperkalemia, hyperphosphatemia, hypocalcemia, increased aspartate aminotransferase, prolonged bleeding time

Metabolism and Nutrition Disorders: Decreased appetite, thirst, decreased weight

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, gait disturbance

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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