PARICALCITOL: Package Insert and Label Information

PARICALCITOL — paricalcitol capsule
ALVOGEN, INC.

1 INDICATIONS AND USAGE

1.1 Chronic Kidney Disease Stages 3 and 4

Paricalcitol Capsules are indicated for the prevention and treatment of secondary hyperparathyroidism associated with Chronic Kidney Disease (CKD) Stages 3 and 4.

1.2 Chronic Kidney Disease Stage 5

Paricalcitol Capsules are indicated for the prevention and treatment of secondary hyperparathyroidism associated with CKD Stage 5 in patients on hemodialysis (HD) or peritoneal dialysis (PD).

2 DOSAGE AND ADMINISTRATION

2.1 Chronic Kidney Disease Stages 3 and 4

Paricalcitol Capsules may be administered daily or three times a week. When dosing three times weekly, the dose should be administered not more frequently than every other day. The total weekly doses for both daily and three times a week dosage regimens are similar [see Clinical Studies (14.1)].

Paricalcitol Capsules may be taken without regard to food. No dosing adjustment is required in patients with mild and moderate hepatic impairment.

Initial Dose

The initial dose of Paricalcitol Capsules for CKD Stages 3 and 4 patients is based on baseline intact parathyroid hormone (iPTH) levels.

*
To be administered not more often than every other day
Baseline iPTH Level Daily Dose Three Times a Week Dose *
≤ 500 pg/mL 1 mcg 2 mcg
> 500 pg/mL 2 mcg 4 mcg

Dose Titration

Dosing must be individualized and based on serum or plasma iPTH levels, with monitoring of serum calcium and serum phosphorus. The following is a suggested approach to dose titration.

*
To be administered not more often than every other day
Dose Adjustment at 2 to 4 Week Intervals
iPTH Level Relative to Baseline Paricalcitol Capsule Dose Daily Dosage Three Times a Week Dosage *
The same, increased or decreased by < 30% Increase dose by 1 mcg 2 mcg
Decreased by ≥ 30% and ≤ 60% Maintain dose - -
Decreased by > 60% or iPTH < 60 pg/mL Decrease dose by 1 mcg 2 mcg

If a patient is taking the lowest dose, 1 mcg, on the daily regimen and a dose reduction is needed, the dose can be decreased to 1 mcg three times a week. If a further dose reduction is required, the drug should be withheld as needed and restarted at a lower dosing frequency. If a patient is on a calcium-based phosphate binder, the phosphate-binder dose may be decreased or withheld, or the patient may be switched to a non-calcium-based phosphate binder. If hypercalcemia is observed, the dose of Paricalcitol should be reduced or withheld until these parameters are normalized.

Serum calcium and phosphorus levels should be closely monitored after initiation of Paricalcitol Capsules, during dose titration periods and during co-administration with strong CYP3A inhibitors [see Warnings and Precautions (5.3), Drug Interactions (7) and Clinical Pharmacology (12.3)].

2.2 Chronic Kidney Disease Stage 5

Paricalcitol Capsules are to be administered three times a week, not more frequently than every other day.

Paricalcitol Capsules may be taken without regard to food. No dosing adjustment is required in patients with mild and moderate hepatic impairment.

Initial Dose

The initial dose of Paricalcitol Capsules in micrograms is based on a baseline iPTH level (pg/mL)/80. To minimize the risk of hypercalcemia patients should be treated only after their baseline serum calcium has been adjusted to 9.5 mg/dL or lower [see Clinical Pharmacology (12.2) and Clinical Studies (14.2)].

Dose Titration

Subsequent dosing should be individualized and based on iPTH, serum calcium and phosphorus levels. A suggested dose titration of Paricalcitol Capsules is based on the following formula:

Titration dose (micrograms) = most recent iPTH level (pg/ml)/80

Serum calcium and phosphorus levels should be closely monitored after initiation, during dose titration periods, and with co-administration of strong P450 3A inhibitors. If an elevated serum calcium is observed and the patient is on a calcium-based phosphate binder, the binder dose may be decreased or withheld, or the patient may be switched to a non-calcium-based phosphate binder. If serum calcium is elevated, the dose should be decreased by 2 to 4 micrograms lower than that calculated by the most recent iPTH/80. If further adjustment is required, the dose of Paricalcitol Capsules should be reduced or withheld until these parameters are normalized.

As iPTH approaches the target range, small, individualized dose adjustments may be necessary in order to achieve a stable iPTH. In situations where monitoring of iPTH, Ca or P occurs less frequently than once per week, a more modest initial and dose titration ratio (e.g., iPTH/100) may be warranted.

3 DOSAGE FORMS AND STRENGTHS

Paricalcitol Capsules are available as 1 mcg, 2 mcg, and 4 mcg soft gelatin capsules.

  • 1 mcg: An oval-shaped, gray soft capsule imprinted with the “1” in black ink.
  • 2 mcg: An oval-shaped, orange-brown soft capsule imprinted with the “2” in black ink.
  • 4 mcg: An oval-shaped, gold soft capsule imprinted with the “3” in black ink.

4 CONTRAINDICATIONS

Paricalcitol Capsules should not be given to patients with evidence of

5 WARNINGS AND PRECAUTIONS

Excessive administration of vitamin D compounds, including Paricalcitol Capsules, can cause over suppression of PTH, hypercalcemia, hypercalciuria, hyperphosphatemia, and adynamic bone disease.

5.1 Hypercalcemia

Progressive hypercalcemia due to overdosage of vitamin D and its metabolites may be so severe as to require emergency attention [see Overdosage (10)]. Acute hypercalcemia may exacerbate tendencies for cardiac arrhythmias and seizures and may potentiate the action of digitalis. Chronic hypercalcemia can lead to generalized vascular calcification and other soft-tissue calcification. Concomitant administration of high doses of calcium-containing preparations or thiazide diueretics with Paricalcitol may increase the risk of hypercalcemia. High intake of calcium and phosphate concomitant with vitamin D compounds may lead to serum abnormalities requiring more frequent patient monitoring and individualized dose titration. 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.

Prescription-based doses of vitamin D and its derivatives should be withheld during Paricalcitol treatment to avoid hypercalcemia.

5.2 Digitalis Toxicity

Digitalis toxicity is potentiated by hypercalcemia of any cause. Use caution when Paricalcitol Capsules are prescribed concomitantly with digitalis compounds.

5.3 Laboratory Tests

During the initial dosing or following any dose adjustment of medication, serum calcium, serum phosphorus, and serum or plasma iPTH should be monitored at least every two weeks for 3 months, then monthly for 3 months, and every 3 months thereafter.

In pre-dialysis patients, Paricalcitol Capsules may increase serum creatinine and therefore decrease the estimated GFR (eGFR). Similar effects have also been seen with calcitriol.

5.4 Aluminum Overload and Toxicity

Aluminum-containing preparations (e.g., antacids, phosphate binders) should not be administered chronically with Paricalcitol, as increased blood levels of aluminum and aluminum bone toxicity may occur.

6 ADVERSE REACTIONS

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.

6.1 Clinical Trials Experience

CKD Stages 3 and 4

The safety of Paricalcitol Capsules has been evaluated in three 24-week (approximately six-month), double-blind, placebo-controlled, multicenter clinical studies involving 220 CKD Stages 3 and 4 patients. Six percent (6%) of Paricalcitol Capsules treated patients and 4% of placebo treated patients discontinued from clinical studies due to an adverse event. Adverse events occurring in the Paricalcitol Capsules group at a frequency of 2% or greater and more frequently than in the placebo group are presented in Table 1:

Table 1: Treatment-Emergent Adverse Events by Body System Occurring in ≥ 2% of Subjects in the Paricalcitol-Treated Group of Three, Double-Blind, Placebo-Controlled, Phase 3, CKD Stages 3 and 4 Studies; All Treated Patients
*
Includes only events more common in the Paricalcitol treatment group.
Number (%) of Subjects
Adverse Event * Paricalcitol Capsules (n=107) Placebo (n=113)
Overall 88 (82%) 86 (76%)
Ear and Labyrinth Disorders
Vertigo 5 (4.7%) 0 (0.0%)
Gastrointestinal Disorders
Abdominal Discomfort 4 (3.7%) 1 (0.9%)
Constipation 4 (3.7%) 4 (3.5%)
Diarrhea 7 (6.5%) 5 (4.4%)
Nausea 6 (5.6%) 4 (3.5%)
Vomiting 5 (4.7%) 5 (4.4%)
General Disorders and Administration Site Conditions
Chest Pain 3 (2.8%) 1 (0.9%)
Edema 6 (5.6%) 5 (4.4%)
Pain 4 (3.7%) 4 (3.5%)
Immune System Disorders
Hypersensitivity 6 (5.6%) 2 (1.8%)
Infections and Infestations
Fungal Infection 3 (2.8%) 0 (0.0%)
Gastroenteritis 3 (2.8%) 3 (2.7%)
Infection 3 (2.8%) 3 (2.7%)
Sinusitis 3 (2.8%) 1 (0.9%)
Urinary Tract Infection 3 (2.8%) 1 (0.9%)
Viral Infection 8 (7.5%) 8 (7.1%)
Metabolism and Nutrition Disorders
Dehydration 3 (2.8%) 1 (0.9%)
Musculoskeletal and Connective Tissue Disorders
Arthritis 5 (4.7%) 0 (0.0%)
Back Pain 3 (2.8%) 1 (0.9%)
Muscle Spasms 3 (2.8%) 0 (0.0%)
Nervous System Disorders
Dizziness 5 (4.7%) 5 (4.4%)
Headache 5 (4.7%) 5 (4.4%)
Syncope 3 (2.8%) 1 (0.9%)
Psychiatric Disorders
Depression 3 (2.8%) 0 (0.0%)
Respiratory, Thoracic and Mediastinal Disorders
Cough 3 (2.8%) 2 (1.8%)
Oropharyngeal Pain 4 (3.7%) 0 (0.0%)
Skin and Subcutaneous Tissue Disorders
Pruritus 3 (2.8%) 3 (2.7%)
Rash 4 (3.7%) 1 (0.9%)
Skin Ulcer 3 (2.8%) 0 (0.0%)
Vascular Disorders
Hypertension 7 (6.5%) 4 (3.5%)
Hypotension 5 (4.7%) 3 (2.7%)

The following adverse reactions, with a causal relationship to Paricalcitol, occurred in <2% of the Paricalcitol treated patients in the above double-blind, placebo-controlled clinical trial data set.

Gastrointestinal Disorders: Dry mouth

Investigations: Hepatic enzyme abnormal

Nervous System Disorders: Dysgeusia

Skin and Subcutaneous Tissue Disorders: Urticaria

CKD Stage 5

The safety of Paricalcitol Capsules has been evaluated in one 12-week, double-blind, placebo-controlled, multicenter clinical study involving 88 CKD Stage 5 patients. Sixty-one patients received Paricalcitol Capsules and 27 patients received placebo.

The proportion of patients who terminated prematurely from the study due to adverse events was 7% for Paricalcitol Capsules treated patients and 7% for placebo patients.

Adverse events occurring in the Paricalcitol Capsules group at a frequency of 2% or greater and more frequently than in the placebo group are as follows:

Table 2. Treatment-Emergent Adverse Events by Body System Occurring in ≥ 2% of Subjects in the Paricalcitol-Treated Group, Double- Blind, Placebo-Controlled, Phase 3, CKD Stage 5 Study; All Treated Patients
*
Includes only events more common in the Paricalcitol treatment group.
Number (%) of Subjects
Adverse Events * Paricalcitol Capsules (n=61) Placebo (n=27)
Overall 43 (70%) 19 (70%)
Gastrointestinal Disorders
Constipation 3 (4.9%) 0 (0.0%)
Diarrhea 7 (11.5%) 3 (11.1%)
Vomiting 4 (6.6%) 0 (0.0%)
General Disorders and Administration Site Conditions
Fatigue 2 (3.3%) 0 (0.0%)
Edema Peripheral 2 (3.3%) 0 (0.0%)
Infections and Infestations
Nasopharyngitis 5 (8.2%) 2 (7.4%)
Peritonitis 3 (4.9%) 0 (0.0%)
Sinusitis 2 (3.3%) 0 (0.0%)
Urinary Tract Infection 2 (3.3%) 0 (0.0%)
Metabolism and Nutrition Disorders
Fluid Overload 3 (4.9%) 0 (0.0%)
Hypoglycemia 2 (3.3%) 0 (0.0%)
Nervous System Disorders
Dizziness 4 (6.6%) 0 (0.0%)
Headache 2 (3.3%) 0 (0.0%)
Psychiatric Disorders
Anxiety 2 (3.3%) 0 (0.0%)
Insomnia 3 (4.9%) 0 (0.0%)
Renal and Urinary Disorders
Renal Failure Chronic 2 (3.3%) 0 (0.0%)

The following adverse reactions, with a causal relationship to Paricalcitol, occurred in <2% of the Paricalcitol treated patients in the above double-blind, placebo-controlled clinical trial data set.

Gastrointestinal Disorders: Gastroesophageal reflux disease

Metabolism and Nutrition Disorders: Decreased appetite, hypercalcemia, hypocalcemia

Reproductive System and Breast Disorders: Breast tenderness

Skin and Subcutaneous Tissue Disorders: Acne

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