ZEMPLAR: Package Insert and Label Information
ZEMPLAR- paricalcitol capsule, liquid filled
Cardinal Health
1 INDICATIONS AND USAGE
1.1 Chronic Kidney Disease Stages 3 and 4
Zemplar 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
Zemplar 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
Zemplar 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) ].
Zemplar 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 Zemplar Capsules for CKD Stages 3 and 4 patients is based on baseline intact parathyroid hormone (iPTH) levels.
| Baseline iPTH Level | Daily Dose | Three Times a Week Dose* |
| ≤ 500 pg/mL | 1 mcg | 2 mcg |
| > 500 pg/mL | 2 mcg | 4 mcg |
| * To be administered not more often than every other day | ||
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.
| Dose Adjustment at 2 to 4 Week Intervals | |||
| iPTH Level Relative to Baseline | Zemplar 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 |
| * To be administered not more often than every other day | |||
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 or an elevated Ca x P is observed, the dose of Zemplar should be reduced or withheld until these parameters are normalized.
Serum calcium and phosphorus levels should be closely monitored after initiation of Zemplar 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
Zemplar Capsules are to be administered three times a week, not more frequently than every other day.
Zemplar 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 Zemplar 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 Zemplar 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 or elevated Ca x P 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 or Ca x P are 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
Zemplar Capsules are available as 1 mcg, 2 mcg, and 4 mcg soft gelatin capsules.
- 1 mcg: oval, gray capsule imprinted with Abbott “A” logo and “ZA”
- 2 mcg: oval, orange-brown capsule imprinted with Abbott “A” logo and “ZF”
- 4 mcg: oval, gold capsule imprinted with Abbott “A” logo and “ZK”
4 CONTRAINDICATIONS
Zemplar Capsules should not be given to patients with evidence of
- hypercalcemia or
- vitamin D toxicity [see Warnings and Precautions (5.1) ].
5 WARNINGS AND PRECAUTIONS
Excessive administration of vitamin D compounds, including Zemplar 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 Zemplar 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 Zemplar treatment to avoid hypercalcemia.
5.2 Digitalis Toxicity
Digitalis toxicity is potentiated by hypercalcemia of any cause. Use caution when Zemplar 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.
5.4 Aluminum Overload and Toxicity
Aluminum-containing preparations (e.g., antacids, phosphate binders) should not be administered chronically with Zemplar, 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 Zemplar 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 Zemplar Capsules treated patients and 4% of placebo treated patients discontinued from clinical studies due to an adverse event. Adverse events occurring in the Zemplar Capsules group at a frequency of 2% or greater and more frequently than in the placebo group are presented in Table 1:
| Number (%) of Subjects | ||||
| Adverse Eventa | Zemplar 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%) |
| a. Includes only events more common in the Zemplar treatment group. | ||||
The following adverse reactions, with a causal relationship to Zemplar, occurred in <2% of the Zemplar 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 Zemplar 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 Zemplar Capsules and 27 patients received placebo.
The proportion of patients who terminated prematurely from the study due to adverse events was 7% for Zemplar Capsules treated patients and 7% for placebo patients.
Adverse events occurring in the Zemplar Capsules group at a frequency of 2% or greater and more frequently than in the placebo group are as follows:
| Number (%) of Subjects | ||||
| Adverse Eventsa | Zemplar 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%) |
| a. Includes only events more common in the Zemplar treatment group. | ||||
The following adverse reactions, with a causal relationship to Zemplar, occurred in <2% of the Zemplar 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
