Zemplar Capsules: Indications, Dosage, Precautions, Adverse Effects
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Zemplar Capsules - Product Information

Manufacture: AbbVie
Country: United States
Condition: Secondary Hyperparathyroidism
Class: Vitamins
Form: Capsules
Ingredients: Paricalcitol, butylhydroxytoluene, medium-chain triglycerides, gelatine, glycerol, titanium dioxide, iron oxide, black dye, purified water

Indications and Usage

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.

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).

Dosage and Administration

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].

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 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, Drug Interactions and Clinical Pharmacology].

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 and Clinical Studies].

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 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.

Dosage Forms and Strengths

Zemplar Capsules are available as 1 mcg and 2 mcg soft gelatin capsules.

  • 1 mcg: oval, gray capsule imprinted with the “a” logo and “ZA”
  • 2 mcg: oval, orange-brown capsule imprinted with the “a” logo and “ZF”

Contraindications

Zemplar Capsules should not be given to patients with evidence of

  • hypercalcemia or
  • vitamin D toxicity [see Warnings and Precautions].

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.

Hypercalcemia

Progressive hypercalcemia due to overdosage of vitamin D and its metabolites may be so severe as to require emergency attention [see Overdosage]. 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.

Digitalis Toxicity

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

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, Zemplar Capsules may increase serum creatinine and therefore decrease the estimated GFR (eGFR). Similar effects have also been seen with calcitriol.

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.

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.

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:

Table 1. Treatment-Emergent Adverse Events by Body System Occurring in ≥ 2% of Subjects in the Zemplar-Treated Group of Three, Double-Blind, Placebo-Controlled, Phase 3, CKD Stages 3 and 4 Studies; All Treated Patients
Number (%) of Subjects
Adverse Event a 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:

Table 2. Treatment-Emergent Adverse Events by Body System Occurring in ≥ 2% of Subjects in the Zemplar-Treated Group, Double-Blind, Placebo-Controlled, Phase 3, CKD Stage 5 Study; All Treated Patients
Number (%) of Subjects
Adverse Events a 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

Postmarketing Experience

The following additional adverse reactions have been reported during post-approval use and post-approval clinical trials with the active ingredient in Zemplar capsules:

Immune System Disorders: Angioedema (including laryngeal edema)

Metabolism and Nutrition Disorders: Hypercalcemia

Investigations: Blood creatinine increased

Drug Interactions

CYP3A Inhibitors

Since paricalcitol is partially metabolized by CYP3A, exposure of paricalcitol will be increased while paricalcitol is co-administered with strong CYP3A inhibitors including the following drugs but not limited to: ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor [see Clinical Pharmacology].

Cholestyramine

Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules.

Mineral Oil

The use of mineral oil or other substances that may affect absorption of fat may influence the absorption of Zemplar Capsules.

Use in Specific Populations

Pregnancy Pregnancy Category

Paricalcitol has been shown to cause minimal decreases in fetal viability (5%) when administered daily to rabbits at a dose 0.5 times a human dose of 14 mcg or 0.24 mcg/kg (based on body surface area, mcg/m2), and when administered to rats at a dose two times the 0.24 mcg/kg human dose (based on body surface area, mcg/m2). At the highest dose tested, 20 mcg/kg administered three times per week in rats (13 times the 14 mcg human dose based on surface area, mcg/m2), there was a significant increase in the mortality of newborn rats at doses that were maternally toxic and are known to produce hypercalcemia in rats. No other effects on offspring development were observed.

Paricalcitol was not teratogenic at the doses tested.

Paricalcitol (20 mcg/kg) has been shown to cross the placental barrier in rats. There are no adequate and well-controlled clinical studies in pregnant women. Zemplar Capsules should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

Nursing Mothers

Studies in rats have shown that paricalcitol is present in the milk. It is not known whether paricalcitol is excreted in human milk. In the nursing patient, 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

Safety and efficacy of Zemplar Capsules in pediatric patients have not been established.

Geriatric Use

Of the total number (n = 220) of CKD Stages 3 and 4 patients in clinical studies of Zemplar Capsules, 49% were age 65 and over, while 17% were age 75 and over. Of the total number (n = 88) of CKD Stage 5 patients in the pivotal study of Zemplar Capsules, 28% were age 65 and over, while 6% were age 75 and over. No overall differences in safety and effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Overdosage

Excessive administration of Zemplar Capsules can cause hypercalcemia, hypercalciuria, and hyperphosphatemia, and over suppression of PTH [see Warnings and Precautions].

Treatment of Overdosage

The treatment of acute overdosage of Zemplar Capsules should consist of general supportive measures. If drug ingestion is discovered within a relatively short time, induction of emesis or gastric lavage may be of benefit in preventing further absorption. If the drug has passed through the stomach, the administration of mineral oil may promote its fecal elimination. 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 institution of a low-calcium diet are also indicated in accidental overdosage. Due to the relatively short duration of the pharmacological action of paricalcitol, further measures are probably unnecessary. If persistent and markedly elevated serum calcium levels occur, there are a variety of therapeutic alternatives that may be considered depending on the patient's underlying condition. These include the use of drugs such as phosphates and corticosteroids, as well as measures to induce an appropriate forced diuresis.

Zemplar is not significantly removed by dialysis.

How Supplied/storage and Handling

Zemplar Capsules are available as 1 mcg and 2 mcg capsules.

The 1 mcg capsule is an oval, gray, soft gelatin capsule imprinted with the “a” logo and ZA, and is available in the following package size:

Bottles of 30 (NDC 0074-4317-30)

The 2 mcg capsule is an oval, orange-brown, soft gelatin capsule imprinted with the “a” logo and ZF, and is available in the following package size: Bottles of 30 (NDC 0074-4314-30)

Storage

Store Zemplar Capsules at 25°C (77°F). Excursions permitted between 15°- 30°C (59°- 86°F). See USP Controlled Room Temperature.

Patient Counseling Information

Patients should be advised:

  • of the most common adverse reactions with use of Zemplar Capsules, which include diarrhea, hypertension, dizziness and
  • to adhere to instructions regarding diet and phosphorus
  • to contact a health care provider if you develop symptoms of elevated calcium, (e.g. feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination and weight loss).
  • to return to the physician's office for routine monitoring. More frequent monitoring is necessary during the initiation of therapy, following dose changes or when potentially interacting medications are started or
  • to inform their physician of all medications, including prescription and nonprescription drugs, supplements, and herbal preparations they are taking and any change to their medical condition. Patients should also be advised to inform their physicians prescribing a new medication that they are taking Zemplar

2015 AbbVie Inc.

Manufactured For

AbbVie Inc.

North Chicago, IL 60064, U.S.A.

03-B217 October, 2015