Zemplar 1 Microgram Capsules Soft
Out of date information, search anotherZemplarlV 5mcg ml SmPC after the renewal Approval Date 21 Sept 07
Zemplar (paricalcitol) SmPC
1
SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
Zemplar 5 microgram/ml Solution for Injection
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml of solution for injection contains 5 micrograms of paricalcitol. Each 2 ml of solution for injection contains 10 micrograms of paricalcitol.
For excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Solution for Injection
A clear and colourless aqueous solution
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Paricalcitol is indicated for the prevention and treatment of secondary hyperparathyroidism in patients with chronic renal failure undergoing haemodialysis.
4.2 Posology and method of administration
Zemplar solution for injection is administered via haemodialysis access.
Adults
1) Initial Dose should be calculated based on baseline parathryroid hormone (PTH) levels:
The initial dose of paricalcitol is based on the following formula:
Initial dose (micrograms) = baseline intact PTH level in pmol/l
8
OR
= baseline intact PTH level in pg/mL 80
and administered as an intravenous (IV) bolus dose no more frequently then every other day at any time during dialysis.
The maximum dose safely administered in clinical studies was as high as 40 pg.
2) Titration Dose:
The currently accepted target range for PTH levels in end-stage renal failure subjects undergoing dialysis is no more than 1.5 to 3 times the non-uremic upper limit of normal, 15.9 to 31.8 pmol/l (150300 pg/ml), for intact PTH. Close monitoring and individual dose titration are necessary to reach appropriate physiological endpoints. If hypercalcaemia or a persistently elevated corrected Ca x P product greater than 5.2 mmol2/l2 (65 mg2/dl2) is noted, the dosage should be reduced or interrupted until these parameters are normalised. Then, paricalcitol administration should be reinitiated at a lower dose. Doses may need to be decreased as the PTH levels decrease in response to therapy.
The following table is a suggested approach for dose titration:
|
Suggested Dosing Guidelines (Dose adjustments at 2 to 4 week intervals) | |
|
iPTH Level Relative to |
Paricalcitol Dose |
|
Baseline |
Adjustment |
|
Same or increased |
Increase by 2 to 4 |
|
Decreased by < 30% |
micrograms |
|
Decreased by >30%, <60% |
Maintain |
|
Decreased > 60% |
Decrease by 2 to 4 micrograms |
|
IPTH < 15.9 pmol/l (150 pg/mL) | |
Once dosage has been established, serum calcium and phosphate should be measured at least monthly. Serum intact PTH measurements are recommended every three months. During dose adjustment with paricalcitol, laboratory tests may be required more frequently.
Hepatic insufficiency
Unbound concentrations of paricalcitol in patients with mild to moderate hepatic impairment are similar to healthy subjects and dose adjustment is not necessary in this patient population. There is no experience in patients with severe hepatic impairment.
Pediatric Use
Data in pediatric patients are limited and no data for children under the age of 5 are available. See Section 5.1 for study results.
Geriatric Use
There is a limited amount of experience with patients 65 years of age or over receiving paricalcitol in the phase III studies. In these studies, no overall differences in efficacy or safety were observed between patients 65 years or older and younger patients.
4.3 Contraindications
Hypersensitivity to paricalcitol or any of the excipients
Vitamin D toxicity
Hypercalcemia
4.4 Special warnings and precautions for use
Over suppression of parathyroid hormone may result in elevations of serum calcium levels and may lead to metabolic bone disease. Patient monitoring and individualized dose titration is required to reach appropriate physiological endpoints.
Digitalis toxicity is potentiated by hypercalcemia of any cause, so caution should be applied when digitalis is prescribed concomitantly with paricalcitol.
If clinically significant hypercalcemia develops, and the patient is receiving a calcium-based phosphate binder, the dose of the calcium-based phosphate binder should be reduced or interrupted.
This medicinal product contains 20% v/v of ethanol (alcohol). Each dose may contain up to 1.3g ethanol.Harmful for those suffering from alcoholism.
To be taken into account in pregnant or breast-feeding women, children and high risk groups such as patients with liver disease or epilepsy.
Caution should be exercised if co-administering paricalcitol with ketoconazole.
4.5 Interaction with other medicinal products and other forms of interaction
Specific interaction studies were not performed. Digitalis toxicity is potentiated by hypercalcaemia of any cause, so caution should be applied when digitalis s is prescribed concomitantly with paricalcitol.
Phosphate or vitamin D-related medicinal products should not be taken concomitantly with paricalcitol, due to an increased risk of hypercalcaemia and Ca x P product elevation.
Aluminium-containing preparations (e.g., antacids, phosphate-binders) should not be administered chronically with Vitamin D medicinal products , as increased blood levels of aluminium and aluminium bone toxicity may occur.
High doses of calcium-containing preparations or thiazide diuretics may increase the risk of hypercalcaemia.
Magnesium-containing preparations (e.g. antacids) should not be taken concomitantly with vitamin D preparations, because hypermagnesemia may occur.
Ketoconazole: The effect of multiple doses of ketaconazole administered as 200 mg, twice daily (BID) for 5 days on the pharmacokinetics of paricalcitol capsule has been studied in healthy subjects. The Cmax of paricalcitol was minimally affected, but AUC0-® approximately doubled in the presence of ketoconazole. The mean half-life of paricalcitol was 17.0 hours in the presence of ketoconazole as compared to 9.8 hours, when paricalcitol was administered alone (See PRECAUTIONS Section 4.4)
4.6 Pregnancy and lactation
There is no adequate data on the use of paricalcitol in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). Potential risk in human use is not known,therefore paricalcitol should be not be used unless clearly necessary.
Lactation: It is not known whether paricalcitol is excreted in human milk. Because many active substances are excreted in human milk, caution should be exercised when paricalcitol is administered to a nursing woman.
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive a car and use machines have been performed.
4.8 Undesirable effects
Approximately 600 patients were treated with Zemplar in Phase II/III/IV clinical trials. Overall, 6% of the Zemplar treated patients reported adverse reactions.
The most common adverse reaction associated with Zemplar therapy was hypercalcaemia, occurring in 4.7% of patients. Hypercalcaemia is dependent on the level of PTH oversuppression and can be minimised by proper dose titration. .
Adverse reactions from clinical trials that were possibly, probably or definitely related to paricalcitol are presented in the following table by body system and frequency. The following frequency categories are used: Very common (>1/10); common (>1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10,000, <1/1000); very rare (<1/10000, including isolated reports).
|
Body System |
Frequency |
Adverse Reaction |
|
Endocrine system |
Common |
parathyroid disorder |
|
Haematological and lymphatic system |
Uncommon |
Anaemia, leucopoenia, lymphadenopathy, increased bleeding time |
|
Immune system disorder |
Common |
pruritus |
|
Uncommon |
allergic reaction, rash |
|
Metabolic and nutrition disorders |
Common |
Hypercalcemia, hyperphosphatemia, |
|
Uncommon |
oedema, , peripheral oedema, increased AST, and weight loss | |
|
Nervous system |
Uncommon |
confusion, delirium, dizziness, abnormal gait, agitation, depersonalisation, hypesthesia, insomnia, myoclonus, nervousness, paraesthesia and stupor |
|
Special senses |
Common |
taste perversion, |
|
Uncommon |
conjunctivitis, ear disorder, and glaucoma | |
|
Cardiovascular system |
Uncommon |
Hypotension, arrhythmia, atrial flutter, cerebral ischaemia, cerebrovascular accident, cardiac arrest, hypertension, and syncope |
|
Respiratory System |
Uncommon |
asthma, increased cough, dyspnoea, epistaxis, pulmonary oedema, pharyngitis, and pneumonia |
|
Digestive system |
Uncommon |
anorexia, colitis, constipation, diarrhoea, dry mouth, dysphagia, gastrointestinal disorder, gastritis, rectal haemmorrhage, thirst, nausea, vomiting, dyspepsia |
|
Skin and Appendages |
Uncommon |
alopecia, hirsutism, rash, sweating, and vesiculobullous |
|
Musculoskeletal System |
Uncommon |
arthralgia, myalgia, joint disorder, and twitching |
|
Urogenitial system |
Uncommon |
Impotence, breast carcinoma, breast pain, and vaginitis |
|
Body as a whole |
Common |
Headache |
|
Uncommon |
injection site pain, pain, asthenia, back pain, chest pain, fever, flu syndrome, infection, malaise, and sepsis |
Post -Marketing Adverse Reactions
Immune system disorders, hypersensitivity
Angioedema, laryngeal oedema and urticaria have been reported rarely.
4.9 Overdose
Overdosage of paricalcitol may lead to hypercalcemia.
Treatment of patients with clinically significant hypercalcaemia consists of immediate dose reduction or interruption of paricalcitol therapy and includes a low calcium diet, withdrawal of calcium supplements, patient mobilisation, attention to fluid and electrolyte imbalances, assessment of electrocardiographic abnormalities (critical in patients receiving digitalis), and haemodialysis or peritoneal dialysis against a calcium-free dialysate, as warranted.
Serum calcium levels should be monitored frequently until normocalcaemia ensues.
Paricalcitol is not significantly removed by dialysis.
Zemplar solution for injection contains 30% v/v of propyleneglycol as an excipient. Isolated cases of Central Nervous System depression, haemolysis and lactic acidosis have been reported as toxic effect associated with propyleneglycol administration at high doses. Although they are not expected to be found with Zemplar administration as propyleneglycol is eliminated during the dialysis process, the risk of toxic effect in overdosing situations has to be taken into account.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmaco-therapeutic group: Vitamin D and analogues - ATC code: A11CC Mechanism of action:
Paricalcitol is a synthetic, biologically active vitamin D analog of calcitriol with modifications to the side chain (D2) and the A (19-nor) ring allowing for selective vitamin D receptor (VDR) activation. Paricalcitol selectively upregulates the VDR in the parathyroid glands without increasing VDR in the intestine and is less active on bone resorption. Paricalcitol also upregulates the calcium sensing receptor (CaSR) in the parathyroid glands. As a result, paricalcitol reduces parathyroid hormone (PTH) levels by inhibiting parathyroid proliferation and decreasing PTH synthesis and secretion, with minimal impact on calcium and phosphorus levels, and can act directly on bone cells to maintain bone volume and improve mineralization surfaces. Correcting abnormal PTH levels, with normalization of calcium and phosphorus homeostasis, may prevent or treat the metabolic bone disease associated with chronic kidney disease.
Paediatric clinical data: The safety and effectiveness of Zemplar were examined in a 12-week randomised, double-blind, placebo-controlled study of 29 pediatric patients, aged 5-19 years, with end-stage renal disease on hemodialysis. The six youngest Zemplar-treated patients in the study were 5 - 12 years old. The initial dose of Zemplar was 0.04 mcg/kg 3 times per week, based on baseline iPTH level of less than 500 pg/mL, or 0.08 mcg/kg 3 times a week based on baseline iPTH level of > 500 pg/mL, respectively. The dose of Zemplar was adjusted in 0.04 mcg/kg increments based on the levels of serum iPTH, calcium, and Ca x P. 67% of the Zemplar-treated patients and 14% placebo-treated patients completed the trial. 60% of the subjects in the Zemplar group had 2 consecutive 30% decreases from baseline iPTH compared with 21% patients in the placebo group. 71% of the placebo patients were discontinued due to excessive elevations in iPTH levels. No subjects in either the Zemplar group or placebo group developed hypercalcemia. No data are available for patients under the age of 5.
5.2 Pharmacokinetic properties
Distribution
The pharmacokinetics of paricalcitol have been studied in patients with chronic renal failure (CRF) requiring haemodialysis. Paricalcitol is administered as an intravenous bolus injection. Within two hours after administering doses ranging from 0.04 to 0.24 microgram/kg, concentrations of paricalcitol decreased rapidly; thereafter, concentrations of paricalcitol declined log-linearly with a mean half-life of about 15 hours. No accumulation of paricalcitol was observed with multiple dosing.
Elimination
In healthy subjects, a study was conducted with a single 0.16 microgram/kg intravenous bolus dose of 3H-paricalcitol (n=4), plasma radioactivity was attributed to parent substance. Paricalcitol was eliminated primarily by hepatobiliary excretion, as 74% of the radioactive dose was recovered in faeces and only 16% was found in urine.
Metabolism
Several unknown metabolites were detected in both the urine and faeces, with no detectable paricalcitol in the urine. These metabolites have not been characterised and have not been identified. Together, these metabolites contributed 51% of the urinary radioactivity and 59% of the faecal radioactivity. In vitro plasma protein binding of paricalcitol was extensive (>99.9%) and nonsaturable over the concentration range of 1 to 100 ng/mL.
|
Paricalcitol Pharmacokinetic Characteristics in CRF Patients (0.24 pg/kg dose) | ||
|
Parameter |
N |
Values (Mean ± SD) |
|
Cmax ( 5 minutes after bolus) |
6 |
1850±664 (pg/mL) |
|
AUCo.o. |
5 |
27382 ± 8230 (pg^hr/mL) |
|
CL |
5 |
0.72 ± 0.24 (L/hr) |
|
Vss |
5 |
6 ± 2 (L) |
Special Populations
Gender, Race and Age : No age or gender related pharmacokinetic differences have been observed in adult patients studied. Pharmacokinetic differences due to race have not been identified.
Hepatic insufficiency: Unbound concentrations of paricalcitol in patients with mild to moderate hapatic inpairment is similar to healthy subjects and dose adjustement is not necessary in this patient population. There is no experience in patients with severe hepatic impairment.
5.3 Preclinical safety data
Salient findings in the repeat dose toxicology studies in rodents and dogs were generally attributed to paricalcitol’s calcaemic activity. Effects not clearly related to hypercalcaemia included decreased white blood cell counts and thymic atrophy in dogs, and altered APTT values (increased in dogs, decreased in rats). WBC changes were not observed in clinical trials of paricalcitol.
Paricalcitol did not affect fertility in rats and there was no evidence of teratogenic activity in rats or rabbits. High doses of other vitamin D preparations applied during pregnancy in animals lead to teratogenesis . Paricalcitol was shown to affect foetal viability, as well as to promote a significant increase of peri-natal and post-natal mortality of newborn rats, when administered at maternally toxic doses.
Paricalcitol did not exhibit genotoxic potential in a set of in-vitro and in-vivo genotoxicity assays
Carcinogenicity studies in rodents did not indicate any special risks for human use.
Doses administered and/or systemic exposures to paricalcitol were slightly higher than therapeutic doses/systemic exposures.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Ethanol (20 % v/v)
Propylene glycol Water for Injections
6.2 Incompatibilities
Propylene glycol interacts with heparin and neutralises its effect. Zemplar solution for injection contains propylene glycol as an excipient and should be administered through a different injection port than heparin.
This medicinal product must not be mixed with other medicinal products.
6.3 Shelf life 2 years.
After opening, use immediately
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and content of container
Zemplar solution for injection 1 ml or 2 ml in Type I glass ampoule; box of 5.
6.6 Instructions for use and handling
Parenteral medicinal products should be inspected visually for particulate matter and discoloration prior to administration. The solution is clear and colourless.
For single use only. Any unused solution should be discarded.
7. MARKETING AUTHORISATION HOLDER
Abbott Laboratories, S.A.
Avenida de Burgos, 91 28050 - Madrid
8. MARKETING AUTHORISATION NUMBER
64.974
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 9 August 2002 Date of Last renewal: 9 August 2007
10. DATE OF REVISION OF THE TEXT
4 October 2007
Date of revision: October 2007