Aetna considers calcitriol (Calcijex) or paricalcitol (Zemplar) injection medically necessary for the management of hypocalcemia and/or secondary hyperparathyroidism in members with chronic renal failure undergoing hemodialysis.
Aetna considers calcitriol injection experimental and investigational for the treatment of the following diseases (not an all-inclusive list) because its safety and effectiveness for these indications has not been established:
Aetna considers paricalcitol injection experimental and investigational for the treatment of the following diseases (not an all-inclusive list) because its safety and effectiveness for these indications has not been established:
See also CPB 0020 - Injectable Medications.Background
Calcitriol is an anti-hypocalcemic agent or calcium regulator. It is used to suppress the levels of parathyroid hormone (PTH). Calcijex, the parenteral form of calcitriol, is used when patients have not responded to an oral form of calcitriol (Rocaltrol). Calcijex is administered intravenously. Paricalcitol (Zemplar), a vitamin D analog, is administered as an intravenous bolus injection and can be delivered at any time during dialysis. Paricalcitol is the most widely used vitamin D analog in the United States.
Studies have reported that parenteral calcitriol is more effective than pulse oral calcitriol in suppressing PTH (Andress 2001). Available evidence indicates that parenteral vitamin D therapy is associated with fewer episodes of hypercalcemia and hyperphosphatemia and that patients receiving pulse oral calcitriol require more phosphate binders. Because of the documented high non-compliance rate with oral medications in the dialysis population, parenterally administered vitamin D or vitamin D analog is expected to more completely suppress PTH and result in fewer parathyroidectomies.
Calcitriol is also available in oral form. Oral calcitriol (Rocaltrol) is indicated for hypoparathyroidism and pseudohypoparathyroidism. Oral calcitriol is also indicated for secondary hyperparathyroidism and resultant metabolic bone diseases in persons with moderate to severe renal failure not yet on dialysis.
Topical calcitriol (e.g., Vectical) is used for treatment of mild to moderate plaque psoriasis in adults.
Investigators are studying the potential anti-tumor effects of calcitriol and paricalcitol. In a review, Beer et al (2005) stated that calcitriol has been reported to exhibit significant anti-neoplastic activity in pre-clinical models of prostate cancer and many other tumor types. Its mechanisms of activity may include inhibition of proliferation, cell cycle arrest, induction of apoptosis, as well as reduction of invasiveness and angiogenesis. Differing mechanisms may be involved in different tumor types and under different experimental conditions. Pre-clinical data suggest that calcitriol acts via a synergistic and/or additive manner when combined with anti-neoplastic agents that are relevant to prostate cancer such as dexamethasone and several classes of cytotoxic agents. However, the anti-neoplastic effects of calcitriol occur at levels that markedly exceed the normal physiological range and cannot be safely attained with conventional daily dosing. Intermittent administration of calcitriol has allowed significant dose escalation. When used with weekly docetaxel (Taxotere), calcitriol produced encouraging results in a single-center phase II clinical trial. These investigators noted that an international placebo-controlled randomized study is under way to ascertain the safety and effectiveness of this combinational therapy.
In a phase I and pharmacokinetics study, Muindi et al (2009) determined the maximum tolerated dose (MTD) of intravenously (i.v.) calcitriol administered in combination with a fixed oral dose of dexamethasone and gefitinib in patients with refractory solid tumors. A fixed oral dose of dexamethasone of 4 mg/day was given every 12 hrs x 3 doses starting 12 hrs prior to i.v. calcitriol administration. Calcitriol was administered i.v. over 1 hr on weeks 1, 3, and weekly thereafter. The starting calcitriol dose level was 57 ug and escalation occurred in cohorts of 3 patients until the MTD was defined. Gefitinib was given at a fixed oral daily dose of 250 mg starting at week 2 (day 8). Serum calcitriol pharmacokinetics studies were performed on day 1 (calcitriol + dexamethasone) and on day 15 (calcitriol + dexamethasone + gefitinib). A total of 20 patients were treated. Dose-limiting hypercalcemia was observed in 2 out of the 4 patients receiving 163 mcg/week of calcitriol. Mean (+/- SE) peak serum calcitriol concentration (C (max)) at the MTD (125 microg/week calcitriol) was 11.17 +/- 2.62 ng/ml and the systemic exposure (AUC (0 to 72 hr)) of 53.30 +/- 10.49 ng h/ml. The relationship between calcitriol dose and either C (max) or AUC was linear over the 57-163 microg dose range. The authors concluded that the addition of a low-dose of dexamethasone allowed the safe escalation of calcitriol to the MTD of 125 microg/week. This dose level resulted in serum calcitriol concentrations that are associated with pre-clinical anti-tumor activity. However, no anti-tumor activity was noted clinically in patients with solid tumors.
Vitamin D analogues are being investigated in pancreatic cancer and other cancers. Chiang and Chen (2009) noted that pancreatic cancer is ranked 5th among cancer-related deaths worldwide with a 5-year survival rate of less than 5 %. Currently, surgery is the only effective therapy. However, most patients are diagnosed in the late stage and are not suitable for receiving curative surgery. Moreover, pancreatic cancer doesn't respond well to traditional chemotherapy and radiotherapy, leaving little effective treatment for advanced pancreatic cancer cases. 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)], the biologically active form of vitamin D(3), was originally identified during studies of calcium and bone metabolism, though it is now recognized that it exerts biological effects in almost every tissue in the body. Abundant evidence has shown that 1alpha,25(OH)(2)D(3) has anti-proliferative, apoptotic, pro-differentiation and anti-angiogensis effects in many types of cancer cells in vivo and in vitro, including breast, prostate, and colon. Similarly, the anti-tumor growth effect of 1alpha,25(OH)(2)D(3) on pancreatic cells has been demonstrated. The clinical use of 1alpha,25(OH)(2)D(3) is impeded by the lethal side effects of hypercalcemia and hypercalciuria. Thus, 1alpha,25(OH)(2)D(3) analogs, which are either equipotent or more potent than 1alpha,25(OH)(2)D(3) in inhibiting tumor cell growth but with fewer hypercalcemic and hypercalciuric side effects, have been developed for the treatment of different cancers. Recently, a pre-clinical study demonstrated that a less calcemic analog of 1alpha,25(OH)(2)D(3), 19-nor-1alpha,25(OH)(2)D(2) (paricalcitol), is effective in inhibiting tumor growth in vitro and in vivo, via up-regulation of p21 and p27 tumor suppressor genes. The authors stated that studies on the anti-tumor effects of a more potent analog of paricalcitol are underway; 1alpha,25(OH)(2)D(3) and its analogs are potentially attractive novel therapies for pancreatic cancer.
In a phase II clinial trial, Chadha et al (2010) examined the effects of intravenous calcitriol at a dose of 74 ug weekly (based on a recent phase I trial) and dexamethasone in patients with castration-resistant prostate cancer (CRPC). A 2-stage Kepner-Chang design was used. Oral dexamethasone at a dose of 4 mg was given weekly on days 1 and 2, and i.v. calcitriol (74 ug over 1 hour) was administered weekly on day 2 from 4 to 8 hours after the dexamethasone dose in patients with CRPC. Laboratory data were monitored weekly, and renal sonograms, computed tomography scans, and bone scans were obtained every 3 months. Disease response was assessed by using the Response Evaluation Criteria in Solid Tumors (RECIST) and standard criteria for prostate-specific antigen (PSA) response. The calcitriol dose was derived from the authors' recent phase I study. Of 18 evaluable patients, 15 patients were Caucasian (83 %). No patients had a complete or partial response by either RECIST or PSA response criteria. Fourteen patients had progressive disease, 2 patients refused to continue treatment (after 64 days and 266 days), and 2 patients remain on the trial (for 306 days and 412 days). The median time to disease progression was 106 days (95 % confidence interval [CI]: 80 to 182 days). Fourteen episodes of grade 3 or 4 toxicity were noted in 7 patients (cardiac arrhythmia, chest pain, dyspnea, hyperglycemia, hypercalcemia, hypocalemia, hypophosphatemia, and pain). Only 1 episode of grade 3/ 4 toxicity was related definitely to calcitriol (hypercalcemia). No treatment-related deaths were noted. The authors concluded that high-dose, i.v. calcitriol at a dose of 74 ug weekly in combination with dexamethasone was well-tolerated but failed to produce a clinical or PSA response in men with CRPC.
In a clinical trial (n = 12), Koeffler and colleagues (2005) examined the effect of oral paricalcitol in the treatment of patients with myelodysplastic syndrome (MDS) whose disease varied between an international prognostic scoring system of low to high. Drug was well-tolerated in all patients. No responses were observed according to international working group criteria. However, the platelet count of 1 of the 12 subjects rose from 53,500 to 120,000/ul blood over 5 weeks; but the patient succumbed to a fatal fungal infection. These investigators concluded that paricalcitol given as a single agent to MDS patients is therapeutically not very effective; further trials of the vitamin D analog should be considered in combination with other approaches.
In a randomized, placebo-controlled, double-blind study, de Zeeuw et al (2010) evaluated if paricalcitol could be used to reduce albuminuria in patients with diabetic nephropathy. Patients with type 2 diabetes and albuminuria who were receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were enrolled. Patients were assigned (1:1:1) by computer-generated randomization sequence to receive 24 weeks’ treatment with placebo,1 μg/day paricalcitol, or 2 μg/day paricalcitol. The primary end-point was the percentage change in geometric mean urinary albumin-to-creatinine ratio (UACR) from baseline to last measurement during treatment for the combined paricalcitol groups versus the placebo group. Analysis was by intention-to-treat. A total of 281 patients were enrolled and assigned to receive placebo(n = 93), 1 μg paricalcitol (n = 93), or 2 μg paricalcitol (n = 95); 88 patients on placebo, 92 on 1 μg paricalcitol, and 92 on2 μg paricalcitol received at least one dose of study drug, and had UACR data at baseline and at least one time-point during treatment, and so were included in the primary analysis. Change in UACR was: -3 % (from 61 to 60 mg/mmol; 95 % CI: 16 to 13) in the placebo group; -16 % (from 62 to 51 mg/mmol; -24 to -9) in the combined paricalcitol groups, with a between-group difference versus placebo of -15 % (95 % CI: -28 to 1; p = 0.071); -14 % (from 63 to 54 mg/mmol; -24 to -1) in the 1 μg paricalcitol group, with a between-group difference versus placebo of -11 % (95 % CI: -27 to 8; p = 0.23); and -20 % (from 61 to 49 mg/mmol; -30 to -8) in the 2 μg paricalcitol group, with a between-group difference versus placebo of -18 % (95 % CI: -32 to 0; p = 0.053). Patients on 2 μg paricalcitol showed a nearly, sustained reduction in UACR, ranging from -18 % to -28 % (p = 0.014 versus placebo). Incidence of hypercalcaemia, adverse events, and serious adverse events was similar between groups receiving paricalcitol versus placebo. The authors concluded that addition of 2 μg/day paricalcitol to renin-angiotensin-aldosterone system inhibition safely lowers residual albuminuria in patients with diabetic nephropathy, and could be a novel approach to lower residual renal risk in diabetes. Moreover, they stated that the safety, effectiveness, and minimal need for monitoring of this drug should encourage future studies with hard renal outcomes to prove its renal and cardiovascular protective effects. Soloway (2010) commented that this study suggests that paricalcitol might augment protection of renal function in patients with diabetes when added to angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. But this trial employed only surrogate endpoints; proof of efficacy will require longer studies with definitive renal and safety endpoints.
Vitamin D analogues are being examined as a treatment for multiple sclerosis. Niino and colleagues (2008) stated that multiple sclerosis (MS) is a major inflammatory and demyelinating disease of the central nervous system and has an increasing prevalence in populations residing at higher latitudes. This observation may indicate a protective effect of sunlight exposure, which is reduced at higher latitudes and may contribute to insufficient levels of vitamin D in the MS population. The vitamin D hormone is important for bone metabolism and can regulate cell proliferation and differentiation as well as apoptosis and immune regulation in immune cells such as T-helper cells and dendritic cells. Evidence from experimental autoimmune encephalomyelitis and prospective studies on MS suggests an important role of vitamin D as a modifiable environmental factor in MS. These provide guidance for future studies with regard to the potential role of vitamin D in the prevention and/or treatment of MS. In this regard, Smolders et al (2008) noted that there is a sound basis on which to initiate double-blind placebo-controlled studies that not only examine the effect of vitamin D on the clinical outcome of MS, but also on the regulatory T-cell compartment..
Reis (2010) stated that the management of cyclosporine A-induced nephrotoxicity remains one of the main challenges in kidney transplantation. The animal study by Park et al proposes that paricalcitol, a vitamin D analog with reno-protective actions reported in other conditions, attenuates cyclosporine A-induced kidney injury via the suppression of inflammatory, fibrotic, and apoptotic factors. However, before paricalcitol can be considered a feasible new therapeutic option for the management of patients with post-transplantation nephropathy, these interesting data require further studies evaluating other mechanisms of cyclosporine A-induced nephrotoxicity.
Henderson and Lester (1997) noted that serum levels of the important hormone 1,25-dihydroxyvitamin D (1,25-diOHD, calcitriol) have not been extensively evaluated in patients with cystic fibrosis (CF) during the critical period of skeletal growth and development. This study was a cross-sectional, observational assessment of 25-hydroxyvitamin D (25-OHD, calcidiol) and 1,25-diOHD levels in 54 patients with CF. The patients' ages ranged from 4.9 years to 19.5 years (mean of 11.0 years). Levels were correlated with pulmonary function tests, chest x-ray scores, height and weight Z scores, skinfold percentiles, CF genotype, serum chemistries, and use of a vitamin supplement. Levels were compared with those in more than 160 other pediatric patients living in the same region, and all assays were done in the same laboratory. Despite low-normal levels of the 25-OHD precursor, there was a high prevalence of low (18 %) and marginal (18 %) levels of 1,25-diOHD. None of the various parameters examined correlated with either 25-OHD or 1,25-diOHD levels. The cause, clinical significance, and treatment of low levels of this important hormone in children with CF warrant further study.
Ferguson and Chang (2009) stated that CF is a genetic disorder with multi-organ effects. In a subgroup with pancreatic insufficiency, malabsorption of the fat soluble vitamins (A, D, E, K) may occur. Vitamin D is involved in calcium homeostasis and bone mineralization and may have extra-skeletal effects. In a Cochrane review, these investigators evaluated the effects of vitamin D supplementation on the frequency of vitamin D deficiency, respiratory outcomes and vitamin D toxicity in the CF population. They searched the Cochrane CF and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Most recent search was June 9, 2009. Randomized and quasi-randomized controlled trials of vitamin D supplementation compared to placebo in the CF population regardless of exocrine pancreatic function. Both authors independently assessed the "risk of bias" of each included trial and extracted outcome data (from published trial information) for assessment of bone mineralization, growth and nutritional status, frequency of vitamin D deficiency, respiratory status, quality of life and adverse events. Three studies were included, although only data from 2 were available (41 adults and children with CF). One of these studies compared supplemental 800 international units (IU) vitamin D and placebo for 12 months in 30 osteopenic pancreatic insufficient adults; both groups continued 900 IU vitamin D daily. The other (abstract only) compared supplemental 1 g calcium alone, 1,600 IU vitamin D alone, 1,600 IU vitamin D and 1 g calcium and placebo in a double-blind randomized cross-over trial; only 11 children (vitamin D and placebo groups) after 6-months supplementation are included; inclusion criteria, pancreatic sufficiency or disease status of participants were not defined. There were no significant differences in primary or secondary outcomes in either study. The studies were not directly comparable due to differences in supplementation, outcome reporting and possibly participant characteristics (e.g., severity of lung disease, growth and nutrition, pancreatic sufficiency). There were no adverse events in either study. The 3rd study (abstract only) compared daily calcitriol (0.25 or 0.5 ug) with placebo in pancreatic insufficient children and young adults, only pre-intervention data were available. The authors concluded that there is no evidence of benefit or harm in the limited number of small-sized published trials.
Tamez et al (2012) noted that left atrial enlargement, a sensitive integrator of left ventricular diastolic function, is associated with increased cardiovascular (CV) morbidity and mortality. Vitamin D is linked to lower CV morbidity, possibly modifying cardiac structure and function; however, firm evidence is lacking. These investigators examined the effect of an activated vitamin D analog on left atrial volume index (LAVi) in a post-hoc analysis of the PRIMO trial. A total of 196 patients with chronic kidney disease (CKD; estimated glomerular filtration rate [GFR] 15 to 60 ml/min per 1.73m(2)), mild-to-moderate left ventricular hypertrophy, and preserved ejection fraction were randomly assigned to 2 μg of oral paricalcitol or matching placebo for 48 weeks. Two-dimensional echocardiography was obtained at baseline and at 24 and 48 weeks after initiation of therapy. Over the study period, there was a significant decrease in LAVi (-2.79 mL/m(2), 95 % CI: -4.00 to -1.59 ml/m(2)) in the paricalcitol group compared with the placebo group (-0.70 ml/m(2) [95 % CI: -1.93 to 0.53 mL/m(2)], p = 0.002). Paricalcitol also attenuated the rise in levels of brain natriuretic peptide (10.8 % in paricalcitol versus 21.3 % in placebo, p = 0.02). For the entire population, the change in brain natriuretic peptide correlated with change in LAVi (r = 0.17, p = 0.03). The authors concluded that 48 weeks of therapy with an active vitamin D analog reduces LAVi and attenuates the rise of BNP. They stated that in a population where only few therapies alter CV-related morbidity and mortality, these post-hoc results warrant further confirmation.
In a multi-national, double-blind, randomized, placebo-controlled trial, Thadhani et al (2012) examined the effects of paricalcitol on left ventricular mass over 48 weeks in patients with an estimated GFR of 15 to 60 ml/min/1.73 m(2). A total of 227 patients (from 11 countries) with CKD, mild-to-moderate left ventricular hypertrophy, and preserved left ventricular ejection fraction, were included in this study. Participants were randomly assigned to receive oral paricalcitol, 2 μg/day (n =115), or matching placebo (n = 112). Main outcome measures were change in left ventricular mass index over 48 weeks by CV magnetic resonance imaging; secondary end points included echocardiographic changes in left ventricular diastolic function. Treatment with paricalcitol reduced PTH levels within 4 weeks and maintained levels within the normal range throughout the study duration. At 48 weeks, the change in left ventricular mass index did not differ between treatment groups (paricalcitol group, 0.34 g/m(2.7) [95 % CI: -0.14 to 0.83 g/m(2.7)] versus placebo group, -0.07 g/m(2.7) [95 % CI: -0.55 to 0.42 g/m(2.7)]). Doppler measures of diastolic function including peak early diastolic lateral mitral annular tissue velocity (paricalcitol group, -0.01 cm/s [95 % CI: -0.63 to 0.60 cm/s] versus placebo group, -0.30 cm/s [95 % CI: -0.93 to 0.34 cm/s]) also did not differ. Episodes of hypercalcemia were more frequent in the paricalcitol group compared with the placebo group. The authors concluded that 48-week therapy with paricalcitol did not alter left ventricular mass index or improve certain measures of diastolic dysfunction in patients with CKD.
Gonzalez-Parra et al (2012) stated that vitamin D has been recently associated with several renal, cardiovascular and inflammatory diseases, beyond mineral metabolism and bone health. This is due in part to widespread expression of vitamin D receptor (VDR) on tissues and cells such as heart, kidney, immune cells, brain and muscle. In CKD and other chronic disorders, vitamin D deficiency [serum 25(OH)D less than 20 ng/ml] is very common and is associated with adverse outcomes. Paricalcitol has demonstrated in several experimental and clinical studies of diabetic and non-diabetic CKD a favorable profile compared to other VDR activators, alone or as add-on to standard therapy. These beneficial effects are mediated by different actions such as reduction of oxidative stress, inflammation, down-regulation of cardiac and renal renin expression, down-regulation of calcifying genes and direct vascular protective effects. Furthermore, paricalcitol beneficial effects may be independent of baseline serum PTH, calcium and phosphate levels. They stated that these benefits should be confirmed in large and well-designed ongoing clinical trials.
Cozzolino et al (2012) noted that in CKD patients, CV morbidity and mortality rate is higher than in the general population, because of frequently concomitant hypertension, peripheral vascular disease, heart failure, vascular calcification (VC), diabetes and mineral bone disease. Recently, another important factor associated to CV risk in CKD has been deeply investigated: vitamin D deficiency. Vitamin D receptors are present in several systems and tissues and VDR activation is associated with positive effects, resulting in better blood pressure control and prevention of diabetic nephropathy. Unfortunately, the natural, non-selective vitamin D receptor activator (VDRA), calcitriol, is associated with higher serum calcium and phosphate levels, thus worsening CV risk in CKD. Recent data showed that the selective VDRA paricalcitol might have ameliorative CV effects. The authors concluded that the potential positive impact of the use of paricalcitol on diabetic nephropathy, cardiac disease, hypertension, and VC may open new paths in the fight against CV disease in CKD patients.
In a phase I/II pharmacokinetic and pharmacogenomic study, Ramnath et al (2013) determined the recommended phase II dose (RP2D) of 1,25-D3 (calcitriol) with cisplatin and docetaxel and its effectiveness in metastatic non-small-cell lung cancer. Patients were greater than or equal to 18 years, PS 0-1 with normal organ function. In the phase I portion, patients received escalating doses of calcitriol intravenously every 21 days prior to docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) using standard 3 + 3 design, targeting dose-limiting toxicity (DLT) rate less than33 %. Dose levels of calcitriol were 30, 45, 60, and 80 mcg/m(2). A 2-stage design was employed for phase II portion. These investigators correlated CYP24A1 tagSNPs with clinical outcome and calcitriol pharmacokinetics (PK). A total of 34 patients were enrolled. At 80 mcg/m(2), 2/4 patients had DLTs of grade 4 neutropenia. Hypercalcemia was not observed. The RP2D of calcitriol was 60 mcg/m(2). Among 20 evaluable phase II patients, there were 2 confirmed, 4 unconfirmed partial responses (PR), and 9 stable disease (SD). Median time to progression was 5.8 months (95 % CI: 3.4 to 6.5), and median overall survival 8.7 months (95 % CI: 7.6 to 39.4). CYP24A1 SNP rs3787554 (C > T) correlated with disease progression (p = 0.03) and CYP24A1 SNP rs2762939 (C > G) trended toward PR/SD (p = 0.08). There was no association between calcitriol PK and CYP24A1 SNPs. The authors concluded that the RP2D of calcitriol with docetaxel and cisplatin was 60 mcg/m(2) every 21 days. Pre-specified end-point of 50 % confirmed RR was not met in the phase II study.
In a randomized, placebo-controlled, cross-over trial, Joergensen et al (2015) evaluated the effects of paricalcitol on markers of cardiovascular risk and kidney function in people with type 1 diabetes mellitus and diabetic nephropathy. A total of 48 participants on stable renin angiotensin aldosterone system blockade and diuretics were assigned, in random order, to 12 weeks of paricalcitol and 12 weeks of placebo therapy, separated by a 4-week washout period. Primary and secondary end-points were changes in plasma N-terminal probrain natriuretic peptide and urinary albumin excretion rate obtained before and after each intervention. Glomerular filtration rates were estimated and measured (51 Cr-EDTA plasma clearance GFR) after each intervention. The mean (SD) age of the participants was 57 (9) years, the baseline geometric mean (95 % CI) urinary albumin excretion rate was 148 (85 to 259) mg/24 hour, the mean (SD) HbA1c was 70 (9) mmol/mol [8.6 (3)%], the mean (SD) estimated GFR was 47 (15) ml/min/1.73 m2 and the mean 24-hour blood pressure was 135 (17)/74 (10) mmHg. Compared with placebo therapy, vitamin D analog therapy had no significant effect on plasma N-terminal probrain natriuretic peptide concentration (p = 0.6), urinary albumin excretion rate was reduced by 18 % (p = 0.03 for comparison), estimated GFR was reduced by 5 ml/min/1.73 m2 (p < 0.001) and measured GFR was reduced by 1.5 ml/min/1.73 m2 (p = 0.2). The authors concluded that paricalcitol therapy did not affect plasma N-terminal probrain natriuretic peptide concentration in people with type 1 diabetes and diabetic nephropathy; however, the urinary albumin excretion rate was significantly lowered.
Trillini et al (2015) noted that secondary hyperparathyroidism contributes to post-transplant CKD mineral and bone disorder. Paricalcitol decreased serum PTH levels and proteinuria in patients with secondary hyperparathyroidism. This single-center, prospective, randomized, cross-over, open-label study compared the effect of 6-month treatment with paricalcitol (1 μg/day for 3 months and then up-titrated to 2 µg/day if tolerated) or non-paricalcitol therapy on serum PTH levels (primary outcome), mineral metabolism, and proteinuria in 43 consenting recipients of renal transplants with secondary hyperparathyroidism. Participants were randomized 1:1 according to a computer-generated sequence. Compared with baseline, median (interquartile range) serum PTH levels significantly declined on paricalcitol from 115.6 (94.8 to 152.0) to 63.3 (52.0 to 79.7) pg/ml (p < 0.001) but not on non-paricalcitol therapy. At 6 months, levels significantly differed between treatments (p< 0.001 by analysis of co-variance). Serum bone-specific alkaline phosphatase and osteocalcin decreased on paricalcitol therapy only and significantly differed between treatments at 6 months (p < 0.001 for all comparisons). At 6 months, urinary deoxypyridinoline-to-creatinine ratio and 24-hour proteinuria level decreased only on paricalcitol (p < 0.05). Moreover, L3 and L4 vertebral mineral bone density, assessed by dual-energy x-ray absorption, significantly improved with paricalcitol at 6 months (p < 0.05 for both densities). Paricalcitol was well-tolerated. Overall, 6-month paricalcitol supplementation reduced PTH levels and proteinuria, attenuated bone remodeling and mineral loss, and reduced eGFR in renal transplant recipients with secondary hyperparathyroidism. The authors concluded that long-term studies are needed to monitor directly measured GFR, ensure that the bone remodeling and mineral effects are sustained, and determine if the reduction in proteinuria improves renal and cardiovascular outcomes.
Note on documentation requirements: Laboratory tests results (before initiation of therapy) should be documented in the member's medical record showing the medical necessity of the treatment. The member's medical record should clearly document the need for the calcitriol or paricalcitol injection(s). These records should be available upon request.
In open-label, randomized controlled study, Chen and colleagues (2015) evaluated the safety and effectiveness of calcitriol in the prevention and treatment of glucocorticoid-induced osteoporosis. A total of 66 patients treated with glucocorticoids (GC) for primary nephrotic syndrome (NS) were randomly assigned to 3 groups. Groups were designated as follows: (i) calcitriol alone (n = 22), (ii) calcitriol plus calcium carbonate (n = 23), or (iii) calcium carbonate alone (n = 21). Serum markers of bone metabolism and bone mineral density (BMD) were tested at 3 different time-points: the initiation of GC treatment (baseline), 12 weeks, and 24 weeks after the initiation of treatment. Levels of serum 25-hydroxy vitamin D, serum osteocalcin, and total serum collagen type N-terminal extension of the peptide were significantly decreased following GC therapy (p < 0.05). β-collagen serum-specific sequences were significantly increased following GC therapy. The above-mentioned changes were less dramatic in patients treated with calcitriol, although the differences were significant (p < 0.05). Changes in serum levels of calcium, phosphorus, alkaline phosphatase, and PTH were not significant; 24 weeks after the initiation of treatment, BMD of the lumbar spine and femoral bone significantly decreased in all of 3 groups. However, patients who received calcitriol had significantly higher BMD of the lumbar spine than patients who received calcium carbonate alone (calcitriol plus calcium carbonate versus calcium carbonate alone: 0.82 ± 0.19 g/cm2 versus 0.62 ± 0.23 g/cm2 p < 0.05; calcitriol versus calcium carbonate alone 0.805 ± 0.203 g/cm2 versus 0.615 ± 0.225 g/cm2 p < 0.05), respectively. No serious adverse events were observed. The authors concluded that calcitriol may be more effective than calcium carbonate in preventing and treating GC-induced osteoporosis in patients with NS. These preliminary findings need to be validated by well-designed studies.
In a phase II clinical trial, Leaf et al (2014) examined if administration of 1calcitriol to critically ill patients with sepsis would have beneficial effects on markers of innate immunity, inflammation, and kidney injury. These researchers performed a double-blind, randomized, placebo-controlled, physiologic study among 67 critically ill patients with severe sepsis or septic shock. Patients were randomized to receive a single dose of calcitriol (2 μg intravenously) versus placebo. The primary outcome was plasma cathelicidin protein levels assessed 24 hours after study drug administration. Secondary outcomes included leukocyte cathelicidin mRNA expression, plasma cytokine levels (IL-10, IL-6, tumor necrosis factor-α, IL-1β, and IL-2), and urinary kidney injury markers. Patients randomized to calcitriol (n = 36) versus placebo (n = 31) had similar plasma cathelicidin protein levels at 24 hours (p = 0.16). Calcitriol-treated patients had higher cathelicidin (p = 0.04) and IL-10 (p = 0.03) mRNA expression than placebo-treated patients 24 hours after study drug administration. Plasma cytokine levels (IL-10, IL-6, tumor necrosis factor-α, IL-1β, and IL-2) and urinary kidney injury markers were similar in calcitriol- versus placebo-treated patients (p > 0.05 for all comparisons). Calcitriol had no effect on clinical outcomes nor were any adverse effects observed. The authors concluded that calcitriol administration did not increase plasma cathelicidin protein levels in critically ill patients with sepsis and had mixed effects on other immunomodulatory markers. They stated that additional phase II trials investigating the dose and timing of calcitriol as a therapeutic agent in specific sepsis phenotypes may be warranted.
Dosage for Calcijex:
The FDA recommended initial dose of Calcijex (calcitriol), depending on the severity of the hypocalcemia and/or secondary hyperparathyroidism, is 1 meg (0.02 meg/kg) to 2 meg administered intravenously 3 times weekly, approximately every other day. Doses as small as 0.5 meg and as large as 4 meg 3 times weekly have been used as an initial dose. If a satisfactory response is not observed, the dose may be increased by 0.5 to 1 meg at 2 to 4 week intervals. During this titration period, serum calcium and phosphorus levels should be obtained at least twice-weekly. If hypercalcemia or a serum calcium times phosphate product greater than 70 is noted, the drug should be immediately discontinued until these parameters are appropriate. Then, the Calcijex dose should be re-initiated at a lower dose. Doses may need to be reduced as the PTH levels decrease in response to the therapy. Thus, incremental dosing must be individualized and commensurate with PTH, serum calcium and phosphorus levels.
Dosage for Zemplar:
Initial dose: 0.04 to 0.1 mcg/kg (2.8 to 7 mcg), injected as a bolus dose through a hemodialysis vascular access port at any time during dialysis.
|CPT Codes / HCPCS Codes / ICD-10 Codes|
|Information in the [brackets] below has been added for clarification purposes.  Codes requiring a 7th character are represented by "+":|
|Other CPT codes related to the CPB:|
|82310 - 82331||Calcium|
|83970||Parathormone (parathyroid hormone)|
|84100||Phosphorus inorganic (phosphate)|
|96372||Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular|
|96379||Unlisted therapeutic, prophylactic, or diagnostic intravenous or intra-arterial injection or infusion|
|HCPCS codes covered if selection criteria are met:|
|J0636||Injection, calcitriol, 0.1 mcg|
|J2501||Injection, paricalcitol, 1 mcg|
|ICD-10 codes covered if selection criteria are met:|
|N18.6||End stage renal disease|
|N25.81||Secondary hyperparathyroidism of renal origin|
|Z99.2||Dependence on renal dialysis|
|ICD-10 codes not covered for indications listed in the CPB:|
|A40.0 - A41.9||Sepsis|
|C00.0 - D09.9||Malignant neoplasm|
|D46.0 - D46.9||Myelodysplastic syndromes|
|E08.21, E09.21, E10.21, E11.21, E13.21||Diabetes mellitus with diabetic nephropathy|
|E84.0 - E84.9||Cystic fibrosis|
|I10||Essential (primary) hypertension|
|I11.0 - I11.9||Hypertensive heart disease|
|I42.1 - I42.2||Hypertrophic cardiomyopathy|
|I50.1 - I50.9||Heart failure|
|I73.0 - I73.9||Other peripheral vascular disease|
|M81.8||Other osteoporosis without current pathological fracture [glucocorticoid – induced]|
|N08||Glomerular disorders in diseases classified elsewhere|
|T86.10 - T86.19||Complications of kidney transplant [post-transplantation nephropathy]|
|Z94.0||Kidney transplant status|