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Aetna Aetna
Clinical Policy Bulletin:
Calcitriol and Paricalcitol Injections
Number: 0022


Policy

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:

  • Cystic fibrosis
  • Multiple sclerosis
  • Non-small-cell lung cancer
  • Prostate cancer, other solid tumors/cancers

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:

  • Cardiovascular diseases (e.g., heart failure, hypertension, peripheral vascular disease, vascular calcification, and ventricular hypertrophy)
  • Diabetic nephropathy
  • Myelodysplastic syndrome
  • Pancreatic cancer
  • Post-transplantation nephropathy

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.

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.

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.

 
CPT Codes / HCPCS Codes / ICD-9 Codes
Other CPT codes related to the CPB:
82310 - 82331
83970
84100
96372
96379
HCPCS codes covered if selection criteria are met:
J0636 Injection, calcitriol, 0.1 mcg
J2501 Injection, paricalcitol, 1 mcg
ICD-9 codes covered if selection criteria are met:
275.41 Hypocalcemia
585.6 End stage renal disease
588.81 Secondary hyperparathyroidism (of renal origin)
V45.11 Renal dialysis status
ICD-9 codes not covered for indications listed in the CPB (not all-inclusive):
140.0 - 209.36, 209.75 Malignant neoplasm
238.72 - 238.75 Myelodysplastic syndromes
249.40 - 249.41 Secondary diabetes with renal manifestations [diabetic nephropathy]
250.40 - 250.43 Diabetes with renal manifestations [diabetic nephropathy]
277.00 - 277.09 Cystic fibrosis
340 Multiple sclerosis
401.0 - 401.9 Hypertension
402.00 - 402.11 Hypertensive heart disease, malignant
425.11 - 425.18 Hypertrophic cardiomyopathy
428.0 - 428.9 Heart failure
443.0 - 443.9 Other peripheral vascular disease
583.81 Nephritis and nephropathy, not specified as acute or chronic, in diseases classified elsewhere
996.81 Complications of transplanted organ [post-transplantation nephropathy]
V42.0 Organ or tissue replaced by transplant (kidney) [post-transplantation nephropathy]
Other ICD-9 codes related to the CPB:
252.00 - 252.08 Hyperparathyroidism
277.89 Other specified disorders of metabolism [resulting in bone diseases]
733.00 - 733.99 Other disorders of bone and cartilage [metabolic]


The above policy is based on the following references:
  1. Llach F, Yudd M. Pathogenic, clinical, and therapeutic aspects of secondary hyperparathyroidism in chronic renal failure. Am J Kidney Dis. 1998;32(2 Suppl 2):S3-S12.
  2. Dabbagh S. Renal osteodystrophy. Curr Opin Pediatr. 1998;10(2):190-196.
  3. Felsenfeld AJ. Considerations for the treatment of secondary hyperparathyroidism in renal failure. J Am Soc Nephrology. 1997;8(6):993-1004.
  4. Fukazawa M, Kuroki K. Pathogenesis and medical treatment of secondary hyperparathyroidism. Semen Surg Oncol. 1997;13(2):73-77.
  5. Tominaga Y, Johansson H, Johansson H, et al. Secondary hyperparathyroidism: Pathophysiology, histopathology, and medical and surgical management. Surg Today. 1997;27(9):787-792.
  6. Fernandez E, Llach F. Guidelines for dosing of intravenous calcitriol in dialysis patients with hyperparathyroidism. Nephrol Dial Transplant. 1996;11(Suppl 3):96-101.
  7. Daisley-Kydd RE, Mason NA. Calcitriol in the management of secondary hyperparathyroidism of renal failure. Pharmacotherapy. 1996;16(4):619-630.
  8. Martin K, Gonzalez E, Gellens M, et al. 19-nor-1-alpha-25-dihydroxyvitamin D2 (Paricalcitol) safely and effectively reduces the levels of intact parathyroid hormone in patients on hemodialysis. J Am Soc Nephrol. 1998;9(8):1427-1432.
  9. Andress DL. Intravenous versus oral vitamin d therapy in dialysis patients: What is the question? Am J Kidney Dis. 2001;38(5 Suppl 5):S41-S44.
  10. Martin KJ, Gonzalez EA. Vitamin D analogues for the management of secondary hyperparathyroidism. Am J Kidney Dis. 2001;38(5 Suppl 5):S34-S40.
  11. Sanchez CP. Prevention and treatment of renal osteodystrophy in children with chronic renal insufficiency and end-stage renal disease. Semin Nephrol. 2001;21(5):441-450.
  12. Brown AJ. Therapeutic uses of vitamin D analogues. Am J Kidney Dis. 2001;38(5 Suppl 5):S3-S19.
  13. Sprague SM, Lerma E, McCormmick D, et al. Suppression of parathyroid hormone secretion in hemodialysis patients: Comparison of paricalcitol with calcitriol. Am J Kidney Dis. 2001;38(5 Suppl 5):S51-S56.
  14. Slatopolsky E, Brown AJ. Vitamin d analogs for the treatment of secondary hyperparathyroidism. Blood Purif. 2002;20(1):109-112.
  15. Turk U, Akbulut M, Yildiz A, et al. Comparative effect of oral pulse and intravenous calcitriol treatment in hemodialysis patients: The effect on serum IL-1 and IL-6 levels and bone mineral density. Nephron. 2002;90(2):188-194.
  16. Morosetti M, Jankovic L, Cetani F, et al. High doses of intravenous calcitriol in the treatment of severe secondary hyperparathyroidism. J Nephrol. 2004;17(1):95-100.
  17. Baskin E, Ozen S, Karcaaltincaba M, et al. Beneficial role of intravenous calcitriol on bone mineral density in children with severe secondary hyperparathyroidism. Int Urol Nephrol. 2004;36(1):113-118.
  18. Beer TM, Myrthue A, Eilers KM. Rationale for the development and current status of calcitriol in androgen-independent prostate cancer. World J Urol. 2005;23(1):28-32.
  19. Tartaglia F, Giuliani A, Sgueglia M, et al. Randomized study on oral administration of calcitriol to prevent symptomatic hypocalcemia after total thyroidectomy. Am J Surg. 2005;190(3):424-429.
  20. Robinson DM, Scott LJ. Paricalcitol: A review of its use in the management of secondary hyperparathyroidism. Drugs. 2005;65(4):559-576.
  21. Koeffler HP, Aslanian N, O'Kelly J. Vitamin D(2) analog (Paricalcitol; Zemplar) for treatment of myelodysplastic syndrome. Leuk Res. 2005;29(11):1259-1262.
  22. Rosery H, Bergemann R, Marx SE, et al. Health-economic comparison of paricalcitol, calcitriol and alfacalcidol for the treatment of secondary hyperparathyroidism during haemodialysis. Clin Drug Investig. 2006;26(11):629-638.
  23. Johnson CS, Muindi JR, Hershberger PA, Trump DL. The antitumor efficacy of calcitriol: Preclinical studies. Anticancer Res. 2006;26(4A):2543-2549.
  24. Beer TM, Myrthue A. Calcitriol in the treatment of prostate cancer. Anticancer Res. 2006;26(4A):2647-2651.
  25. Greenbaum LA, Benador N, Goldstein SL, et al. Intravenous paricalcitol for treatment of secondary hyperparathyroidism in children on hemodialysis. Am J Kidney Dis. 2007;49(6):814-823.
  26. Sowery RD, So AI, Gleave ME. Therapeutic options in advanced prostate cancer: Present and future. Curr Urol Rep. 2007;8(1):53-59. 
  27. Cozzolino M, Galassi A, Gallieni M, Brancaccio D. Pathogenesis and treatment of secondary hyperparathyroidism in dialysis patients: The role of paricalcitol. Curr Vasc Pharmacol. 2008;6(2):148-153.
  28. Tu SM, Lin SH. Current trials using bone-targeting agents in prostate cancer. Cancer J. 2008;14(1):35-39.
  29. Niino M, Fukazawa T, Kikuchi S, Sasaki H. Therapeutic potential of vitamin D for multiple sclerosis. Curr Med Chem. 2008;15(5):499-505.
  30. Smolders J, Damoiseaux J, Menheere P, Hupperts R. Vitamin D as an immune modulator in multiple sclerosis, a review. J Neuroimmunol. 2008;194(1-2):7-17.
  31. Abdul Gafor AH, Saidin R, Loo CY, et al. Intravenous calcitriol versus paricalcitol in haemodialysis patients with severe secondary hyperparathyroidism. Nephrology (Carlton). 2009;14(5):488-492.
  32. Haiyang Zhou, Chenggang Xu. Comparison of intermittent intravenous and oral calcitriol in the treatment of secondary hyperparathyroidism in chronic hemodialysis patients: A meta-analysis of randomized controlled trials. Clin Nephrol. 2009;71(3):276-285.
  33. Muindi JR, Johnson CS, Trump DL, et al. A phase I and pharmacokinetics study of intravenous calcitriol in combination with oral dexamethasone and gefitinib in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2009;65(1):33-40.
  34. Chiang KC, Chen TC. Vitamin D for the prevention and treatment of pancreatic cancer. World J Gastroenterol. 2009;15(27):3349-3354.
  35. de Zeeuw D, Agarwal R, Amdahl M, et al. Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): A randomised controlled trial. Lancet. 2010;376(9752):1543-1551.
  36. Soloway B. Vitamin D receptor activation reduces albuminuria in patients with diabetic nephropathy. Summary and Comment. JWatch Gen Med. 2010 Nov 24.
  37. Chadha MK, Tian L, Mashtare T, et al. Phase 2 trial of weekly intravenous 1,25 dihydroxy cholecalciferol (calcitriol) in combination with dexamethasone for castration-resistant prostate cancer. Cancer. 2010;116(9):2132-2139.
  38. Nuijten M, Andress DL, Marx SE, et al. Cost Effectiveness of Paricalcitol versus a non-selective vitamin D receptor activator for secondary hyperparathyroidism in the UK: A chronic kidney disease markov model. Clin Drug Investig. 2010;30(8):545-557.
  39. Reis FN. The unsolved cyclosporine-induced kidney injury: Is paricalcitol a feasible new renoprotective option? Kidney Int. 2010;77(12):1055-1057.
  40. Henderson RC, Lester G. Vitamin D levels in children with cystic fibrosis. South Med J. 1997;90(4):378-383.
  41. Ferguson JH, Chang AB. Vitamin D supplementation for cystic fibrosis. Cochrane Database Syst Rev. 2009;(4):CD007298.
  42. Tamez H, Zoccali C, Packham D, et al. Vitamin D reduces left atrial volume in patients with left ventricular hypertrophy and chronic kidney disease. Am Heart J. 2012;164(6):902-909.
  43. Thadhani R, Appelbaum E, Pritchett Y, et al. Vitamin D therapy and cardiac structure and function in patients with chronic kidney disease: The PRIMO randomized controlled trial. JAMA. 2012;307(7):674-684.
  44. Gonzalez-Parra E, Rojas-Rivera J, Tunon J, et al. Vitamin D receptor activation and cardiovascular disease. Nephrol Dial Transplant. 2012;27 Suppl 4:iv17-iv21.
  45. Cozzolino M, Stucchi A, Rizzo MA, et al. Vitamin D receptor activation and prevention of arterial ageing. Nutr Metab Cardiovasc Dis. 2012;22(7):547-552.
  46. Ramnath N, Daignault-Newton S, Dy GK, et al. A phase I/II pharmacokinetic and pharmacogenomic study of calcitriol in combination with cisplatin and docetaxel in advanced non-small-cell lung cancer. Cancer Chemother Pharmacol. 2013;71(5):1173-1182.


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