calcitriol administration

ADMINISTRATION OF CALCITRIOL

Introduction

Back in 2001, my veterinarian's initial reaction to using calcitriol to treat my Scooter Cat's chronic renal disease was negative - she believed that calcitriol was expensive and that subsequent monitoring was very expensive and that calcitriol treatment frequently resulted in hypercalcemia. Fortunately for my Scooter Cat, a call from my vet's old pathology professor, Dr. Larry Nagode, helped convince my vet that her understanding of calcitriol was dated, that the frequency of hypercalcemia using the new micro-compounded doses of calcitriol was nil, and that it was worth a try.

The actual first year cost for Scooter's calcitriol treatment was a $120 PTH/iCA test and an $80 prescription for a highly concentrated liquid oral suspension of calcitriol. Subsequent monitoring was already part of the every 3 month testing done for Scooter's renal condition which included serum calcium. Incremental costs for years 2 & 3 ran about $100 a year. Calcitriol's effect on Scooter was immediate, improving his energy and appetite almost instantly. My vet now routinely recommends calcitriol as soon as chronic renal disease is diagnosed.

Overview

Much of this web site is devoted to material to help vets and pet owners decide if calcitriol is an appropriate treatment for their patients and pets. This section, however, assumes that the decision to go ahead with calcitriol has been made and addresses the mechanics of actually starting calcitriol therapy. This is written for both treating veterinarians and cat owners. It is assumed that most decisions will be made jointly by owner and veterinarian. The information here will also help both veterinarians and cat owners estimate the cost of treatment. In brief, the steps involved include:

Controlling Phosphorus. Serum phosphorus values must be less than 6 mg/dl to begin calcitriol therapy. If necessary, aluminum hydroxide binders should be mixed with the animal's food to help bring phosphorus levels within bounds.
PTH/iCA Test. Deciding whether an expensive parathyroid hormone / ionized calcium (PTH/iCA) test is necessary prior to starting calcitriol and conducting the test if appropriate.
Base Daily Dose. Deciding on the base daily dose of calcitriol in nanograms/kilogram/day based on available test results and the cat's condition.
Daily or Intermittent? Deciding whether dosing will be daily or every 3.5 days (intermittent).
Fasting? Deciding whether fasting is necessary and/or desirable and, if yes, deciding on a fasting scheme.
Liquid Suspension or Capsules? Deciding whether to use the liquid suspension or pre-measured capsules for calcitriol administration.
Purchasing calcitriol from a vendor.
Administering calcitriol.
Follow-up testing and monitoring.

1. Controlling Phosphorus. Serum phosphorus values must be less than 6 mg/dl to begin calcitriol therapy. The Phosphorus Binders page of the CRF Supplies site covers aluminum hydroxide binders in some detail, including products, vendors and Dr. Larry Nagode's protocol for dosing aluminum hydroxide binders. If an animal requires phosphorus binders to control phosphorus below 6, binders should be continued during calcitriol administration. IMPORTANT: Epakitin and other calcium-based binders are not appropriate for dogs and cats that are being treated with calcitriol or are candidates for treatment with calcitriol. Calcium-based binders increase the risk of hypercalcemia.

2. PTH/ica Test. A parathyroid hormone (PTH) / ionized calcium (ICa) test is useful in determining whether PTH is elevated and whether hypercalcemia is a concern and deciding on the appropriate dose of calcitriol.. It's an expensive test, however, and not always necessary. For cats in early CRF with normal calcium values, the test is desirable rather than necessary. For cats in the later stages of the disease or for cats with elevated calcium, a PTH/iCA is strongly recommended prior to calcitriol administration. The Michigan State University (MSU) College of Veterinary Medicine Diagnostic Center for Population and Animal Health (DCPAH) does a Intact Parathyroid Hormone and Ionized Calcium test for $28. With the sample preparation and shipping costs (refrigerate or freeze sample prior to shipment - shipment on ice via overnight courier - must arrive below 60 F) and your vet's profit, expect to pay $60-$100. Other commercial labs such as IDEXX and Antech can also do the test (IDEXX actually reships the sample to MSU) – expect your vet to charge $130-$150.

3. Base daily dose. The treating veterinarian will decide the animal's daily dose of calcitriol in nanograms per kilogram (ng/kg) of body weight. Drs. Nagode and Chew recommend a starting dose of 2.5-3.5 ng/kg for most cases. Animals in early CRF with low creatinine values and normal serum calcium are usually prescribed the minimum dose. Animals in later stages of the disease with elevated PTH will likely be prescribed doses at or near the top end of the 2.5-3.5 ng/kg range. In a few cases where PTH is significantly elevated, the starting dose may be higher than 3.5 ng.

Dr. Larry Nagode of the Ohio State University College of Veterinary Medicine is willing to consult with treating veterinarians on the setting the initial dosage and other aspects of calcitriol treatment.. He's now a retired Professor Emeritus so he may be difficult to reach. He's easiest to reach through the Veterinary Information Network (VIN) forums and through leaving a note with "Attn: Dr. Nagode" in the subject line at the Yahoo Calcitriol Group although you can call the phone number below and leave a message for a callback or try his office email.

Dr Larry Nagode, 0331 Goss Laboratory, 1925 Coffey Rd, Columbus, OH 43210
Phone: (614) 292-4262, Email: nagode.1@osu.edu

Once the daily dosing decision has been made, it's easy to calculate the calcitriol dosage in nanograms. Let's say that a typical 10 lb cat in early CRF has been prescribed a 2.5 ng/kg base daily dosage.

Convert the animal's weight from pounds to kilograms	10 lbs * .454 = 4.54 kilograms (kg)
Multiply the animal's weight in kilograms by the base daily dose	4.54 kg * 2.5 ng/kg = 11.3 nanograms (ng daily dose)
If intermittent dosing, multiple daily dose in nanograms by 3.5 (days).	11.3 ng * 3.5 = 39.7 nanograms (every 3.5 day ng intermittent dose)

Here's a spreadsheet that will help calculate doses and help you calculate costs and compare vendors.

The decisions on daily versus intermittent (every 3.5 days) dosing (see #4 below) and fasting (see #5 below) are linked to the medical aspects of the base daily dose decision and should be made at the same time.

4. Daily versus Intermittent Dosing. If the pet in question has calcium issues (consistent serum calcium reading close to the top of the normal range and/or elevated, ionized calcium readings above normal, etc.), Dr. Nagode strongly recommended that every 3.5 day intermittent dosing be used (see the Fasting section below). If the foregoing is not the case, the decision to go daily or intermittent may be influenced by lifestyle, convenience and financial aspects.

Lifestyle: Daily doses are given at the same time every day. Intermittent doses are given 84 hours apart, e.g. , if you give a dose at 7 pm on Tuesday evening, the following dose would be at 7 am on Saturday morning, then back to 7pm on Tuesday and so on

Convenience. Pets getting daily doses usually do not have to be fasted except in some rare cases -- read #5 below. Pets getting every 3.5 day intermittent doses generally require a fast before the calcitriol and a shorter fast after (see #5 below).

Financial: Intermittent dosing can be cheaper, especially if you use the liquid suspension rather than the pre-measured capsules (see #6 below), buy more concentrated suspensions of calcitriol and administer small doses of the concentrated suspension. Although this is covered in more detail below, here's a quick example. Using April 2008 pricing from Franck's Pharmacy [Franck's closed in September 2012], a pet needing a daily dose of 12 nanograms of calcitriol could use 12 nanogram pre-measured capsules from Franck's at a annual cost of about $197, or get daily doses of .13 mL of a 96 mg/mL suspension from Franck's at an annual cost of $158 or get every 3.5 day intermittent doses of .22 mL of a 192 ng/mL solution from Franck's at an annual cost of $105.04. All price estimates include shipping.

5. Fasting. The following was derived from four 2008 emails from Dr. Nagode. Dr. Nagode is quoted extensively below. Dr. Nagode stresses that all decisions on dosing and fasting should be taken in consultation with the treating veterinarian. The information below is a guideline to help in those dosing and fasting decisions.

In general, Dr. Nagode believes "… when calcium levels are at or near top of the normal range, fasting is indicated no matter whether dosing daily or intermittently (each 3.5 days) with the first option pursued when calcium runs high being use of intermittent [every 3.5 days] dosing which is much more powerful versus hypercalcemia than fasting the daily dosed patient." Dr. Nagode currently recommends two dosing schemes – daily and every 3.5 days. He no longer endorses "every other day" (EOD) dosing.

	*Fasting?? (See foot notes)*
*Serum Calcium Levels*	*Daily Dose*	*Every 3.5 Day Dose*
Near the Top of the Normal Range or Higher	Recommended (1)(3)	Recommended (3)
Mid-Range Normal to Top Half of Normal Range	Not Necessary (1)	Advisable (2)
Lower Normal Range	Not Necessary (1)	Desirable (4)

Notes:

Daily Dosing. Fasting is unnecessary UNLESS the cat's calcium is high normal or higher. Dr. Nagode's preference is always for animals with calcium issues to receive every 3.5 day dosing but if that's not possible and daily dosing is necessary, he recommends that cats with high normal or elevated calcium be fasted. He suggests a pre-fast running 2-4 hours and a post-fast from 30 minutes-1 hour – the higher the calcium values, the longer the pre and post fasts. (see #3 below for more details on suggested fasts).

For animals on every 3.5 day dosing with calcium below top-end of normal. Fasting is not required if the animal's serum calcium is in the lower-half of the normal range. For cats with serum calcium in the upper half of the normal range but lower than the top-end of said range, Dr. Nagode suggests a minimal fast --- 1 hour before calcitriol administration and 15-30 minutes after. "Although doses each 3.5 days are higher than daily doses, I would rather use the terminology that "fasting is advisable" rather than mandatory. This would be particularly true for the somewhat unusual case in which the calcium levels were running on the low side and owner wished (presumably for economic reasons) to dose each 3.5 days--then fasting would be of little value. As a precaution, for those with calcium [values] running from mid-normal range to upper limit of normal, however, I would say that it's advisable--but would not wish to go to mandatory" with final judgments made in consultation with the local veterinarian who is on the scene and can make judgments based on all the information at hand."

For cats on every 3.5 day dosing with calcium values at the top end of the normal range or higher, Dr. Nagode recommends fasting. "My definition of a fast is conditional upon how marked the calcium problem is. For truly worrisome elevations like over 13 mg/dl total calcium both going to intermittent dosing and a 3-4 hour before, 1 hour after would be indicated. Milder elevations could go with say 2 hour, 30 minute approach with extent of fast modifiable depending upon what the results of subsequent blood calcium checks were. All of these strategies are impacted by outcomes (resulting blood calcium levels) and modifiable also in accord with how the outcomes fall out. Setting hard and fast protocols are therefore --although seemingly desirable--better avoided with a "feeling the way" to best outcome almost always the better approach."

Last, even for cats being dosed every 3.5 days and in the lower half of the normal range, Dr. Nagode suggests in his protocol that " … when doses > 5 ng/kg are needed [Editor: every 3.5 days doses are all > 5 ng/kg] … best given at bedtime on an empty stomach to prevent hypercalcemia." But Dr. Nagode expands on this in the following, noting that it's desirable rather than necessary and may be precluded by the circumstances of an instant case. "… it [every 3.5 day dosing] has come into use probably more than for any other reasons for financial ones in that it is cheaper and almost certainly (evidence is not as complete as many would wish) just as effective as daily dosing and thus in instances in which hypercalcemia is not feared or existing empty stomach dosing is not as critical. Is it recommended? I would say, yes it is likely wise. Is it MANDATORY? -- I would say no --in many instances such as in particular those described by a [Yahoo Calcitriol] group member ... who had great problems due to many circumstances in keeping her cat adequately fed … [due to] many such factors, therefore, I think it is better to use terms like "suggested." etc., rather than required," although the latter may be more satisfying for the purposes of creating guidelines, they for one thing cut the local veterinarian's judgment (which can be very valuable considering those factors which impact the "whole picture") out of the picture leading owners to views that they "must" do things in a rigid defined way when this may or may not be the case depending upon circumstances.”

6. Capsules or Liquid Suspension. Calcitriol is available in two forms - capsules and a liquid suspension which requires an oral syringe to measure and administer doses.

Capsules. Capsules contain a pre-measured dose of calcitriol. The major advantage of capsules is convenience. But if the dosage of calcitriol is changed, you may be stuck with some expensive, unusable medication -- it's difficult if not impossible to extract the medication from the capsules, remeasure it and repackage it. Also, dosing is less exact than using the liquid suspension. For example, Franck's sold capsules in 14 sizes ranging from 4 nanograms to 160 nanograms. A 10 lb cat prescribed a base daily of calcitriol requires 11.3 nanograms a day would use a 12 nanogram capsule from Franck's. If the same cat were dosed every 3.5 days, however, it would require 39.55 nanograms of calcitriol per dose. That cat's choice would be between a 32 nanogram capsule and a 48 nanogram capsule. Deciding whether to round the dose up or down would be dependent upon the cat's condition. Last, capsules cost more per year than the liquid suspension (see liquid suspension below).

Liquid Suspensions. As long as the dose is kept to a reasonable volume, e.g., between .1 and .25 mL, the oral syringe form of administration using the calcitriol liquid suspension is easy and has several advantages over capsules. First, if the vendor provides a fine syringe such as the Baxa Exacta-Med syringe and an Adapta-Cap (see pictures below), the dosing can be very precise. Second, you can easily change the dosage if necessary. Third, you can use more concentrated calcitriol suspensions (measured in nanograms per of milliliter) that allow small doses (easy to administer) and also can reduce the yearly cost of calcitriol. For example, a 10 lb cat getting a base dose of 2.5 ng/mg requires 11.3 nanograms of calcitriol daily. Franck's sold 100 12-nanogram capsules for $44 plus $9.95 shipping, a yearly cost of $196.92. If a liquid suspension were used instead, however, a pet owner could opt for 15 mL of Franck's 96 ng/mL suspension at $42 plus $9.95 shipping. Each 15 mL bottle would provide 127 .12 mL doses and the 96 ng/mL suspension would cost $xxx per year. Please note that all Franck's prices quoted are from April 2008.

Baxa Exacta-Med Syringe Adapta-Cap

7. Purchasing Calcitriol from a Vendor. Calcitriol must be micro-compounded into doses fit for animal use. Calcitriol is usually purchased from a pharmacy that does veterinary compounding. A prescription from your veterinarian is required. Some veterinary compounding pharmacies will only sell directly to veterinarians. This allows veterinarians to add an additional charge for their profit. If you take your vet's prescription and deal with a veterinary compounding pharmacy that sells directly to pet owners, the price should be lower, often considerably lower. Here is a list of Veterinary Compounding Pharmacies that will sell directly to pet owners and compound calcitriol.

Compounded calcitriol for animal use is available from many compounding pharmacies in the US. Since Franck's has closed, Triad is only one that Dr. Nagode personally recommends because they are the only two that he has personal knowledge of their compounding procedures. If you are thinking about using another provider, Dr. Nagode suggests that your vet or your should " ... check in with the proposed providing pharmacy" simply inquiring "what is done to protect versus oxidative injury?". If the question is met with a puzzled response or the statement that 'we just dilute a stock solution from wholesaler', then a request that they look into the matter should be made--and if they lack interest in so doing, an alternative provider should be sought." "Calcitriol when compounded for veterinary use needs to have stabilizing agents included to protect its three alcoholic groups from oxidation by the polyunsaturated oils used to dilute the calcitriol. Veterinarians are encouraged to use one of the more experienced compounding pharmacies to ensure stable appropriate dosages."

Please note that many compounding pharmacies purchase calcitriol liquid calcitriol suspensions from compounding wholesalers such as PCAA and dilute as needed. The stabilizing agents referred to above may already have been added to the concentrated suspension. Still, the selling pharmacy should be aware of this and/or willing to research the issue. If they don't understand the concern about protecting the alcoholic groups from oxidation, best to buy elsewhere. (Do try to speak to a compounding pharmacist or technician rather than a pharmacy clerk..)

8. Administering Calcitriol.

Daily. If you can, it's best to administer calcitriol at bedtime. Calcitriol should be given separately from other meds and should not be administered with food. You can use either pre-measured capsules purchased from a vendor or an oral suspension. The oral suspension can be administered via an oral syringe or you may place the appropriate dose in an empty gel cap and administer it that way.

Intermittent (Every 3.5 days). Every 3.5 days does mean every 84 hours. During the three years Scooter received calcitriol, he got a dose Tuesday evening (after we picked up his food for an appropriate pre-fast) and 84 hours later got a dose on Saturday morning, after we had picked up his food Friday night for a pre-fast.) Because of the larger doses involved in intermittent dosing, pre and post fasts are critical. See the directions above.

Other Dosing Schemes (Every 3 days). I asked Dr. Nagode whether it was possible to use an every 3 days and then 4 days scheme for intermittent dosing. His answer was no, that a dose of calcitriol would not be effective much beyond 3.5 days. He did, however, say that you could use an every 3 day scheme for calcitriol. This would allow folks to dose at the same time every 3rd night, much easier for the required pre and post fasts.

9. Follow-up Testing and Monitoring. Early experimentation using much higher doses of calcitriol to treat renal disease in animals led to many cases of hypercalcemia. Consequently, vets did a lot of testing to ensure the current microcompounded doses now used were safe. Now that the relatively safety of properly administered calcitriol has been established, the follow-up testing under the protocol of Drs. Nagode and Chew is much reduced.

A PTH/iCA test is "nice to have" rather than necessary in animals in early CRF with normal calcium values. For animals in more advanced stages of renal disease, the test is recommended. Some vets do this test 10-days after commencement of calcitriol treatment rather than prior to treatment to better assess the possible hypercalcemic side effect.
10 days after commencement of calcitriol treatment, Drs. Nagode and Chew recommend a serum calcium test. If calcium is elevated, this is an early-warning sign for hypercalcemia.
If the 10-day serum calcium test is normal, subsequent serum calcium tests should be done at the same time as BUN, creatinine and other normal renal disease follow-ups. For cats in early CRF, this will probably mean every 6 months or so. For cats in the later stages of the disease, such testing will be more frequent. Since the serum calcium monitoring is being done at the same time as other renal disease monitoring, the additional cost (if any) will be nominal.