Protocols For Drug Allergy Desensitization

Protocols for Rapid and Slow Drug Allergy Desensitization First Edition November, 2009 By Timothy J. Sullivan, M.D. Atlanta, Georgia

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Introduction This short monograph is a compilation of representative protocols that have been used in our clinics to desensitize patients who met generally accepted criteria for a diagnosis of drug allergy. The purpose of presenting this information is to facilitate the design of protocols for use by other clinicians or investigators. Approaches to patient specific diagnosis of drug allergy, assessment of relative risks, decisions about premedication, and other patient specific factors crucial to successful use of these protocols is beyond the scope of this monograph. Rapid desensitization protocols have been used to allow use of medications in patients with IgE-mediated sensitivity to medications. The mechanism seems to be primariy acute antigen-specific mast cell desensitization. The general principles are to initiate desensitization with low microgram amounts of drug, doubling the dose every 15 minutes, and then careful observation for 2 hours after the administration of the last dose. Individual patients may require lower starting doses and longer intervals between doses. Representative oral desensitization and intravenous desensitization protocols are presented. Code 95180 per hour of the procedure to the nearest hour. Slow desensitization protocols are used for management of patients with drug allergy involving 2

mechanisms other than antigen-specific IgE. The best evidence at the moment is that gradually increasing doses allow metabolic adaptation to increasing need to clear reactive drug metabolites. This efficient metabolism of the drug minimizes the formation of the haptenated carrier molecules that induce immune responses and elicit allergic reactions. This process would not be expected to work with complete antigens such as insulin or aminoglycosides. Regardless of mechanism, the principles are to start at a low dose and increase over one to four weeks or more to reach therapeutic doses. Approximately 15% of patients will not be controlled with a one or two week protocol and may need slower increases in doses. Modifications of the protocols to accommodate patient and drug issues are common in the published literature. As long as starting doses are low microgram doses, or lower, and the intervals between doses of antigen administration are not shortened the mast cell desensitization or metabolic adaptation has been reported to be successful with a wide variety of drug antigens.

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INTRODUCTION...............................................................................................................2 Rapid desensitization.......................................................................................................2 Slow desensitization.........................................................................................................2 ALENDRONATE (FOSAMAX) DESENSITIZATION....................................................5 AMOXICILLIN/CLAVULANATE DESENSITIZATION................................................6 ANASTROZOLE (ARIMIDEX) DESENSITIZATION.....................................................7 ASPIRIN DESENSITIZATION..........................................................................................8 AZITHROMYCIN DESENSITIZATION...........................................................................9 CEFDINIR DESENSITIZATION.....................................................................................10 CEFPODOXIME DESENSITIZATION...........................................................................11 CEPHALEXIN DESENSITIZATION..............................................................................12 CIPROFLOXACIN DESENSITIZATION.......................................................................13 CITALOPRAM (CELEXA) DESENSITIZATION..........................................................14 CLINDAMYCIN DESENSITIZATION...........................................................................15 CLONAZEPAM (KLONOPIN) DESENSITIZATION....................................................16 CLOPIDOGREL (PLAVIX) DESENSITIZATION.........................................................17 COUMADIN DESENSITIZATION.................................................................................18 COZAAR DESENSITIZATION.......................................................................................19 DEFERASIROX DESENSITIZATION............................................................................20 ESTRADIOL DESENSITIZATION PROTOCOL...........................................................21 ESTRADIOL (ESTRACE) DESENSITIZATION............................................................22 FEBUXOSTAT (ULORIC) DESENSITIZATION...........................................................23 GENTAMICIN INTRAVENOUS DESENSITIZATION.................................................24 HYDROCHLOROTHIAZIDE DESENSITIZATION......................................................25 INFLUENZA VACCINE DESENSITIZATION..............................................................26 INSULIN DESENSITIZATION.......................................................................................27 LEVOFLOXACIN DESENSITIZATION........................................................................28 METRONIDAZOLE DESENSITIZATION.....................................................................29 NITROFURANTOIN DESENSITIZATION....................................................................30 OPIATE SENSITIVITY....................................................................................................31 PACLITAXEL (TAXOL) INTRAVENOUS DESENSITIZATION................................32 PENICILLIN DESENSITIZATION – ORAL..................................................................33 PENICILLIN G INTRAVENOUS DESENSITIZATION - Materials..............................34 PENICILLIN G INTRAVENOUS DESENSITIZATION PROTOCOL..........................35 PIPERACILLIN/TAZOBACTAM INTRAVENOUS DESENSITIZATION .................36 SERTRALINE (ZOLOFT) DESENSITIZATION............................................................37 SULFASALAZINE (AZULFIDINE) DESENSITIZATION............................................38 TRIMETHOPRIM/SULFAMETHOXAZOLE DESENSITIZATION.............................39 VANCOMYCIN INTRAVENOUS DESENSITIZATION.............................................40

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ALENDRONATE (FOSAMAX) DESENSITIZATION Need oral solutions prepared in the pharmacy: 75 mL of 70 mg/ 75 mL Fosamax 100 mL of 0.7 mg/75 mL (1:100 of 75 mg/75 mL) • This protocol will provide a cumulative 10 mg dose of Fosamax. • Then conventional therapy with Fosamax 10 mg daily can begin. • Place the indicated amount of the oral solution in a cup. Add at least 25 mL of water and swirl to make swallowing small doses feasible. • Administer doses at least 15 minutes apart. Observe 2 hours after last dose. Dose Concentration 1 2 3 4 5 6 7 8 9

0.7 mg/75 mL 0.7 mg/75 mL 0.7 mg/75 mL 0.7 mg/75 mL 0.7 mg/75 mL 0.7 mg/75 mL 0.7 mg/75 mL 0.7 mg/75 mL 0.7 mg/75 mL

Amount (mL) 0.1 mL 0.2 0.4 0.8 1.6 3.2 6 12 25

10 11 12 13 14

70 mg/75 mL 70 mg/75 mL 70 mg/75 mL 70 mg/75 mL 70 mg/75 mL

0.5 1 2 3 4

Time

5

Comments

AMOXICILLIN/CLAVULANATE DESENSITIZATION Augmentin Oral Suspension 600 mg amoxicillin/5 mL and 1 : 100 of that (6 mg/5 mL) Dose 1 2 3 4 5 6 7

Concentratio n 6 mg/5 mL 6 mg/5 mL 6 mg/5 mL 6 mg/5 mL 6 mg/5 mL 6 mg/5 mL 6 mg/5 mL

Amount (mL) 0.03 0.06 0.12 0.25 0.5 1 2

8 9 10 11 12 13 14

600 mg/5 mL 600 mg/5 mL 600 mg/5 mL 600 mg/5 mL 600 mg/5 mL 600 mg/5 mL 600 mg/5 mL

0.04 0.08 0.15 0.3 0.6 1.2 2.5

Time

6

Comments

ANASTROZOLE (ARIMIDEX) DESENSITIZATION A slow desensitization (one that allows drug metabolism to keep up with the increasing doses, and also desensitizes mast cells) has been successful with Arimidex. We can use an oral suspension to deliver low doses. Since this is to start chronic therapy, we have used a protocol giving one dose once a day. We give the doses in the office to avoid errors by the patients. This would take ~2 weeks to reach full doses. Weekends provide logistical problems, but we prepare the weekend doses and give them to the patient to take at home on Fridays. We have started at 0.1 mcg (microgram) a day and doubled that amount every day. We reach full doses in about 2 weeks. The patient should be advised that if she stops the medication for more than 1 day, we would need to re-desensitize her. 0.1 mg Arimidex/mL suspension.

Have a compounding pharmacy prepare an oral

0.001 mg Arimidex/mL Have a compounding pharmacy prepare a 1:100 dilution of the 0.1 mg/mL suspension.

Dose

Amount (mL)

1 2 3 4 5 6 7 8 9

Concentratio n Arimidex 0.001mg/mL 0.001mg/mL 0.001mg/mL 0.001mg/mL 0.001mg/mL 0.001mg/mL 0.001mg/mL 0.001mg/mL 0.001mg/mL

10 11 12 13 14

0.1 mg/mL 0.1 mg/mL 0.1 mg/mL 0.1 mg/mL 0.1 mg/mL

0.5 mL 1 mL 2 mL 4 mL 8 mL

Date

0.1 mL 0.2 mL 0.4 mL 0.8 mL 1.6 mL 3.2 mL 6.4 mL 13 mL 25 mL

7

Comments

ASPIRIN DESENSITIZATION 325 mg Alka-Seltzer tablets One tablet in 100 mL water is ~3 mg/mL. Dissolve one tablet in 100 mL of water for each dose. The 0.3 mg/mL concentration is prepared immediately after preparing a 3 mg/mL solution by making a 1:10 dilution (e.g. 2 mL added to 18 mL of water) Each dose is prepared fresh from one Alka-Seltzer tablet in 100 mL of water. Give one dose every 15 minutes. Dose Concentration Volume

Given

Comments

1 0.3 mg/mL 0.1 mL 2 0.3 mg/mL 0.2 mL 3 0.3 mg/mL 0.4 mL 4 3 mg/mL 0.08 mL 5 3 mg/mL 0.16 mL 6 3 mg/mL 0.3 mL 7 3 mg/mL 0.6 mL 8 3 mg/mL 1.2 mL 9 3 mg/mL 2.5 mL 10 3 mg/mL 4 mL 11 3 mg/mL 8 mL 12 3 mg/mL 16 mL 13 3 mg/mL 32 mL 14 3 mg/mL 64 mL Then continue with aspirin therapy as desired, but one dose a day is needed to sustain desensitization.

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AZITHROMYCIN DESENSITIZATION Azithromycin 200 mg/5 mL stock Azithromycin 2 mg/5 mL (1 mL 200/5 + 99 mL water)

Dose Concentration Volume 1 2 3 4 5 6

2 mg/5mL 2 mg/5mL 2 mg/5mL 2 mg/5mL 2 mg/5mL 2 mg/5mL

0.06 mL 0.12 mL 0.25 mL 0.5 mL 1 mL 2 mL

7 8 9 10 11 12 13

200 mg/5mL 200 mg/5mL 200 mg/5mL 200 mg/5mL 200 mg/5mL 200 mg/5mL 200 mg/5mL

0.04 mL 0.08 mL 0.16 mL 0.32 mL 0.64 mL 1.25 mL 2.5 mL

9

Time

Comments

CEFDINIR DESENSITIZATION Cefdinir 250 mg/5 mL oral suspension Also need a 1:100 dilution (e.g. 1 mL of 250 mg/5 mL plus 99 mL of water) Dose Concentration Volume 1 2 3 4 5 6

2.5 mg/5mL 2.5 mg/5mL 2.5 mg/5mL 2.5 mg/5mL 2.5 mg/5mL 2.5 mg/5mL

Time

0.06 mL 0.12 mL 0.25 mL 0.5 mL 1 mL 2 mL

7 250 mg/5mL 0.04 mL 8 250 mg/5mL 0.08 mL 9 250 mg/5mL 0.16 mL 10 250 mg/5mL 0.32 mL 11 250 mg/5mL 0.64 mL 12 250 mg/5mL 1.25 mL 13 250 mg/5mL 2.5 mL Doses given q15minutes. Then 300 mg b.i.d.

10

Comments

CEFPODOXIME DESENSITIZATION Cefpodoxime 50 mg/5 mL oral solution used as starting material Cefpodoxime 0.5 mg/5 mL (1:100) used for initial doses Dose Concentration Volume 1 2 3 4 5 6

0.5 mg/5 mL 0.5 mg/5 mL 0.5 mg/5 mL 0.5 mg/5 mL 0.5 mg/5 mL 0.5 mg/5 mL

0.06 mL 0.12 mL 0.25 mL 0.5 mL 1 mL 2 mL

7 8 9 10 11 12 13

50 mg/5 mL 50 mg/5 mL 50 mg/5 mL 50 mg/5 mL 50 mg/5 mL 50 mg/5 mL 50 mg/5 mL

0.04 mL 0.08 mL 0.16 mL 0.32 mL 0.64 mL 1.25 mL 2.5 mL

11

Time

Comments

CEPHALEXIN DESENSITIZATION Cephaexin oral suspension 250 mg/5 mL and 1:100 of that (2.5 mg/5 mL) Dose Concentration Volume 1 2 3 4 5 6

2.5 mg/5mL 2.5 mg/5mL 2.5 mg/5mL 2.5 mg/5mL 2.5 mg/5mL 2.5 mg/5mL

0.06 mL 0.12 mL 0.25 mL 0.5 mL 1 mL 2 mL

7 8 9 10 11 12 13

250 mg/5mL 250 mg/5mL 250 mg/5mL 250 mg/5mL 250 mg/5mL 250 mg/5mL 250 mg/5mL

0.04 mL 0.08 mL 0.16 mL 0.32 mL 0.64 mL 1.25 mL 2.5 mL

12

Time

Comments

CIPROFLOXACIN DESENSITIZATION Ciprofloxacin Oral Solution 250 mg/mL: Need only about 25 mL Ciprofloxacin Oral Solution 2.5 mg/mL: Need 1 part 250 mg/5mL diluted in 99 parts water. Doses given at 15 minute intervals. Longer intervals OK, shorter are not. The patient should be observed for at least 2 hours after the last dose to be sure no reaction occurs as the drug continues to be absorbed. Once the first dose is given by desensitization, subsequent doses can be given in tablet form. Dose 1 2 3 4 5 6

Concentratio n 2.5 mg/5 mL 2.5 mg/5 mL 2.5 mg/5 mL 2.5 mg/5 mL 2.5 mg/5 mL 2.5 mg/5 mL

Amount (mL) 0.1 0.2 0.4 0.8 1.6 3.2

7 8 9 10 11 12 13 14

250 mg/5 mL 250 mg/5 mL 250 mg/5 mL 250 mg/5 mL 250 mg/5 mL 250 mg/5 mL 250 mg/5 mL 250 mg/5 mL

0.06 0.12 0.24 0.5 1 2 4 8

Time

13

Comments

CITALOPRAM (CELEXA) DESENSITIZATION Slow desensitization with 10 mg/5 mL and 1:100 of that (0.1 mg/5 mL) Day 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Concentration 0.1 mg/5 mL 0.1 mg/5 mL 0.1 mg/5 mL 0.1 mg/5 mL 0.1 mg/5 mL 0.1 mg/5 mL 10 mg/5 mL 10 mg/5 mL 10 mg/5 mL 10 mg/5 mL 10 mg/5 mL 10 mg/5 mL 10 mg/5 mL 10 mg/5 mL

Volume 0.06 mL 0.12 mL 0.25 mL 0.5 mL 1 mL 2 mL 0.05 mL 0.1 mL 0.2 mL 0.4 mL 0.8 mL 1.6 mL 3.2 mL 5 mL

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Comments Done Done Done Done Done Done Done Done Done Done Done Done Done Done

CLINDAMYCIN DESENSITIZATION Slow desensitization Clindamycin oral suspension 75 mg/5 mL, & 1:100 (0.75 mg/5 mL). Dose Concentration Volume

Day

1 2

0.75 mg/5mL 0.75 mg/5mL

0.05 mL 0.1 mL

AM PM

Monday Monday

3 4

0.75 mg/5mL 0.75 mg/5mL

0.2 mL 0.5 mL

AM PM

Tuesday Tuesday

5 6

0.75 mg/5mL 0.75 mg/5mL

1 mL 2 mL

AM PM

Wednesday Wednesday

7 8

75 mg/5mL 75 mg/5mL

0.05 mL 0.1 mL

AM PM

Thursday Thursday

9 10

75 mg/5mL 75 mg/5mL

0.2 mL 0.4 mL

AM PM

Friday Friday

11 12

75 mg/5mL 75 mg/5mL

0.8 mL 1.5 mL

AM PM

Saturday Saturday

13 14

75 mg/5mL 75 mg/5mL

3 mL 5 mL

AM PM

Sunday Sunday

15 16

75 mg/5mL 75 mg/5mL

10 mL 20 mL

AM PM

Monday Monday

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CLONAZEPAM (KLONOPIN) DESENSITIZATION Materials: 1. Prepare 25 mL of 0.2 mg/mL by making a suspension of 5 mg of Klonopin in 25 mL of syrup. 2. Prepare 20 mL of 0.02 mg/mL by placing 2 mL of 0.2 mg/mL in 18 mL of syrup. 3. Prepare 20 mL of 0.002 mg/mL by placing 2 mL of 0.02 mg/mL in 18 mL of syrup. 4. Prepare 20 mL of 0.0002 mg/mL by placing 2 mL of 0.002 mg/mL in 18 mL of syrup. Date

Dose Concentratio n 1 0.0002 mg/mL 2 0.0002 mg/mL 3 0.0002 mg/mL 4 0.0002 mg/mL

Comments

¼ tsp ½ tsp 1 tsp 2 tsp

5 6 7

0.002 mg/mL 0.002 mg/mL 0.002 mg/mL

½ tsp 1 tsp 2 tsp

8 9 10

0.02 mg/mL 0.02 mg/mL 0.02 mg/mL

½ tsp 1 tsp 2 tsp

11 12 13

0.2 mg/mL 0.2 mg/mL 0.2 mg/mL

½ tsp 1 tsp 2 tsp

14 • •

Amount

Oral tablets at desired dose

Doses are in teaspoons measured with a medicine spoon Doses are administered once a day

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CLOPIDOGREL (PLAVIX) DESENSITIZATION Need oral suspensions prepared in the pharmacy: 100 mL of 75 mg PLAVIX/5 mL 100 mL of 0.75 mg PLAVIX/5 mL (1:100 – 1 mL of the 75mg/5mL in 99 mL) • • • • Dose

This protocol will provide a cumulative 75 mg dose of Plavix. Then conventional therapy with Plavix can begin. Place the indicated amount of the oral suspension in a cup. Add at least 25 mL of water and swirl to make swallowing small doses feasible. Administer doses at least 15 minutes apart. Observe 2 hours after last dose.

1 2 3 4 5 6 7 8 9

Concentratio n 0.75 mg/5 mL 0.75 mg/5 mL 0.75 mg/5 mL 0.75 mg/5 mL 0.75 mg/5 mL 0.75 mg/5 mL 0.75 mg/5 mL 0.75 mg/5 mL 0.75 mg/5 mL

Amount (mL) 0.04 mL 0.08 0.15 0.3 0.6 1.2 2.5 5 10

10 11 12 13 14 15 16 17

75 mg/5 mL 75 mg/5 mL 75 mg/5 mL 75 mg/5 mL 75 mg/5 mL 75 mg/5 mL 75 mg/5 mL 75 mg/5 mL

0.2 0.4 0.7 0.15 0.3 0.6 1.3 2.5

Time

17

Comments

COUMADIN DESENSITIZATION Coumadin oral suspensions must be prepared: 2 mg/mL and 1:100 (0.02 mg/mL) Slow desensitization.

Dose Concentration 1 0.02 mg/mL 2 0.02 mg/mL 3 0.02 mg/mL 4 0.02 mg/mL 5 0.02 mg/mL 6 0.02 mg/mL 7 0.02 mg/mL 8 0.02 mg/mL 9 10 11 12 13 14

Amount 0.05 mL 0.1 mL 0.2 mL 0.4 mL 0.8 mL 1.6 mL 3 mL 6 mL

Day 1 2 3 4 5 6 7 8

0.1 mL 0.2 mL 0.4 mL 0.8 mL 1.6 mL 2.5 mL

9 10 11 12 13 14

2 mg/mL 2 mg/mL 2 mg/mL 2 mg/mL 2 mg/mL 2 mg/mL

Administer one dose a day. The last few days you should begin obtaining INR values. After finishing the desensitization you can begin the recommended dosage schedule.

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COZAAR DESENSITIZATION REAGENTS: 1. Cozaar Oral Suspension (0.1 and 10 mg/5mL ) 2. Tap water 3. Syringes and other measuring devices to measure doses from 0.1 mL to 10 mL PROCEDURE: 1. Administer one dose every 15 minutes 3. Follow the protocol below. Add extra water to doses less than 25 mL to make swallowing easier. Dose Concentration 1 0.1 mg/5 mL 2 0.1 mg/5 mL 3 0.1 mg/5 mL 4 0.1 mg/5 mL 5 0.1 mg/5 mL 6 0.1 mg/5 mL 7 0.1 mg/5 mL 8 0.1 mg/5 mL 9 10 11 12 13 14

10 mg/5 mL 10 mg/5 mL 10 mg/5 mL 10 mg/5 mL 10 mg/5 mL 10 mg/5 mL

Amount 0.05 mL 0.1 mL 0.2 mL 0.4 mL 0.8 mL 1.6 mL 3.2 mL 6.4 mL

Date/ Time

0.12 mL 0.25 mL 0.5 mL 1 mL 2 mL 4 mL

Then begin usual dosage regimen, one 25 mg tablet once a day.

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DEFERASIROX DESENSITIZATION 1 mg/mL Place one 125 mg tablet in 125 mL of water. Allow to dissassocaite and stir to make a suspension. Take the required dose and discard. Each dose should be prepared fresh. Administer on an empty stomach. 10 mg/mL Place on 500 mg tablet in 50 mL of water and proceed as above. The final dose will require two 500 mg tablets in 100 mL of water.

Dose 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Concentratio n 1 mg/mL 1 mg/mL 1 mg/mL 1 mg/mL 1 mg/mL 1 mg/mL 1 mg/mL 1 mg/mL 1 mg/mL 1 mg/mL 1 mg/mL 10 mg/mL 10 mg/mL 10 mg/mL

Amount (mL) 0.1 mL 0.2 mL 0.4 mL 0.8 mL 1.6 mL 3.2 mL 6.4 mL 13 mL 25 mL 50 mL 100 mL 20 mL 40 mL 80 mL

Time

20

Comments

ESTRADIOL DESENSITIZATION PROTOCOL REAGENTS: 4. Estradiol Suspensions a. 0.125 mg/5 mL b. 0.00125 mg/5mL 5. Tap water 6. Syringes and other measuring devices to measure doses from 0.05 mL to 10 mL PROCEDURE: 2. Administer one dose every 24 hours 3. Follow the protocol below. Add extra water to doses less than 25 mL to make swallowing easier. Day 1 2 3 4 5 6 7 8

Concentration 0.00125 mg/5 mL 0.00125 mg/5 mL 0.00125 mg/5 mL 0.00125 mg/5 mL 0.00125 mg/5 mL 0.00125 mg/5 mL 0.00125 mg/5 mL 0.00125 mg/5 mL

Amount 0.05 mL 0.1 mL 0.2 mL 0.4 mL 0.8 mL 1.6 mL 3.2 mL 6.4 mL

9 10 11 12 13 14

0.125 mg/5 mL 0.125 mg/5 mL 0.125 mg/5 mL 0.125 mg/5 mL 0.125 mg/5 mL 0.125 mg/5 mL

0.12 mL 0.25 mL 0.5 mL 1 mL 2 mL 4 mL

Date/ Time

Then begin usual dosage regimen, one 0.125 mg capsule once a day.

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ESTRADIOL (ESTRACE) DESENSITIZATION Materials: 5. Estrace Cream #1: 0.000001% 6. Estrace Cream #2: 0.0001% 7. Estrace Cream #3: 0.01% Procedure: Using the Estrace applicator, draw up the amount of cream needed and apply intravaginally. The doses are to be administered ~8 hours apart for 3 days. Then the drug can be administered once a day in whatever doses the physician requires. Date

•

Dose Concentratio Amount Comments n First day – Doses ~8 hours apart 1 Cream #1 1 gram 2 Cream #1 2 gram 3 Cream #1 4 gram Second day – Doses ~8 hours apart 4 Cream #2 1 gram 5 Cream #2 2 gram 6 Cream #2 4 gram Third day – Doses ~8 hours apart 7 Cream #3 1 gram 8 Cream #3 2 gram 9 Cream #3 4 gram After this procedure, Estrace can be used as normally recommended. Estrace should not be stopped for more than one day, or we will need to desensitize again.

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FEBUXOSTAT (ULORIC) DESENSITIZATION Uloric suspension 0.1 mg/mL Uloric suspension 10 mg/mL 1. Shake the correct bottle to resuspend the medication 2. Measure out the amount of medication from the correct bottle and put into a glass of water 3. Take one dose once a day, then advance to the next dose 4. Weekend doses are prepared and marked for the patient to add to water and take at home. Other doses should be given in the office to assure correct doses and absence of reactions 5. Then start one 40 mg Uloric tablet once a day 6. The dose can be adjusted as needed after that 7. If the patient misses more than one dose, the desensitization should be repeated. Day 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Concentration Amount 0.1 mg/mL 0.1 mL 0.1 mg/mL 0.2 mL 0.1 mg/mL 0.4 mL 0.1 mg/mL 0.8 mL 0.1 mg/mL 1.6 mL 0.1 mg/mL 3 mL 0.1 mg/mL 6 mL 0.1 mg/mL 12 mL 0.1 mg/mL 24 mL 10 mg/mL 10 mg/mL 10 mg/mL 10 mg/mL 10 mg/mL

0.5 mL 1 mL 2 mL 3 mL 4 mL

23

Date

Comments

GENTAMICIN INTRAVENOUS DESENSITIZATION Materials: Gentamicin 40 mg/mL most concentrated solution Serial 10 fold dilutions in normal saline Can be prepared as follows: 1:10 (4 mg/mL) – 20 mL of 40 mg/mL + 180 mL saline 1:100 (0.4 mg/mL) - 20 mL of 4 mg/mL + 180 mL saline 1:1000 (0.04 mg/mL) - 20 mL of 0.4 mg/mL + 180 mL saline Procedure: Infuse the indicated concentration of drug for 15 minutes at the flow rate indicated. Then change the flow rate, and if necessary the concentration of drug, and continue with increasing doses until the protocol has been completed. This will constitute the first dose. Usual doses and intervals can then be instituted.

Dose Concentratio n 1

Flow rate

Time

Amount given

0.04 mg/mL

Total Comments giv en

10 15 0.1 mg 0.1 mg mL/hr min. 2 0.04 mg/mL 20 15 0.2 mg 0.3 mg mL/hr min. 3 0.04 mg/mL 40 15 0.4 mg 0.7 mg mL/hr min. 4 0.04 mg/mL 80 15 0.8 mg 1.5 mg mL/hr min. 5 0.04 mg/mL 160 15 1.6 mg 3 mg mL/hr min. 6 0.4 mg/mL 30 15 3 mg 6 mg mL/hr min. 7 0.4 mg/mL 60 15 6 mg 12 mg mL/hr min. 8 0.4 mg/mL 120 15 12 mg 24 mg mL/hr min. 9 0.4 mg/mL 240 15 25 mg 50 mg mL/hr min. 10 4 mg/mL 50 15 50 mg 100 mg mL/hr min. 11 4 mg/mL 100 15 100 mg 200 mg mL/hr min. 12 4 mg/mL 200 15 200 mg 400 mg mL/hr min. 13 40 mg/mL 40 15 400 mg 800 mg mL/hr min. Then begin usual doses and intervals, assuming this to be the first dose.

24

HYDROCHLOROTHIAZIDE DESENSITIZATION REAGENTS: Hydrochlorothiazide oral suspension 50 mg/5 mL and a 1:100 dilution 0.5 mg/mL Tap water Syringes and other measuring devices to measure doses from 0.1 mL to 100 mL

Dose Concentration

1 2 3 4 5 6 7 8 9 10 11 12 13 14

0.5 mg/mL 0.5 mg/mL 0.5 mg/mL 0.5 mg/mL 0.5 mg/mL 0.5 mg/mL 0.5 mg/mL 0.5 mg/mL 0.5 mg/mL 0.5 mg/mL 50 mg/mL 50 mg/mL 50 mg/mL 50 mg/mL

Amount

0.05 mL 0.1 mL 0.2 mL 0.4 mL 0.8 mL 1.6 mL 3.2 mL 6.4 mL 12.8 mL 25 mL 0.5 mL 1 mL 2 mL 4 mL

Then begin usual daily dosage regimen.

25

Time

INFLUENZA VACCINE DESENSITIZATION Undiluted 1:10 = 0.5 mL vaccine + 4.5 mL diluent 1:100 = 1:10 of 1:10 1:1000 = 1:10 of 1:100 Dose Concentration Volume 1 2 3 4 5

1:1000 1:1000 1:1000 1:1000 1:1000

0.03 mL 0.06 mL 0.12 mL 0.25 mL 0.5 mL

6 7 8

1:100 1:100 1:100

0.1 mL 0.2 mL 0.4 mL

9 10 11

1:10 1:10 1:10

0.08 mL 0.16 mL 0.32 mL

12 13 14

Undiluted Undiluted Undiluted

0.05 mL 0.1 mL 3.5 mL

26

Time

Comments

INSULIN DESENSITIZATION For IgE mediated sensitivity Lantus 100 u/mL Dilutions needed: 1:10 (1 part INSULIN 100 U/mL + 9 parts saline) 1:100 (1 part INSULIN 10 U/mL + 9 parts saline) 1:1,000 (1 part INSULIN 1 U/mL + 9 parts saline) 1:10,000 (1 part INSULIN 0.1 U/mL + 9 parts saline)

= 10 u/mL = 1 u/mL = 0.1 u/mL = 0.01 u/mL

Doses are to be given every 15 minutes. Start at 0.05 mL SC of 0.01 mg/mL and build up to 0.8 mL SC of 10 u/mL. The cumulative dose will be 16 u. The final doses may have to be modified depending on how much insulin the patient needs. Dose 1 2 3

Concentratio n 0.01 u/mL 0.01 u/mL 0.01 u/mL

Amount ( SC) 0.05 mL 0.1 mL 0.2 mL

4 5 6 7

0.1 u/mL 0.1 u/mL 0.1 u/mL 0.1 u/mL

0.04 mL 0.08 mL 0.15 mL 0.3 mL

8 9 10

1 u/mL 1 u/mL 1 u/mL

0.06 mL 0.12 mL 0.25 mL

11 12 13 14 15

Time

Comments

10 u/mL 0.05 mL 10 u/mL 0.1 mL 10 u/mL 0.2 mL 10 u/mL 0.4 mL 10 u/mL 0.8 mL Cumulative dose ~16 u

Desensitization depends on the continuous presence of the drug antigen. Do not allow lapses in therapy after desensitization.

27

LEVOFLOXACIN DESENSITIZATION Levofloxacin Oral Solution 25 mg/mL, and 0.25 mg/mL (1:100) Dose Concentration 1 2 3 4 5 6

0.25 mg/mL 0.25 mg/mL 0.25 mg/mL 0.25 mg/mL 0.25 mg/mL 0.25 mg/mL

7 8 9 10 11 12 13 14

25 mg/mL 25 mg/mL 25 mg/mL 25 mg/mL 25 mg/mL 25 mg/mL 25 mg/mL 25 mg/mL

Amount Time (mL) 0.1 0.2 0.4 0.8 1.6 3.2 0.06 0.12 0.24 0.5 1 2 4 8

28

Comments

METRONIDAZOLE DESENSITIZATION Need oral suspensions: 100 mL of 500 mg metronidazole/5mL (100 mg/mL) 100 mL of 5 mg metronidazole/5 mL (1 mg/mL) Administer doses at least 15 minutes apart. Observe 2 hours after last dose. Dose 1 2 3 4 5 6 7 8 9

Concentratio n 5 mg/5 mL 5 mg/5 mL 5 mg/5 mL 5 mg/5 mL 5 mg/5 mL 5 mg/5 mL 5 mg/5 mL 5 mg/5 mL 5 mg/5 mL

Amount (mL) 0.04 mL 0.08 0.15 0.3 0.6 1.2 2.5 5 10

10 11 12 13 14 15 16 17

500 mg/5 mL 500 mg/5 mL 500 mg/5 mL 500 mg/5 mL 500 mg/5 mL 500 mg/5 mL 500 mg/5 mL 500 mg/5 mL

0.2 0.4 0.7 0.15 0.3 0.6 1.3 2.5

Time

29

Comments

NITROFURANTOIN DESENSITIZATION Nitrofurantoin oral suspension 100 mg/5 mL Nitrofurantoin oral suspension 1 mg/5 mL Dose Concentration 1 2 3 4 5 6

1 mg/5 mL 1 mg/5 mL 1 mg/5 mL 1 mg/5 mL 1 mg/5 mL 1 mg/5 mL

7 8 9 10 11 12 13 14

100 mg/5 mL 100 mg/5 mL 100 mg/5 mL 100 mg/5 mL 100 mg/5 mL 100 mg/5 mL 100 mg/5 mL 100 mg/5 mL

Amount Time (mL) 0.1 0.2 0.4 0.8 1.6 3.2 0.06 0.12 0.24 0.5 1 2 4 8

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Comments

OPIATE SENSITIVITY: SUGGESTIONS FOR MANAGEMENT Allergy-like reactions to opiates appear to be the result of pharmacologically-induced cutaneous mast cell mediator release (Tharp MD, Kagey-Sabotka A, Fox CC, Maroni G, Lichtenstein LM, Sullivan TJ. Functional heterogeneity of human mast cells from different anatomical sites: in vitro responses to morphine sulfate. J Allergy Clin Immunol 1987;79:646-652.).

Patients differ in their degree of opiate sensitivity over time, and which opiates they tolerate better than others. Fentanyl appears to be the best tolerated of the opiates, for most patients. Premedication with antihistamines, and perhaps antileukotrienes can be very helpful. Suggested approach to perioperative use of opiates in patients with a history of “pseudoallergic” reactions to opiates: • When feasible use non-opiate medications or approaches to pain control to avoid the need, or reduce the dose of opiates. This includes NSAIDs such as Toradol, local anesthetics, epidural blocks, etc. • When feasible use PCA pumps for opiate administration. This avoids the high blood levels that come from intermittent doses that in turn exaggerate the mast cell stimulation. • When feasible use fentanyl. This can be used in PCA pumps, but in some hospitals the logistics are a problem. • Premedication with diphenhydramine 1 mg/kg q4-6h can help. • We also use Singulair 10 mg PO b.i.d., but there are no data regarding effectiveness. • If blood pressure is a problem we can add an H2 antihistamine such as cimetidine 4 mg/kg q6h. • Peripheral opiate antagonists such as methylnaltrexone or alvimopan may be beneficial without interfering with central pain control. .

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PACLITAXEL (TAXOL) INTRAVENOUS DESENSITIZATION Materials: Taxol 300 mg in 500 mL normal saline – 0.6 mg/mL (Full strength) You may want to add a little more Taxol to make up for the 2% we will use for the dilutions. Put 10 mL of Taxol 300 mg/500 mL into 100 mL of normal saline. This is Taxol 1:10 (0.06 mg/mL) Put 10 mL of Taxol 1:10 into 100 mL normal saline. This is Taxol 1:100 (0.006 mg/mL)

*

Make sure we use the dilute 1:100 first, then the more

concentrated 1:10 next, and then the full strength last. Procedure: Infuse the indicated concentration of drug for 15 minutes at the flow rate indicated. Then change the flow rate, and if necessary the concentration of drug, and continue with the increasing doses until the protocol has been completed.

Dose Concentratio n

Flow rate

Time

Comments

1 2 3 4

Taxol 1:100 Taxol 1:100 Taxol 1:100 Taxol 1:100

2 mL/hr 5 mL/hr 10 mL/hr 20 mL/hr

15 min. 15 min. 15 min. 15 min.

5 6 7 8

Taxol 1:10 Taxol 1:10 Taxol 1:10 Taxol 1:10

5 mL/hr 10 mL/hr 20 mL/hr 40 mL/hr

15 min. 15 min. 15 min. 15 min.

9 10 11 12

Full Strength Full Strength Full Strength Full Strength

10 mL/hr 20 mL/hr 40 mL/hr 80 mL/hr

15 min. 15 min. 15 min. Until infusion of the remaining 300 mg in 500 mL is completed

32

PENICILLIN DESENSITIZATION – ORAL Penicillin 500 mg/5 mL and 1:100 (5 mg/5 mL) For rapid desensitization doses are administered at 15 minute intervals Dose Concentration Volume 1 2 3 4 5 6 7

5 mg/5mL 5 mg/5mL 5 mg/5mL 5 mg/5mL 5 mg/5mL 5 mg/5mL 5 mg/5mL

0.03 mL 0.06 mL 0.12 mL 0.25 mL 0.5 mL 1 mL 2 mL

8 9 10 11 12 13 14

500 mg/5mL 500 mg/5mL 500 mg/5mL 500 mg/5mL 500 mg/5mL 500 mg/5mL 500 mg/5mL

0.04 mL 0.08 mL 0.16 mL 0.32 mL 0.64 mL 1.25 mL 2.5 mL

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Time

Comments

PENICILLIN G INTRAVENOUS DESENSITIZATION - Materials Penicilin G aqueous 1,000,000 units/50 mL (20,000units/mL) Serial 10 fold dilutions in normal saline can be prepared as follows: 1:10 (2,000units/mL) – 20 mL of 20,000 units/mL + 180 mL saline 1:100 200units/mL) -

20 mL of 2,000 units/mL + 180 mL saline

1:1000 (20units/mL) - 20 mL of 200 units/mL + 180 mL saline Procedure: Infuse the indicated concentration of drug for 15 minutes at the flow rate indicated. Then change the flow rate, and if necessary the concentration of drug, and continue with the increasing doses until the protocol has been completed. This will constitute the first dose. Usual doses and intervals can then be instituted. For the treatment of latent syphilis, long acting bicillin is administered IM 2 hours after the last IV dose, if no reaction is evident. Subsequent weekly doses can be given without need for a repeat of the desensitization procedure.

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PENICILLIN G INTRAVENOUS DESENSITIZATION PROTOCOL Desensitization Protocol Dose

Concentration

1

20 units/mL

2

20 units/mL

3

20 units/mL

4

20 units/mL

5

20 units/mL

6

200 units/mL

7

200 units/mL

8

200 units/mL

9

200 units/mL

10 11 12 13 14

Flow rate

Time

50 units

Total give n 50

100 units

150

200 units

350

400 units

750

800 units

1,550

15 min. 15 min. 15 min. 15 min.

1,500 units 3,000 units 6,000 units 12,000 units

3,050

50 mL/hr 100 mL/hr 200 mL/hr

15 min. 15 min. 15 min.

25,000 units 50,000 units 100,000 units

40 mL/hr 80 mL/hr

15 min. 15 min.

200,000 units 400,000 units

10 mL/hr 20 mL/hr 40 mL/hr 80 mL/hr 160 mL/hr

15 min. 15 min. 15 min. 15 min. 15 min.

30 mL/hr 60 mL/hr 120 mL/hr 240 mL/hr

2,000 units/mL 2,000 units/mL 2,000 units/mL 20,000 units/mL 20,000 units/mL

Amount given

35

6,050 12,050 24,050 49,050 99,050 199,050 399,050 799,050

Comments

PIPERACILLIN/TAZOBACTAM INTRAVENOUS DESENSITIZATION (ZOSYN)) Materials: Zosyn (2 gm/0.25 gm) in 50 mL (eqivalent of 40 mg/mL piperacillin) Serial 10 fold dilutions in normal saline Can be prepared as follows: 1:10 (4 mg/mL) – 20 mL of 40 mg/mL + 180 mL saline 1:100 (0.4 mg/mL) - 20 mL of 4 mg/mL + 180 mL saline 1:1000 (0.04 mg/mL) - 20 mL of 0.4 mg/mL + 180 mL saline Procedure: Infuse the indicated concentration of drug for 15 minutes at the flow rate indicated. Then change the flow rate, and if necessary the concentration of drug, and continue with the increasing doses until the protocol has been completed. This will constitute the first dose. Usual doses and intervals can then be instituted.

Dose Concentratio n 1

0.04 mg/mL

2

0.04 mg/mL

3

0.04 mg/mL

4

0.04 mg/mL

5

0.04 mg/mL

6

0.4 mg/mL

7

0.4 mg/mL

8

0.4 mg/mL

9

0.4 mg/mL

10

4 mg/mL

11

4 mg/mL

12

4 mg/mL

13

40 mg/mL

14

40 mg/mL

Flow rate 10 mL/hr 20 mL/hr 40 mL/hr 80 mL/hr 160 mL/hr 30 mL/hr 60 mL/hr 120 mL/hr 240 mL/hr 50 mL/hr 100 mL/hr 200 mL/hr 40 mL/hr 80 mL/hr

Time

Amount given

15 min. 15 min. 15 min. 15 min. 15 min. 15 min. 15 min. 15 min. 15 min. 15 min. 15 min. 15 min. 15 min. 15 min.

0.1 mg

0.1 mg

0.2 mg

0.3 mg

0.4 mg

0.7 mg

0.8 mg

1.5 mg

1.6 mg

3 mg

3 mg

6 mg

6 mg

12 mg

12 mg

24 mg

25 mg

50 mg

50 mg

100 mg

100 mg

200 mg

200 mg

400 mg

400 mg

800 mg

800 mg

1600 mg

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Total Comments giv en

SERTRALINE (ZOLOFT) DESENSITIZATION Zoloft 20 mg mL oral solution used as starting material Zoloft 0.2 mg mL used for initial doses Dose Concentration Volume 1 2 3 4 5 6

0.2 m mL 0.2 mg mL 0.2 mg mL 0.2 mg mL 0.2 mg mL 0.2 mg mL

0.06 mL 0.12 mL 0.25 mL 0.5 mL 1 mL 2 mL

7 8 9 10 11 12 13

20 mg/5 mL 20 mg/5 mL 20 mg/5 mL 20 mg/5 mL 20 mg/5 mL 20 mg/5 mL 20 mg/5 mL

0.04 mL 0.08 mL 0.16 mL 0.32 mL 0.64 mL 1.25 mL 2.5 mL

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Time

Comments

SULFASALAZINE (AZULFIDINE) DESENSITIZATION Azulfidine 10 mg/100 mL oral solution Azulfidine 0.1 mg/100 mL used for initial doses Dose

Concentration

Volume

1 2 3 4 5 6

0.1 gm/100 mL 0.1 gm/100 mL 0.1 gm/100 mL 0.1 gm/100 mL 0.1 gm/100 mL 0.1 gm/100 mL

0.05 mL 0.1 mL 0.2 mL 0.4 mL 0.8 mL 1.6 mL

7 8 9 10 11 12 13 14

10 gm/100 mL 10 gm/100 mL 10 gm/100 mL 10 gm/100 mL 10 gm/100 mL 10 gm/100 mL 10 gm/100 mL 10 gm/100 mL

0.03 mL 0.06 mL 0.12 mL 0.25 mL 0.5 mL 1 mL 2 mL 4 mL

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Time

Comments

TRIMETHOPRIM/SULFAMETHOXAZOLE DESENSITIZATION REAGENTS for pediatric patients. Adults will need higher final dosesl Bactrim Pediatric Suspension (80 mg trimethoprim/400 mg sulfamethoxazole per 5 mL) Tap water Syringes and other measuring devices to measure doses from 0.1 mL to 100 mL

Dose Concentration

1 2 3 4 5 6 7 8 9 10 11 12 13 14

1:100 1:100 1:100 1:100 1:100 1:100 1:100 1:100 1:100 1:100 Undiluted Undiluted Undiluted Undiluted

Amount

Time

0.05 mL 0.1 mL 0.2 mL 0.4 mL 0.8 mL 1.6 mL 3.2 mL 6.4 mL 12.8 mL 25 mL 0.5 mL 1 mL 2 mL 4 mL

Then begin usual dosage regimen, considering this the first dose of 5 mL.

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VANCOMYCIN INTRAVENOUS DESENSITIZATION Materials: Vancomycin 40 mg/mL most concentrated solution Serial 10 fold dilutions in normal saline Can be prepared as follows: 1:10 (4 mg/mL) – 20 mL of 40 mg/mL + 180 mL saline 1:100 (0.4 mg/mL) - 20 mL of 4 mg/mL + 180 mL saline 1:1000 (0.04 mg/mL) - 20 mL of 0.4 mg/mL + 180 mL saline Procedure: Infuse the indicated concentration of drug for 15 minutes at the flow rate indicated. Then change the flow rate, and if necessary the concentration of drug, and continue with the increasing doses until the protocol has been completed. This will constitute the first dose. Usual doses and intervals can then be instituted.

Dose Concentratio n 1

Flow rate

Time

Amount given

0.04 mg/mL

Total Comments giv en

10 15 0.1 mg 0.1 mg mL/hr min. 2 0.04 mg/mL 20 15 0.2 mg 0.3 mg mL/hr min. 3 0.04 mg/mL 40 15 0.4 mg 0.7 mg mL/hr min. 4 0.04 mg/mL 80 15 0.8 mg 1.5 mg mL/hr min. 5 0.04 mg/mL 160 15 1.6 mg 3 mg mL/hr min. 6 0.4 mg/mL 30 15 3 mg 6 mg mL/hr min. 7 0.4 mg/mL 60 15 6 mg 12 mg mL/hr min. 8 0.4 mg/mL 120 15 12 mg 24 mg mL/hr min. 9 0.4 mg/mL 240 15 25 mg 50 mg mL/hr min. 10 4 mg/mL 50 15 50 mg 100 mg mL/hr min. 11 4 mg/mL 100 15 100 mg 200 mg mL/hr min. 12 4 mg/mL 200 15 200 mg 400 mg mL/hr min. 13 40 mg/mL 40 15 400 mg 800 mg mL/hr min. Then begin usual doses and intervals, assuming this to be the first dose.

40