What medications are contraindicated with an alpha-gal allergy? What mammal by-products could be listed as inactive ingredients on the package insert (i.e. magnesium stearate, gelatin)?

Comment by InpharmD Researcher

Table 1 provides alpha-gal content for select medications per manufacturer. The list is not comprehensive, and any medication that includes any natural, mammalian extract as an active/inactive ingredient is at risk for having the alpha-gal moiety and triggering an immune response. Manufacturers are not currently required to report animal products in their final products. Alpha-gal content may be subject to change based on the lot number of the same medications.

Background

An article discusses the difficulty of maintaining a list of medications potentially triggering alpha-gal syndrome based upon their inactive compounds. The inactive ingredients of concern are those derived from animal sources. For example, certain inactive compounds, such as stearic acid and lactic acid, may trigger an allergy if derived from animal sources but not plant sources. While problematic inactive ingredients can be readily identified, it is important to note manufacturers are not beholden to report alpha-gal content or perform testing on the final product to ensure no contamination. Manufacturers may also freely change information regarding their inactive ingredients at any time without warning or follow-up. Even the same drug from the same manufacturer but with different lot numbers may exhibit different effects on alpha-gal allergy. Therefore, the list of medications along with inactive compounds should be tailored per institution based on their current suppliers. [1]

A recent article described the in vitro immunoglobulin E (IgE) response toward medical products such as cardiac patch materials and bioprosthetic valves. In vitro testing utilizing the alpha-gal syndrome (AGS) serum from alpha-gal IgE sensitized patients showed strong reactivity to all the commercially available, nonhuman products tested, including various decellularized cardiac patch materials and bioprosthetic aortic valves. This may induce a non-transient, ongoing immune response in patients with AGS. Complications for such desensitized patients may include early valve degradation/failure and accelerated coronary artery disease following bioprosthetic valve replacement. [2]

A case report highlighted the prevalence of meat byproducts in thyroid hormone formulations. Levothyroxine, liothyronine, combination, and desiccated thyroid formulations can potentially contain alpha-gal. Their case of an alpha-gal allergic patient with postoperative hypothyroidism from a hemithyroidectomy required a multidisciplinary approach to find a thyroid hormone replacement therapy without meat by-products. However, contacting the manufacturers did not reveal sufficient information to make a decision, leading the authors to prescribe pure, pharmaceutical-grade levothyroxine with plant-based filler, capsule, and magnesium stearate. [3]

References:

[1] Dunkman WJ, Rycek W, Manning MW. What does a red meat allergy have to do with anesthesia? Perioperative management of alpha-gal syndrome: Anesthesia & Analgesia. 2019;129(5):1242-1248. doi:10.1213/ANE.0000000000003460
[2] Kuravi KV, Sorrells LT, Nellis JR, et al. Allergic response to medical products in patients with alpha-gal syndrome [published online ahead of print, 2021 Apr 9]. J Thorac Cardiovasc Surg. 2021;S0022-5223(21)00586-9. doi:10.1016/j.jtcvs.2021.03.100
[3] Slayden TA, Shakir MKM, Hoang TD. A bull in a pill shop: alpha-gal allergy complicating treatment options for postprocedural hypothyroidism. AACE Clin Case Rep. 2020;6(3):e101-e104. Published 2020 May 11. doi:10.4158/ACCR-2019-0495
Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

What medications are contraindicated with an alpha-gal allergy? What mammal by-products could be listed as inactive ingredients on the package insert (i.e. magnesium stearate, gelatin)?

Please see Tables 1-4 for your response.

 

Alpha-gal Content for Select Medications Per Manufacturer (Updated 2019)*
Drug Name Manufacturer OK to Use? Notes
Acetaminophen 325 mg tablet McNeill, McKesson No Contains magnesium stearate and gelatin
Acetaminophen 160 mg/5 mL liquid Pharmaceutical Associates No Contains glycerin
Acetaminophen suppository G&W, Perrigo No - 
Acetaminophen-butalbital-caffeine (Fioricet) tablet American Health No - 
Acetaminophen-codeine 300mg-30mg tablet Mallinckrodt No - 
Acetaminophen-codeine 120mg-12mg elixir Pharmaceutical Associates No Contains glycerin
Alprazolam tablet (all strengths) Major, Mylan, Mckesson No -
Alvimopan 12 mg capsule Cubist No Contains gelatin (bovine and porcine)
Aminocaproic acid 500 mg tablet  Hospira No  Contains magnesium stearate and stearic acid
Aprepitant 40 mg capsule Merck, Sandoz No  Contains gelatin (bovine and porcine)
Armour thyroidTM Allergan Unknown Animal thyroid extract
Aspirin 81 mg EC tablet GeriCare No  -
Aspirin 325 mg EC tablet McKesson No  Contains anhydrous lactose (Phone: 855-625-4677)
Bacitracin 50,000 unit injection X-Gen No  May contain milk and milk-derivatives (bovine)
Baclofen 10 mg tablet McKesson & American Health No  Contains magnesium stearate
Bisacodyl 5 mg tablet Major, Rugby No  -
Bupivacaine liposome injection (Exparel) Pacira No  Glycerol is of animal origin (could not specify bovine or porcine)
Carbidopa-levodopa 25mg-100mg tablet McKesson No Contains magnesium stearate
Carbidopa-levodopa 25mg-100mg ER tablet Mylan No Contains magnesium stearate
Carisoprodol 350mg tablet American Health No - 
Celecoxib 100 mg, 200 mg capsule Mylan, Major No  Contains gelatin (bovine and porcine)
Clindamycin injection Hospira Unknown Product divested
Clonazepam tablet Mckesson No - 
Clonidine 0.1mg tablet Mylan No  - 
Cyclobenzaprine tablet- McKesson, Major, Mylan No  - 
Cyclosporine 25mg, 100mg capsule Novartis No  Contains gelatin
CytomelTM Pfizer Unknown Gelatin
Diazepam 5 mg, 10 mg tablet McKesson, Mylan No  -
Diphenhydramine tablet Contract Pharm & Major No  Need specific lot number; ingredient sources lot-specific (Lactose, Mg stearate, gelatin listed)
EuthyroxTM Provell Pharmaceuticals Unknown Magensium stearate, gelatin
Ezetimibe 10 mg tablet Sun Pharma, Avkare No  -
Floseal hemostatic matrix Baxter No  Bovine gelatin
Furosemide 20 mg tablet Sandoz No  - 
Gabapentin capsule (all strengths) Amneal & McKesson No  Contains gelatin (bovine and porcine)
Gabapentin capsule (all strengths) AvKARE No Contains gelatin (bovine, porcine) & gluten (not gliaden gluten - type responsible for celiac sprue)
Gabapentin capsule (all strengths)  Mylan & American Health No  Contains gelatin (bovine and porcine)
Gabapentin capsule (all strengths)  Ascend No  Gelatin - bovine
Gabapentin capsule (all strengths)  Pfizer No  Gelatin
Gabapentin (Neurontin) 250 mg/5 mL oral solution Pfizer  No  -
Gabapentin 250 mg/5 mL oral solution Greenstone No  Animal source gelatin
Gelflim 25 mm-50 mm/125 mm-100 mm Pfizer No  Contains porcine gelatin
Glucagon injection Bedford No  Contains lactose monohydrate (maybe animal-derived)
Haloperidol 5 mg/mL injection Fresenius Kabi No Lactic Acid may be animal-derived
Heparin All (porcine) No  Porcine derived
Hydrocodone-acetaminophen tablet Mallinckrodt No  Magnesium stearate; typically gluten-free, but due to sourcing there may be cross-contamination. Final testing is done for this.
Hydromorphone injection Hospira No  Lactic Acid may be animal-derived
Hydromorphone 2mg, 4mg tablet Westward, Rhodes No  -
Hydromorphone ER tablet Paddock No  - 
Ibuprofen tablet (all strengths) LNK; Major & McKesson No  Contains lactose (bovine)
Ibuprofen 100 mg/5 mL suspension Precision Dose No  Contains glycerin
Imitrex 100 mg tablet GSK No  Magnesium stearate - animal-derived
Influenza vaccine (Flulaval) GSK No  Sodium deoxycholate may be of animal origin - ovine or bovine
Instat Microfibrillar Collagen Hemostat Ethicon No  Contains bovine collagen
Isosorbide Dinitrate 5 mg tablet Sandoz No  -
Lacosamide 10 mg/mL oral solution UCB No  Contains glycerin
Lacosamide tablet (all strengths) UCB No  - 
Levetiracetam tablet American Health No  Contains magnesium stearate
LevothroidTM Pfizer Unknown Magensium stearate
Levothyroxine (authorized generic) Bryant Ranch Prepack Unknown Magensium stearate
LevoxylTM Pfizer Unknown Magensium stearate
Lidocaine (Lidoderm) patch Qualitest No  Contains gelatin which is bovine-derived
Liothyronine sodium (authorized generic) Greenstone Unknown Gelatin
Lisinopril tablet (all strengths) Major No  Contains magnesium stearate
Lorazepam tablet McKesson No  - 
Magnesium hydroxide solution Pharmaceutical Assoc No  Contains glycerin
Magnesium oxide - Unknown -
Methadone 5 mg, 10 mg tablet Westward, Roxane No  - 
Methadone 5 mg/5 mL oral solution   No  Contains glycerin
Methocarbamol 500 mg tablet McKesson Unknown - 
Methylergonovine 0.2 mg tablet Lupin No  - 
Metoclopramide 1 gm/mL oral solution Vistapharm No  Glycerin - may be animal-derived
Metoclopramide 5 mg orally disintegrating tablet Lupin No  Magnesium stearate - animal-derived
Metoclopramide 10 mg tablet Impax, Mylan No  Magnesium stearate - animal-derived
Metoprolol tartrate tablets (all strengths) Major No  -
Montelukast 10 mg tablet Various No  - 
Mycophenolate 500 mg tablet Mylan No  - 
Mycophenolate 180mg EC tablet (Myfortic) Mylan No  - 
Morphine ER tablet (MS Contin) Mallinckrodt No  - 
Morphine 15 mg, 30 mg IR tablet Westward, Roxane No  - 
Morphine oral solution   No  Contains glycerin
Nature-ThroidTM RLC Labs Unknown Animal thyroid extract, magnesium stearate, lactose monohydrate
Naproxen 500mg tablet McKesson No  -
Nitroglycerin 0.4 mg tablet Pfizer No  - 
Nystatin oral suspension   Unknown *couldn't find in the pharmacy
Oxybutynin tablet American health No  Contains magnesium stearate
Oxycodone 5 mg tablet Hospira, mallinkroft No  Contains animal-derived stearic acid
Oxycodone oral solution Vista No  contains glycerin
Oxycontin tablet Purdue No  contains magnesium stearate
Oxycodone-acetaminophen 5mg-325mg tablet Mallinckrodt No  -
Pantoprazole 20 mg, 40 mg DR tablet Mylan Unknown Contains no gluten
Phenazopyridine 100 mg, 200 mg tablet ECI & Gemini No  Contains magnesium stearate
Pregabalin capsule (all strengths) Pfizer No  Gelatin of animal origin; lot-specific ingredient sourcing
Promethazine 25 mg/mL injection West-Ward Unknown Company not able to confirm or deny the presence of alpha-galactose in the raw materials
Prothrombin complex concentrate (Kcentra) CSL Behring No  Heparin porcine
Rifampin capsule Eon Labs, Mylan No  Gelatin - Porcine, bovine derived
Sennokot S tablet Major No  Contains bovine
Sotalol 80 mg tablet Teva No  -
Spironolactone 25 mg tablet Amneal No  - 
Sumatriptan 25 mg, 50 mg, 100 mg tablet Mylan, Sun Pharma No  Magnesium stearate - animal-derived
Surgifoam powder Ethicon No  Contains porcine gelatin
Surgifoam Absorbable Gelatin Sponge Ethicon No  Contains porcine gelatin
SynthroidTM AbbVie Unknown Magnesium stearate, lactose monohydrate
Tamsulosin capsule 0.4 mg capsule Boehringer Ingelheim No  Bovine and porcine derivatives
TirosintTM IBSA Pharma Unknown Gelatin
TirostatTM Par Pharmaceutical Unknown Animal thyroid extract
Thrombin   No -
ThyrolarTM Allergan Unknown Magnesium stearate and gelatin
Verapamil ER 100 mg capsule Mylan No  - 
Visipaque GE Healthcare Unknown No information available from manufacturer
Zofran 4 mg orally disintegrating tablet Novartis No  Contains gelatin; company does not perform tests to determine if ingredients are animal-sourced

*Disclaimer: Information is subject to change based on the lot number of medications. There may also be cases where risk vs benefit needs to be assessed in deciding whether to use alpha-gal medications. Please contact Pharmacy for review of medications prior to ordering and/or to determine if there are potential alternatives that should be considered as part of this assessment.

This list is not comprehensive. Any medication that includes any natural, mammalian extract as an active/inactive ingredient is at risk for having the alpha-gal moiety and triggering an immune response

 

 

References:

Excerpt from:
Alpha-gal Information (AGI). Alpha-gal content for select medications per manufacturer. Available: https://alphagalinformation.org/wp-content/uploads/2019/10/Copy-of-Medications_Alpha-gal-allergy_Edited-1-1.pdf. Updated January 2021. Accessed October 26, 2021.

Slayden TA, Shakir MKM, Hoang TD. A bull in a pill shop: alpha-gal allergy complicating treatment options for postprocedural hypothyroidism. AACE Clin Case Rep. 2020;6(3):e101-e104. Published 2020 May 11. doi:10.4158/ACCR-2019-0495

 

Gelatin-Containing Vaccines for Varicella, Zoster, Measles, Mumps, and Rubella Induce Basophil Activation in Patients with Alpha-Gal Syndrome

Design

Single-center, experimental study  

N= 6

Objective

To evaluate if basophil activation tests (BATs) performed with vaccines containing hydrolyzed gelatin were positive in patients with alpha-gal syndrome (AGS)

Study Groups

Confirmed AGS: patient 1 and 2 (n= 2)

Suspicious AGS: patient 3 and 4 (n= 2)

Healthy individuals (n= 2)

Inclusion Criteria

Confirmed AGS: patients with a confirmed diagnosis of AGS based on positive oral provocation tests (OPT)

Suspicious AGS: patients with histories of anaphylaxis after exposure to alpha-gal-containing food products

Healthy individuals: patients without any previous medical history of allergies 

All patients: history of varicella infection in childhood; not immunized with varicella or varicella-zoster (VZ) vaccine before 

Exclusion Criteria

N/A

Methods

Basophil activation tests were performed with different concentrations of vaccines (undiluted, 1:5, 1:25, 1:125, 1:625, and 1:3,250 diluted). All patients were tested with gelatin-containing, attenuated varicella vaccine (Varivax®; Sanofi Pasteur MSD, France). Patients 1, 2, 3, and healthy controls were tested with gelatin-containing MMR live vaccine (M-M-RVax®; Chiron Behring, Germany, MMR vaccine). Patient 4 was tested with another MMR live vaccine (Priorix®; GlaxoSmithKline, Germany, non-gelatin MMR vaccine). Patients 1 and 2 and healthy controls were tested with gelatin-containing attenuated VZ vaccine (Zostavax®; Sanofi Pasteur MSD, France). 

Duration

N/A 

Outcome Measures

 Basophil activation tests results 

Baseline Characteristics

  

Patient 1

Patient 2

 Patient 3  Patient 4

Age, years

81

 68 68 46

Gender 

F

 F M F

Atopy

 No No No No

History 

One episode with rash, shortness of breath, and loss of consciousness 3 h after ingestion of pork kidney

 One episode with rash, shortness of breath, and loss of consciousness 3 h after ingestion of pork kidney Three delayed anaphylactic reactions (rash, generalized urticaria, and shortness of breath) following exposure to red meat Since 2 years recurrent episodes with severe abdominal pain 2 to 3 h after ingestion of red meat, and tolerance of chicken and turkey

SPT (mm diameter wheal size)

Raw pork kidney suspension (3)

Raw pork kidney suspension (3)

Raw pork kidney suspension (6)

Raw pork kidney suspension (4)

IDT (mm diameter wheal size)

Gelafundin 4% diluted 1:1 (5)

Gelafundin 4% diluted 1:1 (6)

Gelafundin 4% diluted 1:1 (9)

Gelafundin 4% diluted 1:1 (8)

IgE test 

Total IgE, IU/mL

sIgE alpha-gal, kU/L

sIgE gelatin, kU/L 

 

38.7

15.2

< 0.1

 

78.4

3.65 

< 0.1 

 

736

68.5

< 0.1 

 

796 

38 

< 0.1 

OPT

Anaphylactic reaction to 1.5 g cooked pork kidney

 Anaphylactic reaction to 18 g cooked pork kidney Refused  Pending 

h, hours; SPT, skin prick test; IDT, intradermal test; OPT, oral provocation test; Gelafundin, a gelatin-derived colloid rich in alpha-gal.

Results

Endpoint

Patient 1

Patient 2

Patient 3

 Patient 4 

CD63 expression 

VZ vaccine (concentration)

Varicella vaccine 

MMR vaccine

 

92.1% (undiluted)

87.3% (1: 25 diluted)

88.7% (1:125)

 

51.3% (1:5)

62.5% (1:5)

61.2% (1:5)

 

--

22.1% (1:5)

23.1% (1:125) 

 

--

77.8% (1:5)

No activation observed

CD63 expression with alpha-gal

1,000 ng/mL

200 ng/mL

40 ng/mL

22.5 ng/mL

8 ng/mL

4.5 ng/mL 

0.32 ng/mL

0.18 ng/mL

 

19.6%

13.9%

16.3%

--

49.3% (highest)

--

44%

--

 

48.6%

38.9%

65.3%

--

74% (highest)

--

26.0%

--

 

--

--

--

7.4%

--

6.4%

--

16.6% (highest)

 

--

--

--

53%

--

53.5%

--

84% (highest)

The 2 healthy individuals did not show any basophil activation for any of the tested vaccines but showed positive results for the positive controls. 

Adverse Events

 N/A

Study Author Conclusions

All patients with confirmed AGS showed strongly positive basophil activation for all tested gelatin-containing vaccines, whereas healthy controls and the non-gelatin vaccine remained negative. Although this test does not prove clinical relevance in real-life situations, these vaccines should be administered with caution in patients with AGS. It has been postulated that alpha-gal epitopes in gelatin or other nonprimate mammal-derived products are the triggers. Information on the exact amount of gelatin in vaccines might be useful for better risk stratification. Also, BAT is a useful additional tool screening for potential high-risk and alternative drugs.

InpharmD Researcher Critique

Given the experimental nature of the study, the results can only be considered hypothesis-generating instead of validated evidence for clinical practice.

However, it may still be worth taking precautions to vaccines containing gelatin and following the general practice to carefully screen patients with histories of severe allergic reaction before administering vaccines. 

 

 

References:

Schmidle P, Mehlich J, Brockow K, Darsow U, Biedermann T, Eberlein B. Gelatin-Containing Vaccines for Varicella, Zoster, Measles, Mumps, and Rubella Induce Basophil Activation in Patients with Alpha-Gal Syndrome. Int Arch Allergy Immunol. 2021;182(8):716-722. doi:10.1159/000514263

 

Inactive Ingredients Which May Be Animal-Derived

Stearic acid

Lactic acid

Magnesium stearate

Glycerin

Gelatin

Lactose monohydrate

 

 

References:

[1] Dunkman WJ, Rycek W, Manning MW. What does a red meat allergy have to do with anesthesia? Perioperative management of alpha-gal syndrome: Anesthesia & Analgesia. 2019;129(5):1242-1248. doi:10.1213/ANE.0000000000003460
[2] Slayden TA, Shakir MKM, Hoang TD. A bull in a pill shop: alpha-gal allergy complicating treatment options for postprocedural hypothyroidism. AACE Clin Case Rep. 2020;6(3):e101-e104. Published 2020 May 11. doi:10.4158/ACCR-2019-0495

 

Cetuximab-Induced Anaphylaxis and IgE Specific for Galactose-Alpha-1,3-Galactose

Design

Retrospective analysis

N= 538

Objective

To investigate the hypothesis that severe hypersensitivity reactions occurring during the initial infusion of cetuximab are mediated by preexisting IgE antibodies against cetuximab

Study Groups

Group 1:

Tennesse case subjects (n= 35)

Other case subjects (n= 41)

Group 2: Tennessee control subjects (n= 72)

Group 3: Califronia control subject (n= 49)

Group 4: Boston control subjects (n= 341)

Inclusion Criteria

Available serum samples from subjects who had received cetuximab and whose clinical response had been documented. 

Exclusion Criteria

N/A

Methods

Serum samples from four groups of subjects for IgE antibodies against cetuximab were analyzed: pretreatment samples from 76 case subjects who had been treated with cetuximab at multiple centers, predominantly in Tennessee, Arkansas, and North Carolina; samples from 72 control subjects in Tennessee; samples from 49 control subjects with cancer in northern California; and samples from 341 female control subjects in Boston.

Duration

June 2005 and December 2006

Outcome Measures

Hypersensitivity reaction to cetuximab.

Baseline Characteristics

  

All Groups (N= 538)

Age, years

Median

Range

 

58

32-97

Female

417 (77.5%)

Race

White

Black

Other 

Unknown

 

392 (72.9%)

70 (13.0%)

35 (6.51%)

41 (7.62%)

Tumor site

Total

Head and neck

Colorectal

Lung

 

125 

72 (57.6%)

52 (41.6%)

1 (0.8%)

Clinical stage

Total

I or II

III

IV

76

13 (17.1%)

14 (18.4%)

39 (51.3%)

10 (13.2%)

Hypersensitivity reaction

Total

Rated by investigators

Low-grade

High-grade

Late response

Rated retrospectively‡

Low-grade

High-grade

 

26

 

13

12

1

 

2

24

‡Retrospective scoring of the severity of hypersensitivity reactions was performed by blinded analysis of case reports.

Results

Among 76 cetuximab-treated subjects, 25 (32.9%) had a hypersensitivity reaction to cetuximab. IgE antibodies against cetuximab were found in pretreatment samples from 17/25 (68%) of these subjects; only 1 of 51 subjects who did not have a hypersensitivity reaction had such antibodies (p<0.001).

IgE antibodies against cetuximab were found in 15 of 72 samples (20.8%) from control subjects in Tennessee, in 3 of 49 samples (6.1%) from northern California, and in 2 of 341 samples (0.6%) from Boston. The IgE antibodies were shown to be specific for an oligosaccharide, galactose-α-1,3-galactose, which is present on the Fab portion of the cetuximab heavy chain.

Adverse Events

N/A

Study Author Conclusions

In most subjects who had a hypersensitivity reaction to cetuximab, IgE antibodies against cetuximab were present in serum before therapy. The antibodies were specific for galactose-α-1,3-galactose.

InpharmD Researcher Critique

The study provided an underlying mechanism for hypersensitivity reaction to cetuximab which is the preexisting IgE antibodies against an oligosaccharide present on the recombinant molecule. 



References:

Chung CH, Mirakhur B, Chan E, et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. N Engl J Med. 2008;358(11):1109-1117. doi:10.1056/NEJMoa074943