SEARCH

SEARCH BY CITATION

Keywords:

  • drug reaction;
  • patent blue;
  • rifampicin;
  • tuberculosis

Colorants are commonly used excipients in many prescription and nonprescription drugs. As these agents are capable of various reactions, it may be postulated that at least a part of drug reactions are not attributed to the active drug. There may be unknown additives in drugs that cause in reactions. In this report, the case of a 22-year-old male patient who developed an unusual skin reaction to a specific additive of a rifampicin preparation has been described.

Adverse drug reaction is a commonly encountered problem in daily medical practice. Some frequent drug reactions occur with certain drugs and are well known. However, there is always a possibility of experiencing extraordinary or unreported reactions with commonly used drugs. In rare occasions, some drug-related reactions can be attributed to drug additives only. In this report, the case of a 22-year-old male patient who developed an unusual skin reaction to a specific rifampicin formulation has been described. The steps leading to the diagnosis of an adverse drug reaction and the role of pharmacologically inert substances of formulations are also discussed.

A 22-year-old man was admitted to a physician with painless swellings at the right-side of his neck for 4 weeks. Initial physical examination revealed multiple, nontender, soft, rubbery and movable lymph node enlargements at the right cervical region. Ultrasonographic examination showed multiple lymph node enlargements at the right cervical region. The largest lymph node was 63 × 37 mm in diameter, and of centric hypoechoic nature. An excisional biopsy of this lymph node was performed. Histopathologic findings were compatible with tuberculosis lymphadenitis (caseous necrosis in the central part of the node). Tuberculosis bacillus was not identified by cultures, polymerase chain reaction (PCR) assay and other known methods. On the basis of strong pathological evidences, antituberculous therapy was started with isoniazid, rifampicin, ethambutol and morphazinamide (1).

On the 11th month of treatment, cervical lesion re-enlarged, became tender and warm because of superinfection and abscess formation. The patient was hospitalized and wound debridement, dressing and topical treatment with rifamycine SV were performed in addition to antituberculous therapy. Response to treatment was achieved and superinfection controlled. However, the patient developed recurring skin eruptions during this treatment. At this stage, the patient consulted our Allergy Department to evaluate the skin eruptions.

The clinical findings were daily recurring, self limited, macular, itchy rashes, symmetrically placed on the face, ears, buttocks, elbows and knees. The lesions appeared at the same time every day and lasted about 45 min, then disappeared spontaneously without any treatment. These findings were considered as an unusual drug reaction. The patient was taking isoniazid, rifampicin, ethambutol and topical rifamycine SV when referred to our department. So, there are four different drugs that may cause this reaction.

As the elimination and re-administration procedure is the keystone in evaluating a possible drug reaction, rifamycine SV application was discontinued in the first step. It was the strongest possibility because reactions caused by topical rifamycine SV application have been reported several times (2–5). Skin testing with rifamycine SV was performed as well, as the IgE-mediated hypersensitivity reactions to rifamycine SV have been described repeatedly (3–5). Epidermal skin testing (prick test) was carried out with undiluted rifamycine SV. Skin response was negative. Then intradermal testing with 1/1000 and 1/100 dilutions of the drug was performed. Intradermal testing was also negative in each dilution. Furthermore, the skin lesions did not disappear even before the discontinuation of rifamycine SV. Depending on these results it was concluded that rifamycine SV was not the causative drug.

At the second step, other three drugs were evaluated. All drugs were discontinued and re-administered one by one. The skin eruptions recurred only after rifampicin re-administration. In addition, a close relationship between the daily onset time of the reaction and rifampicin intake was established when reviewed retrospectively. In fact, the symptoms were recurring regularly about half an hour after rifampicin administration.

But another clinical observation conflicted this finding: some days the patient did not experience skin eruptions after rifampicin dose. This inconsistency was examined in detail. The drugs given to inpatients were provided by the hospital pharmacy. Two different brands of rifampicin preparation were available in stock and the patients were having either brand randomly.

Diagnostic procedures were revised in accordance with the recent finding. Challenges with different rifampicin formulations (named as ‘Brand-A-rifampicin’ and ‘Brand-B-rifampicin’) were performed on different days. Skin eruptions appeared only with Brand-A-rifampicin. Additional challenges with Brand-A-rifampicin were repeated two more times on different days (re-challenge). The same results were obtained in each challenge. Brand-A-rifampicin was found to be responsible for the allergic reactions.

Why Brand-A-rifampicin causes skin eruption while the Brand-B-rifampicin did not? As active components in each preparation are the same, any pharmacologically inert substance like drug capsule material, might have been responsible. To find out the responsible factor within Brand-A-rifampicin preparation, the patient was challenged with empty capsule and with active drug powder on separate days. No reaction was observed with active drug challenge, but the skin rashes recurred after the administration of an empty capsule which implies that the patient was sensitive to one of the capsule shell excipients of Brand-A-rifampicin.

Rifampicin is one of the major drugs used for the treatment of mycobacterial infections, and has been prescribed throughout the world for over 20 years. It is usually well tolerated, however, many reports have shown that rifampicin could induce a variety of adverse effects including flu-like syndrome, thrombocytopenia, hemolytic anemia, renal failure, various cutaneous reactions and life-threatening anaphylactic reactions. Many of these reactions have been considered allergic in origin (6, 7).

Several types of cutaneous reactions, from urticaria to toxic epidermal necrolysis, associated with rifampicin treatment have been described (8–12). However, daily recurring, symmetric and self-limited itchy macular eruptions have not been reported. Furthermore, all the previously described skin reactions were linked directly to rifampicin. But, in our case, the eruptions were related to a specific rifampicin preparation, most probably arising from a specific excipient of that preparation.

Two available rifampicin preparations contain the same active drug and drug capsule shell excipients titanium-dioxide and erythrosine, except patent blue V (PBV) in Brand-A-rifampicin and indigotin (indigo blue) in Brand-B-rifampicin. So, it may be postulated that PBV might be causative agent for the skin reaction.

Drug capsule shell materials contain pharmaceutically acceptable coloring agents such as PBV (E131). This dark bluish-violet synthetic coal tar dye is also used as a food color additive and diagnostic aid in lymphatic mapping. As in other coloring agents, PBV may also cause allergic or pseudo-allergic reactions (either by direct histamine release, or by alternate activation of the complement system) such as rashes similar to nettle rash, itching, nausea, low blood pressure, tremors and breathing problems (13, 14). For this reason, using PBV as a food additive is banned in some countries (15, 16). Most of the reported reactions were related to PBV injections for radiologic imaging (17–19). However, PBV may also cause adverse events when used as a drug additive. Chadwick et al. reported an urticarial reaction in a 5-year-old girl after the use of tablets containing PBV (20). In addition, there are some reports about allergic and pseudo-allergic reactions arising from different drug coloring agents (21–26).

Colorants are commonly used excipients in many prescription and nonprescription drugs. As these agents are capable of various reactions, it may be postulated that at least a part of drug reactions are not attributed to the active drug. There may be unknown additives in drugs, that cause in reactions. Therefore, many drugs might be excluded from the treatment schemes and patients erroneously labeled as allergic to questionable drugs.

In this case, had rifampicin been wrongly implicated to cause the allergic reaction, this patient would have been deprived of an important drug. However, careful clinical observation and through investigations have shown that the patient could tolerate another rifampicin formulation without any complication.

This case also reveals an important detail: when an adverse reaction attributed to a drug is reported, the additives of suspected drug should also be mentioned. These kinds of reports may provide an opportunity to recognize drug additive-related adverse events. Furthermore, as many colorants associated with a wide range of health problems have been banned in some countries, their continued use within drug formulations is controversial. The safer formulations may offer safer treatment courses.

As a result, when a drug-related adverse event was investigated, active components and excipients should be evaluated together, as all reactions may not be attributable directly to the active component. So, using the names of the inert substances associated with proprietary name or approved name of the drug may be vital in our opinion.

References

  1. Top of page
  2. References
  • 1
    Kanlikama M, Mumbuc S, Bayazit Y, Sirikci A. Management strategy of mycobacterial cervical lymphadenitis. J Laryngol Otol 2000;114: 274278.
  • 2
    Mancuso G, Masara N. Contact urticaria and severe anaphylaxis from rifamycin SV. Contact Dermatitis 1992;27: 124125.
  • 3
    Cardot E, Tillie Leblond I, Jeannin P, Facon A, Breuil K, Patte F, Tonnel AB. Anaphylactic reaction to local administration of rifamycin SV. J Allergy Clin Immunol 1995;95: 17.
  • 4
    Erel F, Karaayvaz M, Deveci M, Ozanguc N. Severe anaphylaxis from rifamycin SV. Ann Allergy Asthma Immunol 1998;81: 257260.
  • 5
    Magnan A, Venemalm L, Porri F, Vervloet D. Anaphylactic reaction to rifamycin SV: presence of specific IgE antibodies. J Allergy Clin Immunol 1999;103: 954956.
  • 6
    Martinez E, Collazos J, Mayo J. Hypersensitivity reactions to rifampin. Pathogenetic mechanisms, clinical manifestations, management strategies, and review of the anaphylactic-like reactions. Medicine (Baltimore) 1999;78: 361369.
  • 7
    Grosset J, Leventis S. Adverse effects of rifampin. Rev Infect Dis 1983;3: 440450.
  • 8
    Goel A, Balachandran C. Bullous necrotizing fixed drug eruption with hepatitis due to rifampicin. Indian J Lepr 2001;73: 159156.
  • 9
    Iredale JP, Sankaran R, Wathen CG. Cutaneous vasculitis associated with rifampin therapy. Chest 1989;96: 215216.
  • 10
    Goldin HM, Schweitzer WJ, Bronson DM. Rifampin and exfoliative dermatitis. Ann Intern Med 1987;107: 789.
  • 11
    Gupta CM, Bhate RD. Shortness of breath with urticaria due to once monthly rifampicin. Lepr Rev 1987;58: 308309.
  • 12
    Okano M, Kitano Y, Igarashi T. Toxic epidermal necrolysis due to rifampicin. J Am Acad Dermatol 1987;17: 303304.
  • 13
    Dubost JL, Chevallier H. Allergic reactions to patent blue violet: mechanisms, frequency and treatment. Phlebologie 1982;35: 739746.
  • 14
    Diagnostic agents. In: ReynoldsEFJ, ed. Martindale. The extra pharmacopenia. London: The Pharmoceutical Press, 1993, 777 pp.
  • 15
    Smolinske SC. Handbook of food, drug, and cosmetic excipients. Boca Raton, FL: CRC Press, 1992.
  • 16
    Goldsmith E, Hillyard N. Battle for the Earth: today's key environmental issues. Child & Associates, Brookvale, UK, NSW, 1988.
  • 17
    Mostafa A, Carpenter R. Anaphylaxis to patent blue dye during sentinel lymph node biopsy for breast cancer. Eur J Surg Oncol 2001;27: 610.
  • 18
    Mullan MH, Deacock SJ, Quiney NF, Kissin MW. Anaphylaxis to patent blue dye during sentinel lymph node biopsy for breast cancer. Eur J Surg Oncol 2001;27: 218219.
  • 19
    Barber CJ. Serious adverse reaction to patent blue violet at lymphography. Clin Radiol 1989;40: 631.
  • 20
    Chadwick BL, Hunter ML, Evans MT, Hunter B. Allergic reaction to the food dye patent blue. Br Dent J 1990;168: 386387.
  • 21
    Bell T. Colourants and drug reactions. Lancet 1991;338: 5556.
  • 22
    Levesque H, Moore N, Courtois H. Reporting advers reactions by proprietary name. Lancet 1991;338: 393.
  • 23
    Magner J, Gerber P. Urticaria due to blue dye in synthroid tablets. Thyroid 1994;4: 341.
  • 24
    Gross PA, Lance K, Whitlock RJ, Blume RS. Additive allergy: allergic gastroenteritis due to yellow dye #6. Ann Intern Med 1989;111: 8788.
  • 25
    Frazier CA. Allergic reaction to yellow dye no. 5. South Med J 1990;83: 1234.
  • 26
    Matheu V, Zapatero L, Alcazar M, Martinez-Molero MI, Baeza ML. IgE-mediated reaction to a banana-flavored drug additive. J Allergy Clin Immunol 2000;106: 12021203.