Toxicology Litigation Support

Phenylpropanolamine (PPA)

The Food and Drug Administration has recommended recently that phenylpropanolamine (PPA) be removed from over-the-counter cold and diet medications. Products containing phenylpropanolamine or PPA include Alka-Seltzer Plus®, Acutrim®, Contac®, Comtrex®, Dexatrim™, Dimetapp®, Triaminic®, Robitussin CF®, among others. Although an association between phenylpropanolamine and stroke has been known for some time (see discussion below), no significant epidemiological studies were ever reported. Recently (May 10, 2000), a final report of the Hemorrhagic Stroke Project [1] was issued. Based on its case-control epidemiological study, this report concludes that phenylpropanolamine significantly increases the risk of hemorrhagic stroke. In this brief report, I will address the results of the Hemorrhagic Stroke Project (HSP) and earlier published literature. Both the HSP and the early literature suggest a causal relationship between the ingestion of phenylpropanolamine (PPA) at normal dosing levels and subarachnoid and intra cerebral hemorrhage. The literature also suggests the potential for PPA to cause birth defects as a result of exposure at normal dosing levels by pregnant women.[2]

There have been many reports relating PPA ingestion to various hypertension and central nervous system problems. This should not be surprising since phenylpropanolamine (PPA), is very similar chemically to other amines that increase blood pressure including epinephrine, phenylephrine, and ephedrine and other central nervous system stimulants such as ephedrine and amphetamine. It should be noted that PPA is a metabolite of ephedrine.

Signs and symptoms associated with PPA ingestion that have been reported in the literature include cerebral arteritis,[3] severe headaches,[3-5] nausea/vomiting,[3] acute hypertension,[4,6,7] psychoses,[5] seizures,[5] increased cardiac output[7] and death.[4,7,8] One publication[6] describes a controlled study showing dose-related increases in blood pressure associated with controlled dosing of PPA and PPA/caffeine mixtures. Lake et al.[6] consider their findings to be one possible explanation for nontraumatic intra cranial hemorrhage in young healthy persons who have ingested PPA at normal dosing levels. Thomas, et al.[9] conducted a double-blind study of 16 volunteers taking cold tablets containing PPA and found significant increases in blood pressure, stroke volume, and total peripheral resistance which they attribute to PPA induced vasoconstriction. Of particular interest is stroke.

Although earlier work has not been investigated, much concern about a possible causal connection between PPA and stroke has been expressed in literature published in the 1980s and early 1990s.[10-16] Lake et al.[4] reported on 142 cases involving PPA of which 24 involved intra cranial hemorrhages, and 8 resulted in death mostly due to stroke. Another report by Lake et al.[8] described severe adverse drug reactions relating to PPA including hypertensive crisis, stroke, and death. In 1989, Uldry and Regli[17] suggested that amphetamine as well as PPA can cause cerebral infarction or hemorrhage. Intra cerebral hemorrhages were reported by Glick et al[5] and Kase et al.,[14] and the latter report[14] “strongly suggest an association between phenylpropanolamine ingestion and hemorrhagic stroke.” Johnson et al.[18] also suggested a causal relationship between stroke and PPA ingestion. Cerebral infarctions were reported by Montalban et al.[19] and Edwards et al.[20]

It appears that there was ample information available in the published literature to warrant concern for the potential of phenylpropanolamine (PPA) to cause stroke. Some authors have warned against the toxic effects of PPA.[5,9,21] Thomas et al.[9] stated “. . . its [PPA] use in patients with heart disease or hypertension is hazardous.” In two 1990 publications Lake et al.[4,8] warn of adverse effects including strokes and, in particular, state that overweight patients are particularly at high risk of adverse reactions to PPA because they are likely to be hypertensive. Mathew and Wilson[22] warn of an increased risk of stroke from using PPA-caffeine mixtures. While reporting on a case of intra cerebral hematoma related to PPA, Glick et al.[5] stated “This report should alert physicians in general, to this potentially fatal side effect of PPA, a commonly used over-the-counter drug”. In 1991, the American Medical Association[23] in its “Drug Evaluation Annual” stated, “This agent can cause strokes and other sequella of elevated blood pressure in susceptible individuals.”

Finally, in May of this year, Horwitz et al.[1] issued the “Final Report of the Hemorrhagic Stroke Project”. This was a case-control study involving men and women between the ages of 18 and 49 who were hospitalized for either subarachnoid hemorrhage or intra cerebral hemorrhage with no prior history of stroke. Exposure to phenylpropanolamine (PPA) was defined as having taken PPA within three days of having a stroke. The final cohort consisted of 702 case subjects and 1,376 controls. Adjusted odds ratios between hemorrhagic stroke and any use of PPA within 3 days was 1.49 (ns), and for use of PPA in cough medicines within 3 days, the adjusted odds ratio was 1.23 (ns). On the other hand, the adjusted odds ratio for hemorrhagic stroke and PPA use in appetite suppressants within the three-day preceding period was 15.92 (ss, p=0.013); for women under the same conditions the odds ratio was 16.58 (ss, p=0.011). For first use of cold remedies among women, the adjusted odds ratio was 3.13 (ss, p=0.042).

It would appear then that phenylpropanolamine (PPA) does increase risk of hemorrhagic stroke in both those using cough medicines and, in particular, in those using appetite suppressants containing PPA. I believe that this data, coupled with other published information on PPA, is adequate to establish a causal relationship between phenylpropanolamine (PPA) and stroke.

PHENYLPROPANOLAMINE (PPA) REFERENCES

1. Horwitz, R. I., Brass, L. M., Kernan, W. N., Viscoli, C. M., Phenylpropanolamine and risk of hemorrhagic stroke. May 10, 2000
2. Hazardous Substance Data Bank, National Library of Medicine, Bethesda, MD, October 21, 2000.
3. Ryu, S. J. and Lin, S. K., Cerebral arteritis associated with oral use of phenylpropanolamine: report of a case. J. Formos. Med. Assoc., 94(12), 5355 (1995).
4. Lake, C. R., Gallant, S., Masson, E. and Miller, P., Adverse drug effects attributed to phenylpropanolamine: a review of 142 cases. Am. J. Med., 89(2), 195208 (1990).
5. Glick, R., Hoying, J., Cerullo, L. and Perlman, S., Phenylpropanolamine: an overthecounter drug causing central nervous system vasculitis and intra cerebral hemorrhage. Case report and review. Neurosurgery, 20(6), 969974 (1987).
6. Lake, C. R., Zaloga, G., Bray, J., Rosenberg, D. and Chernow, B., Transient hypertension after two phenylpropanolamine diet aids and the effects of caffeine: a placebocontrolled followup study. Am. J. Med., 86(4), 427432 (1989).
7. Pental, P. R., Asinger, R. W. and Benowitz, N. L., Propranolol antagonism of phenylpropanolamine induced hypertension. Clin. Pharmacol. Ther., 37(5), 488494 (1985).
8. Lake, C. R., Rosenberg, D. and Quirk, R., Phenylpropanolamine and caffeine use among diet center clients. Int. J. Obes., 14(7), 171582 (1990).
9. Thomas, S. H., Clark, K. L., Allen, R. and Smith, S. E., A comparison of the cardiovascular effects of phenylpropanolamine and phenylephrine containing proprietary cold remedies. Br. J. Clin. Pharmacol., 32(6), 705711 (1991).
10. Kikta, D. G., Devereaux, M. W. and Chandar, K., Intra cranial hemorrhages due to phenylpropanolamine. Stroke, 16 510512 (1985).
11. Fallis, R. J. and Fisher, M., Cerebral vasculitis and hemorrhage associated with phenylpropanolamine. Neurology, 35, 405407 (1985).
12. McDowell, J. R. and Leblanc, H. J., Phenylpropanolamine and cerebral hemorrhage. Western J. Med., 142, 688691 (1985).
13. Forman, H. P., Levin, S., Stewart, B., Patel, M. and Feinstein, S., Cerebral vasculitis and hemorrhage in an adolescent taking diet pills containing phenylpropanolamine: case report and review of the literature. Pediatrics, 83, 737741 (1989).
14. Kase, C. S., Foster, T. E., Reed, J. E., Spatz, E. L. and Girgis, G. N., Intercerebral hemorrhage and phenylpropanolamine use. Neurology, 37, 399404 (1987).
15. Chung, Y. T., Hung, D. Z., Hsu, C. P., Yang, D. Y. and Wu, T. C., Intra cerebral hemorrhage in a young woman with arteriovenous malformation after taking diet control pills containing phenylpropanolamine: A case report. Chinese Med. J., 61, 432435 (1998).
16. Jick, H., Aselton, P. and Hunter, J. R., Propanolamine and cerebral haemorrhage. Lancet, 1017 (1984).
17. Uldry, P. A. and Regli, F., Cerebrovascular accidents in relation to drug consumption or drug abuse. Schweiz. Rundsch. Med. Prax., 78(12), 663666 (1989).
18. Johnson, D. A., Etter, H. S. and Reeves, D. M., Stroke and phenylpropanolamine use. Lancet, 2(8356), 970 (1983).
19. Montalban, J., Ibanez, L., Rodriguez, C., Lopez, M., Sumalla, J. and Codina, A., Cerebral infarction after excessive use of nasal decongestants. J. Neurol. Neurosurg. Psychiatry, 52(4), 541543 (1989).
20. Edwards, M., Russo, L. and HarwoodNuss, A., Cerebral infarction with single oral dose of phenylpropanolamine. Am. J. Emerg. Med., 5(2), 163164 (1987).
21. Bernstein, E. and Diskant, B. M., Phenylpropanolamine: a potentially hazardous drug. Ann. Emerg. Med., 11, 311315 (1982).
22. Mathew, R. J. and Wilson, W. H., Substance abuse and cerebral blood flow. Am. J. Psychiatry, 148(3), 292305 (1991).
23. Anonymous, In: AMA Drug Evaluations Annual, p. 416, Chicago, IL (1991).

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