Skip to main content

Drug Interactions between Cardizem CD and vamorolone

This report displays the potential drug interactions for the following 2 drugs:

Edit list (add/remove drugs)

Interactions between your drugs

Moderate

dilTIAZem vamorolone

Applies to: Cardizem CD (diltiazem) and vamorolone

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations and pharmacologic effects of vamorolone. The proposed mechanism is inhibition of CYP450 3A4, one of the isoenzymes involved in the metabolic clearance of vamorolone. Drug interaction studies have shown that administration of vamorolone following multiple doses of the potent CYP450 3A4 inhibitor itraconazole increased the systemic exposure (AUC) and peak plasma concentration (Cmax) by 44% and 8%, respectively, compared to vamorolone administered alone. Data are not available for other, less potent CYP450 3A4 inhibitors. However, the possibility for increased risk of corticosteroid-related adverse effects should not be excluded.

MANAGEMENT: Caution is recommended with the concomitant use of vamorolone with CYP450 3A4 inhibitors. Although the manufacturer of vamorolone advises that no dosage adjustment is required when coadministered with weak to moderate CYP450 3A4 inhibitors, the possibility of increased corticosteroid effects should be considered. Patients should be monitored for corticosteroid-related adverse effects, including signs and symptoms of immunosuppression, behavioral and mood disturbances, posterior subcapsular cataracts, glaucoma, bone loss, and growth retardation (in children and adolescents). Monitoring for signs and symptoms of hypercorticism such as acne, striae, thinning of the skin, easy bruising, moon facies, dorsocervical "buffalo" hump, truncal obesity, increased appetite, acute weight gain, edema, hypertension, hirsutism, hyperhidrosis, proximal muscle wasting and weakness, glucose intolerance, exacerbation of preexisting diabetes, and depression may also be advisable. In addition, if vamorolone therapy is to be discontinued, those who have received treatment lasting longer than one week should have their dose of vamorolone gradually decreased, due to the risk of adrenal suppression. Signs and symptoms of adrenal insufficiency include anorexia, hypoglycemia, nausea, vomiting, weight loss, muscle wasting, fatigue, weakness, dizziness, postural hypotension, depression, and adrenal crisis manifested as inability to respond to stress (e.g., illness, infection, surgery, trauma).

References

  1. Zurcher RM, Frey BM, Frey FJ (1989) "Impact of ketoconazole on the metabolism of prednisolone." Clin Pharmacol Ther, 45, p. 366-72
  2. Yamashita SK, Ludwig EA, Middleton E Jr, Jusko WJ (1991) "Lack of pharmacokinetic and pharmacodynamic interactions between ketoconazole and prednisolone." Clin Pharmacol Ther, 49, p. 558-70
  3. Ulrich B, Frey FJ, Speck RF, Frey BM (1992) "Pharmacokinetics/pharmacodynamics of ketoconazole-prednisolone interaction." J Pharmacol Exp Ther, 260, p. 487-90
  4. Kandrotas RJ, Slaughter RL, Brass C, Jusko WJ (1987) "Ketoconazole effects on methylprednisolone disposition and their joint suppression of endogenous cortisol." Clin Pharmacol Ther, 42, p. 465-70
  5. Glynn AM, Slaughter RL, Brass C, et al. (1986) "Effects of ketoconazole on methylprednisolone pharmacokinetics and cortisol secretion." Clin Pharmacol Ther, 39, p. 654-9
  6. Itkin IH, Menzel ML (1970) "The use of macrolide antibiotic substances in the treatment of asthma." J Allergy Clin Immunol, 45, p. 146-62
  7. LaForce CF, Szefler SJ, Miller MF, Ebling W, Brenner M (1983) "Inhibition of methylprednisolone elimination in the presence of erythromycin therapy." J Allergy Clin Immunol, 72, p. 34-9
  8. Finkenbine RD, Frye MD (1998) "Case of psychosis due to prednisone-clarithromycin interaction." Gen Hosp Psychiat, 20, p. 325-6
  9. Varis T, Kaukonen KM, Kivisto KT, Neuvonen PJ (1998) "Plasma concentrations and effects of oral methylprednisolone are considerably increased by itraconazole." Clin Pharmacol Ther, 64, p. 363-8
  10. Hillebrand-Haverkort ME, Prummel MF, ten Veen JH (1999) "Ritonavir-induced Cushing's syndrome in a patient treated with nasal fluticasone." AIDS, 13, p. 1803
  11. Varis T, Kivisto KT, Neuvonen PJ (2000) "The effect of itraconazole on the pharmacokinetics and pharmacodynamics of oral prednisolone." Eur J Clin Pharmacol, 56, p. 57-60
  12. Varis T, Backman JT, Kivisto KT, Neuvonen PJ (2000) "Diltiazem and mibefradil increase the plasma concentrations and greatly enhance the adrenal-suppressant effect of oral methylprednisolone." Clin Pharmacol Ther, 67, p. 215-21
  13. Garey KW, Rubinstein I, Gotfried MH, Khan IJ, Varma S, Danziger LH (2000) "Long-term clarithromycin decreases prednisone requirements in elderly patients with prednisone-dependent asthma." Chest, 118, p. 1826-7
  14. Lebrun-Vignes B, Archer VC, Diquest B, et al. (2001) "Effect of itraconazole on the pharmacokinetics of prednisolone and methylprednisolone and cortisol secretion in healthy subjects." Br J Clin Pharmacol, 51, p. 443-50
  15. Couturier J, Steele M, Hussey L, Pawliuk G (2001) "Steroid-induced mania in an adolescent: risk factors and management." Can J Clin Pharmacol, 8, p. 109-12
  16. Gupta SK, Dube MP (2002) "Exogenous Cushing syndrome mimicking human immunodeficiency virus lipodystrophy." Clin Infect Dis, 35, E69-71
  17. Raaska K, Niemi M, Neuvonen M, Neuvonen PJ, Kivisto KT (2002) "Plasma concentrations of inhaled budesonide and its effects on plasma cortisol are increased by the cytochrome P4503A4 inhibitor itraconazole." Clin Pharmacol Ther, 72, p. 362-369
  18. Main KM, Skov M, Sillesen IB, et al. (2002) "Cushing's syndrome due to pharmacological interaction in a cystic fibrosis patient." Acta Paediatr, 91, p. 1008-11
  19. Skov M, Main KM, Sillesen IB, Muller J, Koch C, Lanng S (2002) "Iatrogenic adrenal insufficiency as a side-effect of combined treatment of itraconazole and budesonide." Eur Respir J, 20, p. 127-33
  20. Kotlyar M, Brewer ER, Golding M, Carson SW (2003) "Nefazodone inhibits methylprednisolone disposition and enhances its adrenal-suppressant effect." J Clin Psychopharmacol, 23, p. 652-6
  21. Bolland MJ, Bagg W, Thomas MG, Lucas JA, Ticehurst R, Black PN (2004) "Cushing's syndrome due to interaction between inhaled corticosteroids and itraconazole." Ann Pharmacother, 38, p. 46-9
  22. Edsbacker S, Andersson T (2004) "Pharmacokinetics of budesonide (Entocort EC) capsules for Crohn's disease." Clin Pharmacokinet, 43, p. 803-21
  23. Samaras K, Pett S, Gowers A, McMurchie M, Cooper DA (2005) "Iatrogenic Cushing's syndrome with osteoporosis and secondary adrenal failure in HIV-infected patients receiving inhaled corticosteroids and ritonavir-boosted protease inhibitors: six cases." J Clin Endocrinol Metab, 90, p. 4394-8
  24. Soldatos G, Sztal-Mazer S, Woolley I, Stockigt J (2005) "Exogenous glucocorticoid excess as a result of ritonavir-fluticasone interaction." Intern Med J, 35, p. 67-8
  25. Penzak SR, Formentini E, Alfaro RM, Long M, Natarajan V, Kovacs J (2005) "Prednisolone pharmacokinetics in the presence and absence of ritonavir after oral prednisone administration to healthy volunteers." J Acquir Immune Defic Syndr, 40, p. 573-80
  26. EMEA. European Medicines Agency (2007) EPARs. European Union Public Assessment Reports. http://www.ema.europa.eu/ema/index.jsp?curl=pages/includes/medicines/medicines_landingpage.jsp&mid
  27. Bhumbra NA, Sahloff EG, Oehrtman SJ, Horner JM (2007) "Exogenous Cushing syndrome with inhaled fluticasone in a child receiving lopinavir/ritonavir." Ann Pharmacother, 41, p. 1306-9
  28. Busse KH, Formentini E, Alfaro RM, Kovacs JA, Penzak SR (2008) "Influence of antiretroviral drugs on the pharmacokinetics of prednisolone in HIV-infected individuals." J Acquir Immune Defic Syndr, 48, p. 561-6
  29. Agencia Española de Medicamentos y Productos Sanitarios Healthcare (2008) Centro de información online de medicamentos de la AEMPS - CIMA. https://cima.aemps.es/cima/publico/home.html
  30. (2023) "Product Information. Agamree (vamorolone)." Santhera Pharmaceuticals (US)
View all 30 references

Switch to consumer interaction data

Drug and food interactions

Moderate

dilTIAZem food

Applies to: Cardizem CD (diltiazem)

MONITOR: Like many CNS-active agents, alcohol can exhibit hypotensive effects. Coadministration with antihypertensive agents including diltiazem may result in additive effects on blood pressure and orthostasis.

MONITOR: Grapefruit juice may increase the plasma concentrations of orally administered diltiazem in some patients. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. In a study of ten healthy male volunteers, administration of a single 120 mg oral dose of immediate-release diltiazem in combination with 250 mL of grapefruit juice increased the diltiazem peak plasma concentration (Cmax) and systemic exposure (AUC) by an average of 22% and 20%, respectively, compared to administration with water. The time to reach Cmax (Tmax) and the terminal half-life were not affected, and no statistically significant differences in blood pressure and heart rate were observed during administration with grapefruit juice relative to water. In a different study, repeated administration of 200 mL of grapefruit juice at 0, 2, 4, 8 and 12 hours had no significant effect on the Cmax or AUC of a single 120 mg oral dose of diltiazem, but increased its half-life from 4.1 to 5.1 hours. The ratios for the N-demethyl and deacetyl metabolites to diltiazem were also not affected by grapefruit juice. However, because pharmacokinetic interactions involving grapefruit juice are often subject to a high degree of interpatient variability, the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Patients should be advised that alcohol may potentiate the hypotensive effects of diltiazem, especially during the initiation of therapy and following a dosage increase. Caution should be exercised when rising from a sitting or recumbent position, and patients should notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia. Patients who regularly consume grapefruit or grapefruit juice should be monitored for increased adverse effects of diltiazem such as such as headache, irregular heartbeat, edema, unexplained weight gain, and chest pain. Grapefruit and grapefruit juice should be avoided if an interaction is suspected.

References

  1. Bailey DG, Arnold JMO, Spence JD (1994) "Grapefruit juice and drugs - how significant is the interaction." Clin Pharmacokinet, 26, p. 91-8
  2. Sigusch H, Henschel L, Kraul H, Merkel U, Hoffmann A (1994) "Lack of effect of grapefruit juice on diltiazem bioavailability in normal subjects." Pharmazie, 49, p. 675-9
  3. Bailey DG, Malcolm J, Arnold O, Spence JD (1998) "Grapefruit juice-drug interactions." Br J Clin Pharmacol, 46, p. 101-10
  4. Christensen H, Asberg A, Holmboe AB, Berg KJ (2002) "Coadministration of grapefruit juice increases systemic exposure of diltiazem in healthy volunteers." Eur J Clin Pharmacol, 58, p. 515-520
  5. Cerner Multum, Inc. "UK Summary of Product Characteristics."
View all 5 references

Switch to consumer interaction data

Moderate

vamorolone food

Applies to: vamorolone

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of vamorolone. The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism in the gut wall by certain compounds present in grapefruit. The metabolism of vamorolone is mediated by the isoenzymes CYP450 3A4/5, and CYP450 2C8, and uridine diphosphate glucuronosyltransferases (UGT) 1A3, 2B7, and 2B17. In general, the effect of grapefruit juice is concentration-, dose-, and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Increased systemic exposure to vamorolone may increase the risk of corticosteroid adverse effects such as hypercorticism, hyperglycemia, adrenal suppression, immunosuppression, hypertension, salt and water retention, electrolyte abnormalities, behavioral and mood disturbances, posterior subcapsular cataracts, glaucoma, bone loss, and growth retardation in children and adolescents.

MANAGEMENT: Until further information is available, it may be advisable for patients to avoid the consumption of large amounts of grapefruit and grapefruit juice during vamorolone therapy unless otherwise directed by their doctor, as the interaction is unreliable and subject to a high degree of interpatient variation. If coadministration is considered necessary, patients should be closely monitored for signs and symptoms of corticosteroid adverse effects. Patients should also be monitored for signs and symptoms of hypercorticism such as acne, striae, thinning of the skin, easy bruising, moon facies, dorsocervical "buffalo" hump, truncal obesity, increased appetite, acute weight gain, edema, hypertension, hirsutism, hyperhidrosis, proximal muscle wasting and weakness, glucose intolerance, exacerbation of preexisting diabetes, and depression. Signs and symptoms of adrenal insufficiency include anorexia, hypoglycemia, nausea, vomiting, weight loss, muscle wasting, fatigue, weakness, dizziness, postural hypotension, depression, and adrenal crisis manifested as an inability to respond to stress (e.g., illness, infection, surgery, trauma). Consultation with product labeling for specific recommendations is advisable.

References

  1. Zurcher RM, Frey BM, Frey FJ (1989) "Impact of ketoconazole on the metabolism of prednisolone." Clin Pharmacol Ther, 45, p. 366-72
  2. Yamashita SK, Ludwig EA, Middleton E Jr, Jusko WJ (1991) "Lack of pharmacokinetic and pharmacodynamic interactions between ketoconazole and prednisolone." Clin Pharmacol Ther, 49, p. 558-70
  3. Ulrich B, Frey FJ, Speck RF, Frey BM (1992) "Pharmacokinetics/pharmacodynamics of ketoconazole-prednisolone interaction." J Pharmacol Exp Ther, 260, p. 487-90
  4. Kandrotas RJ, Slaughter RL, Brass C, Jusko WJ (1987) "Ketoconazole effects on methylprednisolone disposition and their joint suppression of endogenous cortisol." Clin Pharmacol Ther, 42, p. 465-70
  5. Glynn AM, Slaughter RL, Brass C, et al. (1986) "Effects of ketoconazole on methylprednisolone pharmacokinetics and cortisol secretion." Clin Pharmacol Ther, 39, p. 654-9
  6. Itkin IH, Menzel ML (1970) "The use of macrolide antibiotic substances in the treatment of asthma." J Allergy Clin Immunol, 45, p. 146-62
  7. LaForce CF, Szefler SJ, Miller MF, Ebling W, Brenner M (1983) "Inhibition of methylprednisolone elimination in the presence of erythromycin therapy." J Allergy Clin Immunol, 72, p. 34-9
  8. Finkenbine RD, Frye MD (1998) "Case of psychosis due to prednisone-clarithromycin interaction." Gen Hosp Psychiat, 20, p. 325-6
  9. Varis T, Kaukonen KM, Kivisto KT, Neuvonen PJ (1998) "Plasma concentrations and effects of oral methylprednisolone are considerably increased by itraconazole." Clin Pharmacol Ther, 64, p. 363-8
  10. Hillebrand-Haverkort ME, Prummel MF, ten Veen JH (1999) "Ritonavir-induced Cushing's syndrome in a patient treated with nasal fluticasone." AIDS, 13, p. 1803
  11. Varis T, Kivisto KT, Neuvonen PJ (2000) "The effect of itraconazole on the pharmacokinetics and pharmacodynamics of oral prednisolone." Eur J Clin Pharmacol, 56, p. 57-60
  12. Varis T, Backman JT, Kivisto KT, Neuvonen PJ (2000) "Diltiazem and mibefradil increase the plasma concentrations and greatly enhance the adrenal-suppressant effect of oral methylprednisolone." Clin Pharmacol Ther, 67, p. 215-21
  13. Garey KW, Rubinstein I, Gotfried MH, Khan IJ, Varma S, Danziger LH (2000) "Long-term clarithromycin decreases prednisone requirements in elderly patients with prednisone-dependent asthma." Chest, 118, p. 1826-7
  14. Lebrun-Vignes B, Archer VC, Diquest B, et al. (2001) "Effect of itraconazole on the pharmacokinetics of prednisolone and methylprednisolone and cortisol secretion in healthy subjects." Br J Clin Pharmacol, 51, p. 443-50
  15. Couturier J, Steele M, Hussey L, Pawliuk G (2001) "Steroid-induced mania in an adolescent: risk factors and management." Can J Clin Pharmacol, 8, p. 109-12
  16. Gupta SK, Dube MP (2002) "Exogenous Cushing syndrome mimicking human immunodeficiency virus lipodystrophy." Clin Infect Dis, 35, E69-71
  17. Raaska K, Niemi M, Neuvonen M, Neuvonen PJ, Kivisto KT (2002) "Plasma concentrations of inhaled budesonide and its effects on plasma cortisol are increased by the cytochrome P4503A4 inhibitor itraconazole." Clin Pharmacol Ther, 72, p. 362-369
  18. Main KM, Skov M, Sillesen IB, et al. (2002) "Cushing's syndrome due to pharmacological interaction in a cystic fibrosis patient." Acta Paediatr, 91, p. 1008-11
  19. Skov M, Main KM, Sillesen IB, Muller J, Koch C, Lanng S (2002) "Iatrogenic adrenal insufficiency as a side-effect of combined treatment of itraconazole and budesonide." Eur Respir J, 20, p. 127-33
  20. Kotlyar M, Brewer ER, Golding M, Carson SW (2003) "Nefazodone inhibits methylprednisolone disposition and enhances its adrenal-suppressant effect." J Clin Psychopharmacol, 23, p. 652-6
  21. Bolland MJ, Bagg W, Thomas MG, Lucas JA, Ticehurst R, Black PN (2004) "Cushing's syndrome due to interaction between inhaled corticosteroids and itraconazole." Ann Pharmacother, 38, p. 46-9
  22. Edsbacker S, Andersson T (2004) "Pharmacokinetics of budesonide (Entocort EC) capsules for Crohn's disease." Clin Pharmacokinet, 43, p. 803-21
  23. Samaras K, Pett S, Gowers A, McMurchie M, Cooper DA (2005) "Iatrogenic Cushing's syndrome with osteoporosis and secondary adrenal failure in HIV-infected patients receiving inhaled corticosteroids and ritonavir-boosted protease inhibitors: six cases." J Clin Endocrinol Metab, 90, p. 4394-8
  24. Soldatos G, Sztal-Mazer S, Woolley I, Stockigt J (2005) "Exogenous glucocorticoid excess as a result of ritonavir-fluticasone interaction." Intern Med J, 35, p. 67-8
  25. Penzak SR, Formentini E, Alfaro RM, Long M, Natarajan V, Kovacs J (2005) "Prednisolone pharmacokinetics in the presence and absence of ritonavir after oral prednisone administration to healthy volunteers." J Acquir Immune Defic Syndr, 40, p. 573-80
  26. EMEA. European Medicines Agency (2007) EPARs. European Union Public Assessment Reports. http://www.ema.europa.eu/ema/index.jsp?curl=pages/includes/medicines/medicines_landingpage.jsp&mid
  27. Bhumbra NA, Sahloff EG, Oehrtman SJ, Horner JM (2007) "Exogenous Cushing syndrome with inhaled fluticasone in a child receiving lopinavir/ritonavir." Ann Pharmacother, 41, p. 1306-9
  28. Busse KH, Formentini E, Alfaro RM, Kovacs JA, Penzak SR (2008) "Influence of antiretroviral drugs on the pharmacokinetics of prednisolone in HIV-infected individuals." J Acquir Immune Defic Syndr, 48, p. 561-6
  29. Agencia Española de Medicamentos y Productos Sanitarios Healthcare (2008) Centro de información online de medicamentos de la AEMPS - CIMA. https://cima.aemps.es/cima/publico/home.html
  30. (2023) "Product Information. Agamree (vamorolone)." Santhera Pharmaceuticals (US)
View all 30 references

Switch to consumer interaction data

Moderate

dilTIAZem food

Applies to: Cardizem CD (diltiazem)

MONITOR: Calcium-containing products may decrease the effectiveness of calcium channel blockers by saturating calcium channels with calcium. Calcium chloride has been used to manage acute severe verapamil toxicity.

MANAGEMENT: Management consists of monitoring the effectiveness of calcium channel blocker therapy during coadministration with calcium products.

References

  1. Henry M, Kay MM, Viccellio P (1985) "Cardiogenic shock associated with calcium-channel and beta blockers: reversal with intravenous calcium chloride." Am J Emerg Med, 3, p. 334-6
  2. Moller IW (1987) "Cardiac arrest following intravenous verapamil combined with halothane anaesthesia." Br J Anaesth, 59, p. 522-6
  3. Oszko MA, Klutman NE (1987) "Use of calcium salts during cardiopulmonary resuscitation for reversing verapamil-associated hypotension." Clin Pharm, 6, p. 448-9
  4. Schoen MD, Parker RB, Hoon TJ, et al. (1991) "Evaluation of the pharmacokinetics and electrocardiographic effects of intravenous verapamil with intravenous calcium chloride pretreatment in normal subjects." Am J Cardiol, 67, p. 300-4
  5. O'Quinn SV, Wohns DH, Clarke S, Koch G, Patterson JH, Adams KF (1990) "Influence of calcium on the hemodynamic and anti-ischemic effects of nifedipine observed during treadmill exercise testing." Pharmacotherapy, 10, p. 247
  6. Woie L, Storstein L (1981) "Successful treatment of suicidal verapamil poisoning with calcium gluconate." Eur Heart J, 2, p. 239-42
  7. Morris DL, Goldschlager N (1983) "Calcium infusion for reversal of adverse effects of intravenous verapamil." JAMA, 249, p. 3212-3
  8. Guadagnino V, Greengart A, Hollander G, Solar M, Shani J, Lichstein E (1987) "Treatment of severe left ventricular dysfunction with calcium chloride in patients receiving verapamil." J Clin Pharmacol, 27, p. 407-9
  9. Luscher TF, Noll G, Sturmer T, Huser B, Wenk M (1994) "Calcium gluconate in severe verapamil intoxication." N Engl J Med, 330, p. 718-20
  10. Bar-Or D, Gasiel Y (1981) "Calcium and calciferol antagonise effect of verapamil in atrial fibrillation." Br Med J (Clin Res Ed), 282, p. 1585-6
  11. Lipman J, Jardine I, Roos C, Dreosti L (1982) "Intravenous calcium chloride as an antidote to verapamil-induced hypotension." Intensive Care Med, 8, p. 55-7
  12. McMillan R (1988) "Management of acute severe verapamil intoxication." J Emerg Med, 6, p. 193-6
  13. Perkins CM (1978) "Serious verapamil poisoning: treatment with intravenous calcium gluconate." Br Med J, 2, p. 1127
  14. Moroni F, Mannaioni PF, Dolara A, Ciaccheri M (1980) "Calcium gluconate and hypertonic sodium chloride in a case of massive verapamil poisoning." Clin Toxicol, 17, p. 395-400
View all 14 references

Switch to consumer interaction data

Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.

See also

Report options

Loading...
QR code containing a link to this page

Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Medical Disclaimer