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Drug Interactions between isoniazid / rifampin and phenytoin

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

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Major

rifAMPin isoniazid

Applies to: isoniazid / rifampin and isoniazid / rifampin

MONITOR CLOSELY: The risk of hepatotoxicity is greater when rifampin and isoniazid (INH) are given concomitantly, than when either drug is given alone. The proposed mechanism is rifampin's induction of isoniazid hydrolase, an enzyme involved in the conversion of INH to isonicotinic acid and hydrazine. Hydrazine is the proposed toxic metabolite of INH, which has been shown in animal studies to cause steatosis, hepatocyte vacuolation and glutathione depletion. Some studies have also shown that slow acetylators have a two-fold increased risk of developing antituberculosis drug-induced hepatotoxicity (ATDH) as compared with fast acetylators due to more available INH for direct hydrolysis to hydrazine. Theoretically, a similar reaction may occur with rifabutin and isoniazid. Additional risk factors for developing hepatotoxicity include patients with advanced age, malnutrition, existing hepatic impairment, daily alcohol consumption, female gender, HIV infection, extra-pulmonary tuberculosis and/or patients who are taking other potent CYP450-inducing agents.

MANAGEMENT: Caution and close monitoring should be considered if isoniazid (INH) is coadministered with rifampin or rifabutin. In cases where coadministration is required, careful monitoring of liver function, especially ALT and AST, should be done at baseline and then every 2 to 4 weeks during therapy, or in accordance with individual product labeling. Some manufacturers of INH recommend strongly considering its discontinuation if serum aminotransferase concentrations (AST or SGOT, ALT or SGPT) exceed 3 to 5 times the upper limit of normal. Product labeling for rifampin also recommends the immediate discontinuation of therapy if hepatic damage is suspected. INH product labeling suggests alternate drugs be used if hepatitis is attributed to INH in patients with tuberculosis. However, if INH must be used, it should only be resumed after the patient's symptoms and laboratory abnormalities have cleared. It should also be restarted in very small, gradually increasing doses and immediately withdrawn if there is any indication of recurrent liver involvement. Patients should be counseled to immediately report signs or symptoms consistent with liver damage and notified that prodromal symptoms usually consist of fatigue, weakness, malaise, anorexia, nausea, and/or vomiting.

References

  1. O'Brien RJ, Long MW, Cross FS, et al. (1983) "Hepatotoxicity from isoniazid and rifampin among children treated for tuberculosis." Pediatrics, 72, p. 491-9
  2. Kumar A, Misra PK, Mehotra R, et al. (1991) "Hepatotoxicity of rifampin and isoniazid." Am Rev Respir Dis, 143, p. 1350-2
  3. Abadie-Kemmerly S, Pankey GA, Dalvisio JR (1988) "Failure of ketoconazole treatment of blastomyces dermatidis due to interaction of isoniazid and rifampin." Ann Intern Med, 109, p. 844-5
  4. Acocella G, Bonollo L, Garimoldi M, et al. (1972) "Kinetics of rifampicin and isoniazid administered alone and in combination to normal subjects and patients with liver disease." Gut, 13, p. 47-53
  5. Yamamoto T, Suou T, Hirayama C (1986) "Elevated serum aminotransferase induced by isoniazid in relation to isoniazid acetylator phenotype." Hepatology, 6, p. 295-8
  6. Steele MA, Burk RF, Des Prez RM (1991) "Toxic hepatitis with isoniazid and rifampin." Chest, 99, p. 465-71
  7. "Product Information. INH (isoniazid)." Ciba Pharmaceuticals, Summit, NJ.
  8. Sarma G, Immanuel C, Kailasam S, Narayana AS, Venkatesan P (1986) "Rifampin-induced release of hydrazine from isoniazid." Am Rev Respir Dis, 133, p. 1072-5
  9. (2001) "Product Information. Mycobutin (rifabutin)." Pharmacia and Upjohn
  10. (2001) "Product Information. Rifadin (rifampin)." Hoechst Marion Roussel
  11. Askgaard DS, Wilcke T, Dossing M (1995) "Hepatotoxicity caused by the combined action of isoniazid and rifampicin." Thorax, 50, p. 213-4
  12. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  13. Canadian Pharmacists Association (2006) e-CPS. http://www.pharmacists.ca/function/Subscriptions/ecps.cfm?link=eCPS_quikLink
  14. Cerner Multum, Inc. "Australian Product Information."
  15. (2023) "Product Information. Isoniazid (isoniazid)." Chartwell RX, LLC.
  16. (2023) "Product Information. Isoniazid (Arrotex) (isoniazid)." Arrotex Pharmaceuticals Pty Ltd
  17. (2023) "Product Information. Isoniazid (isoniazid)." RPH Pharmaceuticals AB
  18. Sarma GR, Immanual C, Kailasam S, Narayana AS, Venkatesan P (2024) Rifampin-induced release of hydrazine from isoniazid. A possible cause of hepatitis during treatment of tuberculosis with regimens containing isoniazid and rifampin https://pubmed.ncbi.nlm.nih.gov/3717759/
  19. Tostmann A, Boeree MJ, Aarnoutse RE, De Lange WCM, Van Der Ven AJAM, Dekhuijzen R (2024) Antituberculosis drug-induced hepatotoxicity: concise up-to-date review https://onlinelibrary.wiley.com/doi/10.1111/j.1440-1746.2007.05207.x
  20. (2021) "Product Information. Isotamine (isoniazid)." Bausch Health, Canada Inc.
  21. (2022) "Product Information. Rifampin (rifAMPin)." Akorn Inc
  22. (2022) "Product Information. Rifampicin (rifampicin)." Mylan Pharmaceuticals Inc
  23. (2023) "Product Information. Rifadin (rifampicin)." Sanofi
  24. (2024) "Product Information. Rifadin (rifaMPICin)." Sanofi-Aventis Australia Pty Ltd
  25. (2019) "Product Information. Rofact (rifampin)." Bausch Health, Canada Inc.
View all 25 references

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Major

rifAMPin phenytoin

Applies to: isoniazid / rifampin and phenytoin

MONITOR CLOSELY: Coadministration with rifampin may decrease the serum concentrations of phenytoin. The proposed mechanism is rifampin induction of CYP450 2C9 and 2C19, the isoenzymes responsible for the metabolic clearance of phenytoin. In 6 study subjects, intravenous administration of phenytoin following a two-week treatment with rifampin 450 mg daily resulted in a 109% increase in phenytoin clearance and a 53% decrease in phenytoin half-life compared to administration of phenytoin alone. In 14 patients with pulmonary tuberculosis receiving daily treatment with rifampin 450 mg, isoniazid 300 mg, and ethambutol 900 to 1200 mg, clearance of phenytoin increased by 73% and half-life decreased by 47% after two weeks of antituberculosis treatment. Since isoniazid is an inhibitor of both CYP450 2C9 and 2C19, there may have been an attenuation of the inducing effect of rifampin relative to rifampin given alone. Six of the 14 patients were re-examined after 3 months of antituberculosis treatment, and no further changes were observed in the pharmacokinetic parameters of phenytoin.

MONITOR CLOSELY: Coadministration with phenytoin may decrease the plasma concentrations of rifampin. Phenytoin is a potent inducer of CYP450 3A4 and may increase the metabolism of rifampin beyond that due to auto-induction by rifampin. However, no clinical data are available regarding this potential interaction.

MANAGEMENT: Pharmacologic response and serum phenytoin levels should be monitored more closely whenever rifampin is added to or withdrawn from therapy, and the phenytoin dosage adjusted as necessary. Patients should be advised to contact their physician if they experience loss of seizure control during coadministration. The potential for diminished therapeutic effects of rifampin should also be considered when given with phenytoin.

References

  1. Venkatesan K (1992) "Pharmacokinetic drug interactions with rifampicin." Clin Pharmacokinet, 22, p. 47-65
  2. Borcherding SM, Baciewicz AM, Self TH (1992) "Update on rifampin drug interactions." Arch Intern Med, 152, p. 711-6
  3. Abajo FJ (1988) "Phenytoin interaction with rifampicin." Br Med J, 297, p. 1048
  4. Kay L, Kampmann JP, Svedsen L, et al. (1985) "Influence of rifampicin and isoniazid on the kinetics of phenytoin." Br J Clin Pharmacol, 20, p. 323-6
  5. Strayhorn VA, Baciewicz AM, Self TH (1997) "Update on rifampin drug interactions, III." Arch Intern Med, 157, p. 2453-8
  6. Van Berkel MA, Hurdle AC, Twilla JD (2013) "Phenytoin-rifampin drug interaction in a hypoalbuminemic, renal failure patient: a complex clinical case." Pharmacotherapy, 33, e96-100
View all 6 references

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Moderate

isoniazid phenytoin

Applies to: isoniazid / rifampin and phenytoin

MONITOR: Isoniazid frequently increases serum phenytoin levels and may induce phenytoin toxicity in up to 20% of patients receiving the combination. The mechanism is related to inhibition of CYP450 hepatic metabolism by isoniazid. Slow acetylators of isoniazid may be at greater risk for this interaction. Patients should be closely observed for signs of hydantoin toxicity if these drugs must be given concurrently. Other hydantoins may interact similarly.

MANAGEMENT: Serum hydantoin concentrations should be measured if a drug interaction is suspected. Patients should be advised to notify their physician if they experience symptoms of toxicity, including drowsiness, visual disturbances, change in mental status, seizures, nausea, or ataxia. The hydantoin dose may need to be decreased.

References

  1. Sandyk R (1982) "Phenytoin toxicity induced by antituberculosis drugs." S Afr Med J, 61, p. 382
  2. Witmer DR, Ritschel WA (1984) "Phenytoin-isoniazid interaction: a kinetic approach to management." Drug Intell Clin Pharm, 18, p. 483-6
  3. Yew WW, Lau KS, Ling MH (1991) "Phenytoin toxicity in a patient with isoniazid-induced hepatitis." Tubercle, 72, p. 309-10
  4. Kutt H, Winters W, McDowell FH (1966) "Depression of parahydroxylation of diphenylhydantoin by antituberculosis chemotherapy." Neurology, 16, p. 594-602
  5. Miller RR, Porter J, Greenblatt DJ (1979) "Clinical importance of the interaction of phenytoin and isoniazid." Chest, 75, p. 356-8
  6. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  7. Cerner Multum, Inc. "Australian Product Information."
View all 7 references

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Drug and food interactions

Moderate

rifAMPin food

Applies to: isoniazid / rifampin

GENERALLY AVOID: Concurrent use of rifampin in patients who ingest alcohol daily may result in an increased incidence of hepatotoxicity. The increase in hepatotoxicity may be due to an additive risk as both alcohol and rifampin are individually associated with this adverse reaction. However, the exact mechanism has not been established.

ADJUST DOSING INTERVAL: Administration with food may reduce oral rifampin absorption, increasing the risk of therapeutic failure or resistance. In a randomized, four-period crossover phase I study of 14 healthy male and female volunteers, the pharmacokinetics of single dose rifampin 600 mg were evaluated under fasting conditions and with a high-fat meal. Researchers observed that administration of rifampin with a high-fat meal reduced rifampin peak plasma concentration (Cmax) by 36%, nearly doubled the time to reach peak plasma concentration (Tmax) but reduced overall exposure (AUC) by only 6%.

MANAGEMENT: The manufacturer of oral forms of rifampin recommends administration on an empty stomach, 30 minutes before or 2 hours after meals. Patients should be encouraged to avoid alcohol or strictly limit their intake. Patients who use alcohol and rifampin concurrently or have a history of alcohol use disorder may require additional monitoring of their liver function during treatment with rifampin.

References

  1. (2022) "Product Information. Rifampin (rifAMPin)." Akorn Inc
  2. (2022) "Product Information. Rifampicin (rifampicin)." Mylan Pharmaceuticals Inc
  3. (2023) "Product Information. Rifadin (rifampicin)." Sanofi
  4. (2024) "Product Information. Rifadin (rifaMPICin)." Sanofi-Aventis Australia Pty Ltd
  5. Peloquin CA, Namdar R, Singleton MD, Nix DE (2024) Pharmacokinetics of rifampin under fasting conditions, with food, and with antacids https://pubmed.ncbi.nlm.nih.gov/9925057/
  6. (2019) "Product Information. Rofact (rifampin)." Bausch Health, Canada Inc.
View all 6 references

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Moderate

isoniazid food

Applies to: isoniazid / rifampin

GENERALLY AVOID: Concurrent use of isoniazid (INH) in patients who ingest alcohol daily may result in an increased incidence of both hepatotoxicity and peripheral neuropathy. The increase in hepatotoxicity may be due to an additive risk as both alcohol and INH are individually associated with this adverse reaction. INH-associated hepatotoxicity is believed to be due to an accumulation of toxic metabolites and may also be partly immune mediated, though the exact mechanisms are not universally agreed upon. INH is metabolized by N-acetyltransferase and CYP450 2E1. The rate of acetylation is genetically determined and generally classified as slow or rapid. Slow acetylators have been identified by some studies as having a higher risk of hepatotoxicity; therefore, this interaction may be more significant for patients who fall into this category. Other studies have postulated that alcohol-mediated CYP450 2E1 induction may play a role, as this isoenzyme is involved in INH metabolism and may be responsible for producing hepatotoxic metabolites. However, available literature is conflicting. The labeling for some INH products lists daily alcohol use or chronic alcoholism as a risk factor for hepatitis, but not all studies have found a significant association between alcohol use and INH-induced hepatotoxicity. Additionally, INH and alcohol are both associated with pyridoxine (B6) deficiency, which may increase the risk of peripheral neuropathy.

GENERALLY AVOID: Concomitant administration of isoniazid (INH) with foods containing tyramine and/or histamine may increase the risk of symptoms relating to tyramine- and/or histamine toxicity (e.g., headache, diaphoresis, flushing, palpitations, and hypotension). The proposed mechanism is INH-mediated inhibition of monoamine oxidase (MAO) and diamine oxidase (DAO), enzymes responsible for the metabolism of tyramine and histamine, respectively. Some authors have suggested that the reactions observed are mainly due to INH's effects on DAO instead of MAO or the amounts of histamine instead of tyramine present in the food. A Japanese case report recorded an example in 8 out of 25 patients on the tuberculosis ward who developed an accidental histamine poisoning after ingesting a fish paste (saury). Patients developed allergy-like symptoms, which started between 20 minutes and 2 hours after ingesting the food. A high-level of histamine (32 mg/100 g of fish) was confirmed in the saury paste and all 8 patients were both on INH and had reduced MAO concentrations. The 17 remaining patients were not on INH (n=5) or reported not eating the saury paste (n=12).

ADJUST DOSING INTERVAL: Administration with food significantly reduces oral isoniazid (INH) absorption, increasing the risk of therapeutic failure or resistance. The mechanism is unknown. Pharmacokinetic studies completed in both healthy volunteers (n=14) and tuberculosis patients (n=20 treatment-naive patients during days 1 to 3 of treatment) have resulted in almost doubling the time to reach INH's maximum concentration (tmax) and a reduction in isoniazid's maximum concentration (Cmax) of 42%-51% in patients who consumed high-fat or high-carbohydrate meals prior to INH treatment.

MANAGEMENT: The manufacturer of oral forms of isoniazid (INH) recommends administration on an empty stomach (i.e., 30 minutes before or 2 hours after meals). Patients should be encouraged to avoid alcohol or strictly limit their intake. Patients who use alcohol and INH concurrently or have a history of alcohol use disorder may require additional monitoring of their liver function during treatment with INH. Concomitant pyridoxine (B6) administration is also recommended to reduce the risk of peripheral neuropathy, with some authorities suggesting a dose of at least 10 mg/day. Patients should be advised to avoid foods containing tyramine (e.g., aged cheese, cured meats such as sausages and salami, fava beans, sauerkraut, soy sauce, beer, or red wine) or histamine (e.g., skipjack, tuna, mackerel, salmon) during treatment with isoniazid. Consultation of product labeling for combination products containing isoniazid and/or relevant guidelines may be helpful for more specific recommendations.

References

  1. Smith CK, Durack DT (1978) "Isoniazid and reaction to cheese." Ann Intern Med, 88, p. 520-1
  2. Dimartini A (1995) "Isoniazid, tricyclics and the ''cheese reaction''." Int Clin Psychopharmacol, 10, p. 197-8
  3. Uragoda CG, Kottegoda SR (1977) "Adverse reactions to isoniazid on ingestion of fish with a high histamine content." Tubercle, 58, p. 83-9
  4. Self TH, Chrisman CR, Baciewicz AM, Bronze MS (1999) "Isoniazid drug and food interactions." Am J Med Sci, 317, p. 304-11
  5. (2021) "Product Information. Isoniazid/Rifapentine 300 mg/300 mg (Macleods) (isoniazid-rifapentine)." Imported (India), 2
  6. (2023) "Product Information. Isoniazid (isoniazid)." Chartwell RX, LLC.
  7. (2023) "Product Information. Isoniazid (Arrotex) (isoniazid)." Arrotex Pharmaceuticals Pty Ltd
  8. (2023) "Product Information. Isoniazid (isoniazid)." RPH Pharmaceuticals AB
  9. Saukkonen JJ, Cohn DL, Jasmer RM, et al. (2006) "An official ATS statement: hepatotoxicity of antituberculosis therapy." Am J Respir Crit Care Med, 174, p. 935-52
  10. Bouazzi OE, Hammi S, Bourkadi JE, et al. (2024) First line anti-tuberculosis induced hepatotoxicity: incidence and risk factors. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5326068/
  11. Wang P, Pradhan K, Zhong XB, Ma X (2016) "Isoniazid metabolism and hepatoxicity." Acta Pharm Sin B, 6, p. 384-92
  12. Saktiawati AM, Sturkenboom MG, Stienstra Y, et al. (2016) "Impact of food on the pharmacokinetics of first-line anti-TB drugs in treatment naive TB patients: a randomized cross-over trial." J Antimicrob Chemother, 71, p. 703-10
  13. Hahn JA, Ngabirano C, Fatch R, et al. (2023) "Safety and tolerability of isoniazid preventive therapy for tuberculosis for persons with HIV with and without alcohol use." AIDS, 37, p. 1535-43
  14. Huang YS, Chern HD, Su WJ, et al. (2003) "Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis." Hepatology, 37, p. 924-30
  15. Sousou JM, Griffith EM, Marsalisi C, Reddy P (2024) Pyridoxine deficiency and neurologic dysfunction: an unlikely association. https://www.cureus.com/articles/188310-pyridoxine-deficiency-and-neurologic-dysfunction-an-unlikely-association?score_article=true#!/
  16. Miki M, Ishikawa T, Okayama H (2005) "An outbreak of histamine poisoning after ingestion of the ground saury paste in eight patients taking isoniazid in tuberculous ward." Intern Med, 44, p. 1133-6
  17. (2021) "Product Information. Isotamine (isoniazid)." Bausch Health, Canada Inc.
View all 17 references

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Moderate

phenytoin food

Applies to: phenytoin

ADJUST DOSING INTERVAL: Phenytoin bioavailability may decrease to subtherapeutic levels when the suspension is given concomitantly with enteral feedings. The mechanism may be related to phenytoin binding to substances in the enteral formula (e.g., calcium, protein) and/or binding to the tube lumen. Data have been conflicting and some studies have reported no changes in phenytoin levels, while others have reported significant reductions.

MONITOR: Acute consumption of alcohol may increase plasma phenytoin levels. Chronic consumption of alcohol may decrease plasma phenytoin levels. The mechanism of this interaction is related to induction of phenytoin metabolism by ethanol during chronic administration. Other hydantoin derivatives may be similarly affected by ethanol.

MANAGEMENT: Some experts have recommended interrupting the feeding for 2 hours before and after the phenytoin dose, giving the phenytoin suspension diluted in water, and flushing the tube with water after administration; however, this method may not entirely avoid the interaction and is not always clinically feasible. Patients should be closely monitored for clinical and laboratory evidence of altered phenytoin efficacy and levels upon initiation and discontinuation of enteral feedings. Dosage adjustments or intravenous administration may be required until therapeutic serum levels are obtained. In addition, patients receiving phenytoin therapy should be warned about the interaction between phenytoin and ethanol and they should be advised to notify their physician if they experience worsening of seizure control or symptoms of toxicity, including drowsiness, visual disturbances, change in mental status, nausea, or ataxia.

References

  1. Sandor P, Sellers EM, Dumbrell M, Khouw V (1981) "Effect of short- and long-term alcohol use on phenytoin kinetics in chronic alcoholics." Clin Pharmacol Ther, 30, p. 390-7
  2. Holtz L, Milton J, Sturek JK (1987) "Compatibility of medications with enteral feedings." JPEN J Parenter Enteral Nutr, 11, p. 183-6
  3. Sellers EM, Holloway MR (1978) "Drug kinetics and alcohol ingestion." Clin Pharmacokinet, 3, p. 440-52
  4. (2001) "Product Information. Dilantin (phenytoin)." Parke-Davis
  5. Doak KK, Haas CE, Dunnigan KJ, et al. (1998) "Bioavailability of phenytoin acid and phenytoin sodium with enteral feedings." Pharmacotherapy, 18, p. 637-45
  6. Rodman DP, Stevenson TL, Ray TR (1995) "Phenytoin malabsorption after jejunostomy tube delivery." Pharmacotherapy, 15, p. 801-5
  7. Au Yeung SC, Ensom MH (2000) "Phenytoin and enteral feedings: does evidence support an interaction?" Ann Pharmacother, 34, p. 896-905
  8. Ozuna J, Friel P (1984) "Effect of enteral tube feeding on serum phenytoin levels." J Neurosurg Nurs, 16, p. 289-91
  9. Faraji B, Yu PP (1998) "Serum phenytoin levels of patients on gastrostomy tube feeding." J Neurosci Nurs, 30, p. 55-9
  10. Marvel ME, Bertino JS (1991) "Comparative effects of an elemental and a complex enteral feeding formulation on the absorption of phenytoin suspension." JPEN J Parenter Enteral Nutr, 15, p. 316-8
  11. Fleisher D, Sheth N, Kou JH (1990) "Phenytoin interaction with enteral feedings administered through nasogastric tubes." JPEN J Parenter Enteral Nutr, 14, p. 513-6
  12. Haley CJ, Nelson J (1989) "Phenytoin-enteral feeding interaction." DICP, 23, p. 796-8
  13. Guidry JR, Eastwood TF, Curry SC (1989) "Phenytoin absorption in volunteers receiving selected enteral feedings." West J Med, 150, p. 659-61
  14. Krueger KA, Garnett WR, Comstock TJ, Fitzsimmons WE, Karnes HT, Pellock JM (1987) "Effect of two administration schedules of an enteral nutrient formula on phenytoin bioavailability." Epilepsia, 28, p. 706-12
  15. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  16. Cerner Multum, Inc. "Australian Product Information."
View all 16 references

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Therapeutic duplication warnings

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


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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.