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Stop Drug-Induced Lupus
Author(s)
Michele B. Kaufman, PharmD, BSc, RPh

The chronic inflammatory disease lupus, usually traced to environmental and genetic causes, also can be drug-induced (DILE). It occurs in patients differently than systemic lupus erythematosus (SLE).

DILE tends to strike:

  • Older patients (ages 50-70);

  • Men more than women; and

  • Whites more than blacks.

It was first described in 1945 as a side effect of sulfadiazine. Between 15,000 and 20,000 cases of drug-induced lupus erythematosus (DILE) occur yearly. Symptoms usually appear within three to six months of taking an offending drug.1 However, it also can occur within two years of receiving a triggering drug.2,3 The reaction usually resolves within days or months after removal of the offending medication. Care must be taken to correctly diagnose DILE and differentiate it from the systemic autoimmune disease SLE.

DILE arises mainly from the production of autoantibodies in reaction to certain drugs.4 Patients may also have a genetic predisposition, particularly for agents that are metabolically acetylated (e.g., hydralazine, procainamide). DILE is likely to appear more rapidly in patients who are slow acetylators. These patients include those with the HLA-DR4 or HLA-DR0301 genes, the complement C4 null allele, and females.

DILE symptoms include anorexia, arthralgia, fever, lymphadenopathy, malaise, myalgia, rash, serositis, and weight loss.5 The rash usually presents as polycyclic, with scaling and erythema in sun-exposed areas. Serologic findings include a positive antinuclear antibody (ANA) in 75% or more of patients and anti-histone antibodies. Levels of C3/C4 are usually normal. Antibodies to anti-double stranded DNA (anti-ds DNA) are rare, in contrast to SLE where C3/C4 levels usually decrease and anti-ds DNA is usually (50%-70%) positive. An elevated erythrocyte sedimentation rate (ESR 80%) may also be present. The absence of renal or central nervous system involvement is more suggestive of DILE. Renal effects occur in 5% to 10% of hydralazine-induced DILE cases, and renal deaths have been reported in rare cases.

The Agents

New Warnings

Formoterol fumarate (Foradil) and tiotropium bromide (Spiriva). The FDA has issued a warning regarding the proper use of these two inhalation powders, the former through the Aerolizer device, the latter through the HandiHaler device. These two devices are used to deliver powder contained in capsules. The FDA and the National Poison Control Center have received numerous reports of patients swallowing the capsules rather than administering them in their inhalation devices. The following information is provided for the correct use of these products for in-hospital use or for discharge prescriptions:

  • The capsules should not be swallowed;

  • The contents of the Foradil/Spiriva capsules are to be inhaled into the lungs using the respective inhalation devices. The capsule should be removed from the blister pack prior to use and the capsule placed in the inhalation device prior to inhalation;

  • Instruct patients on the proper use of each device, whether it is a new prescription, or whether the patient has been on it for a while. This will ensure proper medication use; and

  • If a patient is prescribed formoterol or tiotropium and does not experience breathing improvement, ascertain how the patient is taking the medication in order to determine if they are swallowing the capsule rather than inhaling its contents.

The FDA and the company’s manufacturers continue to monitor this problem.—MK

Many agents can cause DILE. A large number of these agents rarely are used in present-day medicine. The more commonly used agents/classes include:

  • Carbamazepine;

  • Diltiazem;

  • Docetaxel;

  • Hydralazine;

  • Isoniazid;

  • Minocycline;

  • Procainamide; and

  • Sulfasalazine.

 

 

Other agents that may possibly cause DILE include:

  • Anti-tumor necrosis factor agents (adalimumab, etanercept, infliximab);

  • Bupropion;

  • Fluorouracil;

  • Interferon;

  • Lisinopril;

  • Non-steroidal anti-inflammatory agents;

  • Propylthiouracil;

  • Statins; and

  • Terbinafine.

Diagnosis is made by confirming the patient has:

  • One or more clinical symptoms;

  • A positive ANA;

  • No SLE history prior to using the suspected agent;

  • Not taken the drug anytime from three weeks to two years before the symptoms appeared; and

  • Clinical resolution occurs rapidly upon “suspected drug” discontinuation.

A complete blood count should be obtained to evaluate for anemia (rare in DILE, common in SLE). Liver function tests, blood urea nitrogen, creatinine, and urinalysis can be performed to evaluate for other complications.

DILE usually resolves following drug discontinuation, but severe cases may require low doses of systemic corticosteroids. TH

Michele B Kaufman, PharmD, BSc, is a registered pharmacist based in New York City.

References

  1. Vasoo S. Drug-induced lupus: an update. Lupus 2006;15:757-761.

  2. Kauffman CL. Lupus erythematosus, drug-induced. eMedicine 2007. Available at www.emedicine.com/derm/TOPIC107.htm. Accessed April 8, 2008.

  3. MedlinePlus. www.nlm.nih.gov/medlineplus/ print/ency/article/000446.htm. Accessed April 8, 2008.

  4. Schur PH, Rose BD. Drug-induced lupus 2008; Patients UpToDate Version 16.1. Available www.uptodate.com/patients/content/topic.do;jsessionid=1934E0AFFCBBB588269DBFEE5F96BDF4.1002?topicKey=~kU3CGByPyaH&selectedTitle=2~103&source=search_result. Accessed April 8, 2008.

  5. Borchers A, Keen CL, Gershwin ME. Drug-induced lupus. Ann NY Acad Sci. 2007;1108:166-182.

Market watch

First-time generics:

  • Alendronate once-weekly tablets (generic Fosamax);

  • Granisetron injection (generic Kytril injection);

  • Lansoprazole (generic Prevacid); the brand drug patent expires this month; and

  • Venlafaxine XR (generic Effexor XR); the brand drug patent expires this month.

Approvals:

A fixed-dose combination product of Niaspan 1,000 mg/simvastatin 20 mg (Simcor) has Food and Drug Administration (FDA) approval for hyperlipidemia.

New device:

The FDA has approved Endeavor, a zotarolimus-eluting coronary stent, to be used in patients with coronary artery disease. Patients allergic to zotarolimus, cobalt, nickel, chromium, or molybdenum should not receive the Endeavor stent.

New indications:

Colesevelam tablets (Welchol) have been FDA approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Approval was based on results of three clinical trials that were double-blind, placebo-controlled add-on therapy trials. Patients (n=1,018) had baseline A1C values of 7.5%-9.5%. The subjects received colesevelam in combination with metformin, sulfonylureas, insulin or placebo. Colesevelam is available as 625 mg tablets and dosed three tablets twice daily with a meal or liquid.

Palonosetron injection (Aloxi) has been FDA approved for the prevention of postoperative nausea and vomiting for up to 24 hours after surgery. It was studied in elective gynecologic and abdominal laparoscopic surgery.

New information:

The National Osteoporosis Foundation recently published a new “Clinician’s Guide to Prevention and Treatment of Osteoporosis.” View it online at www.nof.org/professionals/Clinicians_Guide.htm 3/4/08

Withdrawals:

Atenolol injection 0.5mg/ml (Tenormin). Astra Zeneca has discontinued Tenormin due to effective generic products available.

Cefadroxil powder for suspension (Duricef). Warner Chilcott has discontinued Duricef due to effective generic products available.

Humatin capsules (Paromomycin). King Pharmaceuticals has discontinued Humatin due to effective generic products available.—MK

Issue
The Hospitalist - 2008(06)
Publications
The Hospitalist
Sections
Medicolegal Issues
News
Career
Practice Management
All Content
Author(s)
Michele B. Kaufman, PharmD, BSc, RPh
Author(s)
Michele B. Kaufman, PharmD, BSc, RPh

The chronic inflammatory disease lupus, usually traced to environmental and genetic causes, also can be drug-induced (DILE). It occurs in patients differently than systemic lupus erythematosus (SLE).

DILE tends to strike:

  • Older patients (ages 50-70);

  • Men more than women; and

  • Whites more than blacks.

It was first described in 1945 as a side effect of sulfadiazine. Between 15,000 and 20,000 cases of drug-induced lupus erythematosus (DILE) occur yearly. Symptoms usually appear within three to six months of taking an offending drug.1 However, it also can occur within two years of receiving a triggering drug.2,3 The reaction usually resolves within days or months after removal of the offending medication. Care must be taken to correctly diagnose DILE and differentiate it from the systemic autoimmune disease SLE.

DILE arises mainly from the production of autoantibodies in reaction to certain drugs.4 Patients may also have a genetic predisposition, particularly for agents that are metabolically acetylated (e.g., hydralazine, procainamide). DILE is likely to appear more rapidly in patients who are slow acetylators. These patients include those with the HLA-DR4 or HLA-DR0301 genes, the complement C4 null allele, and females.

DILE symptoms include anorexia, arthralgia, fever, lymphadenopathy, malaise, myalgia, rash, serositis, and weight loss.5 The rash usually presents as polycyclic, with scaling and erythema in sun-exposed areas. Serologic findings include a positive antinuclear antibody (ANA) in 75% or more of patients and anti-histone antibodies. Levels of C3/C4 are usually normal. Antibodies to anti-double stranded DNA (anti-ds DNA) are rare, in contrast to SLE where C3/C4 levels usually decrease and anti-ds DNA is usually (50%-70%) positive. An elevated erythrocyte sedimentation rate (ESR 80%) may also be present. The absence of renal or central nervous system involvement is more suggestive of DILE. Renal effects occur in 5% to 10% of hydralazine-induced DILE cases, and renal deaths have been reported in rare cases.

The Agents

New Warnings

Formoterol fumarate (Foradil) and tiotropium bromide (Spiriva). The FDA has issued a warning regarding the proper use of these two inhalation powders, the former through the Aerolizer device, the latter through the HandiHaler device. These two devices are used to deliver powder contained in capsules. The FDA and the National Poison Control Center have received numerous reports of patients swallowing the capsules rather than administering them in their inhalation devices. The following information is provided for the correct use of these products for in-hospital use or for discharge prescriptions:

  • The capsules should not be swallowed;

  • The contents of the Foradil/Spiriva capsules are to be inhaled into the lungs using the respective inhalation devices. The capsule should be removed from the blister pack prior to use and the capsule placed in the inhalation device prior to inhalation;

  • Instruct patients on the proper use of each device, whether it is a new prescription, or whether the patient has been on it for a while. This will ensure proper medication use; and

  • If a patient is prescribed formoterol or tiotropium and does not experience breathing improvement, ascertain how the patient is taking the medication in order to determine if they are swallowing the capsule rather than inhaling its contents.

The FDA and the company’s manufacturers continue to monitor this problem.—MK

Many agents can cause DILE. A large number of these agents rarely are used in present-day medicine. The more commonly used agents/classes include:

  • Carbamazepine;

  • Diltiazem;

  • Docetaxel;

  • Hydralazine;

  • Isoniazid;

  • Minocycline;

  • Procainamide; and

  • Sulfasalazine.

 

 

Other agents that may possibly cause DILE include:

  • Anti-tumor necrosis factor agents (adalimumab, etanercept, infliximab);

  • Bupropion;

  • Fluorouracil;

  • Interferon;

  • Lisinopril;

  • Non-steroidal anti-inflammatory agents;

  • Propylthiouracil;

  • Statins; and

  • Terbinafine.

Diagnosis is made by confirming the patient has:

  • One or more clinical symptoms;

  • A positive ANA;

  • No SLE history prior to using the suspected agent;

  • Not taken the drug anytime from three weeks to two years before the symptoms appeared; and

  • Clinical resolution occurs rapidly upon “suspected drug” discontinuation.

A complete blood count should be obtained to evaluate for anemia (rare in DILE, common in SLE). Liver function tests, blood urea nitrogen, creatinine, and urinalysis can be performed to evaluate for other complications.

DILE usually resolves following drug discontinuation, but severe cases may require low doses of systemic corticosteroids. TH

Michele B Kaufman, PharmD, BSc, is a registered pharmacist based in New York City.

References

  1. Vasoo S. Drug-induced lupus: an update. Lupus 2006;15:757-761.

  2. Kauffman CL. Lupus erythematosus, drug-induced. eMedicine 2007. Available at www.emedicine.com/derm/TOPIC107.htm. Accessed April 8, 2008.

  3. MedlinePlus. www.nlm.nih.gov/medlineplus/ print/ency/article/000446.htm. Accessed April 8, 2008.

  4. Schur PH, Rose BD. Drug-induced lupus 2008; Patients UpToDate Version 16.1. Available www.uptodate.com/patients/content/topic.do;jsessionid=1934E0AFFCBBB588269DBFEE5F96BDF4.1002?topicKey=~kU3CGByPyaH&selectedTitle=2~103&source=search_result. Accessed April 8, 2008.

  5. Borchers A, Keen CL, Gershwin ME. Drug-induced lupus. Ann NY Acad Sci. 2007;1108:166-182.

Market watch

First-time generics:

  • Alendronate once-weekly tablets (generic Fosamax);

  • Granisetron injection (generic Kytril injection);

  • Lansoprazole (generic Prevacid); the brand drug patent expires this month; and

  • Venlafaxine XR (generic Effexor XR); the brand drug patent expires this month.

Approvals:

A fixed-dose combination product of Niaspan 1,000 mg/simvastatin 20 mg (Simcor) has Food and Drug Administration (FDA) approval for hyperlipidemia.

New device:

The FDA has approved Endeavor, a zotarolimus-eluting coronary stent, to be used in patients with coronary artery disease. Patients allergic to zotarolimus, cobalt, nickel, chromium, or molybdenum should not receive the Endeavor stent.

New indications:

Colesevelam tablets (Welchol) have been FDA approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Approval was based on results of three clinical trials that were double-blind, placebo-controlled add-on therapy trials. Patients (n=1,018) had baseline A1C values of 7.5%-9.5%. The subjects received colesevelam in combination with metformin, sulfonylureas, insulin or placebo. Colesevelam is available as 625 mg tablets and dosed three tablets twice daily with a meal or liquid.

Palonosetron injection (Aloxi) has been FDA approved for the prevention of postoperative nausea and vomiting for up to 24 hours after surgery. It was studied in elective gynecologic and abdominal laparoscopic surgery.

New information:

The National Osteoporosis Foundation recently published a new “Clinician’s Guide to Prevention and Treatment of Osteoporosis.” View it online at www.nof.org/professionals/Clinicians_Guide.htm 3/4/08

Withdrawals:

Atenolol injection 0.5mg/ml (Tenormin). Astra Zeneca has discontinued Tenormin due to effective generic products available.

Cefadroxil powder for suspension (Duricef). Warner Chilcott has discontinued Duricef due to effective generic products available.

Humatin capsules (Paromomycin). King Pharmaceuticals has discontinued Humatin due to effective generic products available.—MK

The chronic inflammatory disease lupus, usually traced to environmental and genetic causes, also can be drug-induced (DILE). It occurs in patients differently than systemic lupus erythematosus (SLE).

DILE tends to strike:

  • Older patients (ages 50-70);

  • Men more than women; and

  • Whites more than blacks.

It was first described in 1945 as a side effect of sulfadiazine. Between 15,000 and 20,000 cases of drug-induced lupus erythematosus (DILE) occur yearly. Symptoms usually appear within three to six months of taking an offending drug.1 However, it also can occur within two years of receiving a triggering drug.2,3 The reaction usually resolves within days or months after removal of the offending medication. Care must be taken to correctly diagnose DILE and differentiate it from the systemic autoimmune disease SLE.

DILE arises mainly from the production of autoantibodies in reaction to certain drugs.4 Patients may also have a genetic predisposition, particularly for agents that are metabolically acetylated (e.g., hydralazine, procainamide). DILE is likely to appear more rapidly in patients who are slow acetylators. These patients include those with the HLA-DR4 or HLA-DR0301 genes, the complement C4 null allele, and females.

DILE symptoms include anorexia, arthralgia, fever, lymphadenopathy, malaise, myalgia, rash, serositis, and weight loss.5 The rash usually presents as polycyclic, with scaling and erythema in sun-exposed areas. Serologic findings include a positive antinuclear antibody (ANA) in 75% or more of patients and anti-histone antibodies. Levels of C3/C4 are usually normal. Antibodies to anti-double stranded DNA (anti-ds DNA) are rare, in contrast to SLE where C3/C4 levels usually decrease and anti-ds DNA is usually (50%-70%) positive. An elevated erythrocyte sedimentation rate (ESR 80%) may also be present. The absence of renal or central nervous system involvement is more suggestive of DILE. Renal effects occur in 5% to 10% of hydralazine-induced DILE cases, and renal deaths have been reported in rare cases.

The Agents

New Warnings

Formoterol fumarate (Foradil) and tiotropium bromide (Spiriva). The FDA has issued a warning regarding the proper use of these two inhalation powders, the former through the Aerolizer device, the latter through the HandiHaler device. These two devices are used to deliver powder contained in capsules. The FDA and the National Poison Control Center have received numerous reports of patients swallowing the capsules rather than administering them in their inhalation devices. The following information is provided for the correct use of these products for in-hospital use or for discharge prescriptions:

  • The capsules should not be swallowed;

  • The contents of the Foradil/Spiriva capsules are to be inhaled into the lungs using the respective inhalation devices. The capsule should be removed from the blister pack prior to use and the capsule placed in the inhalation device prior to inhalation;

  • Instruct patients on the proper use of each device, whether it is a new prescription, or whether the patient has been on it for a while. This will ensure proper medication use; and

  • If a patient is prescribed formoterol or tiotropium and does not experience breathing improvement, ascertain how the patient is taking the medication in order to determine if they are swallowing the capsule rather than inhaling its contents.

The FDA and the company’s manufacturers continue to monitor this problem.—MK

Many agents can cause DILE. A large number of these agents rarely are used in present-day medicine. The more commonly used agents/classes include:

  • Carbamazepine;

  • Diltiazem;

  • Docetaxel;

  • Hydralazine;

  • Isoniazid;

  • Minocycline;

  • Procainamide; and

  • Sulfasalazine.

 

 

Other agents that may possibly cause DILE include:

  • Anti-tumor necrosis factor agents (adalimumab, etanercept, infliximab);

  • Bupropion;

  • Fluorouracil;

  • Interferon;

  • Lisinopril;

  • Non-steroidal anti-inflammatory agents;

  • Propylthiouracil;

  • Statins; and

  • Terbinafine.

Diagnosis is made by confirming the patient has:

  • One or more clinical symptoms;

  • A positive ANA;

  • No SLE history prior to using the suspected agent;

  • Not taken the drug anytime from three weeks to two years before the symptoms appeared; and

  • Clinical resolution occurs rapidly upon “suspected drug” discontinuation.

A complete blood count should be obtained to evaluate for anemia (rare in DILE, common in SLE). Liver function tests, blood urea nitrogen, creatinine, and urinalysis can be performed to evaluate for other complications.

DILE usually resolves following drug discontinuation, but severe cases may require low doses of systemic corticosteroids. TH

Michele B Kaufman, PharmD, BSc, is a registered pharmacist based in New York City.

References

  1. Vasoo S. Drug-induced lupus: an update. Lupus 2006;15:757-761.

  2. Kauffman CL. Lupus erythematosus, drug-induced. eMedicine 2007. Available at www.emedicine.com/derm/TOPIC107.htm. Accessed April 8, 2008.

  3. MedlinePlus. www.nlm.nih.gov/medlineplus/ print/ency/article/000446.htm. Accessed April 8, 2008.

  4. Schur PH, Rose BD. Drug-induced lupus 2008; Patients UpToDate Version 16.1. Available www.uptodate.com/patients/content/topic.do;jsessionid=1934E0AFFCBBB588269DBFEE5F96BDF4.1002?topicKey=~kU3CGByPyaH&selectedTitle=2~103&source=search_result. Accessed April 8, 2008.

  5. Borchers A, Keen CL, Gershwin ME. Drug-induced lupus. Ann NY Acad Sci. 2007;1108:166-182.

Market watch

First-time generics:

  • Alendronate once-weekly tablets (generic Fosamax);

  • Granisetron injection (generic Kytril injection);

  • Lansoprazole (generic Prevacid); the brand drug patent expires this month; and

  • Venlafaxine XR (generic Effexor XR); the brand drug patent expires this month.

Approvals:

A fixed-dose combination product of Niaspan 1,000 mg/simvastatin 20 mg (Simcor) has Food and Drug Administration (FDA) approval for hyperlipidemia.

New device:

The FDA has approved Endeavor, a zotarolimus-eluting coronary stent, to be used in patients with coronary artery disease. Patients allergic to zotarolimus, cobalt, nickel, chromium, or molybdenum should not receive the Endeavor stent.

New indications:

Colesevelam tablets (Welchol) have been FDA approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Approval was based on results of three clinical trials that were double-blind, placebo-controlled add-on therapy trials. Patients (n=1,018) had baseline A1C values of 7.5%-9.5%. The subjects received colesevelam in combination with metformin, sulfonylureas, insulin or placebo. Colesevelam is available as 625 mg tablets and dosed three tablets twice daily with a meal or liquid.

Palonosetron injection (Aloxi) has been FDA approved for the prevention of postoperative nausea and vomiting for up to 24 hours after surgery. It was studied in elective gynecologic and abdominal laparoscopic surgery.

New information:

The National Osteoporosis Foundation recently published a new “Clinician’s Guide to Prevention and Treatment of Osteoporosis.” View it online at www.nof.org/professionals/Clinicians_Guide.htm 3/4/08

Withdrawals:

Atenolol injection 0.5mg/ml (Tenormin). Astra Zeneca has discontinued Tenormin due to effective generic products available.

Cefadroxil powder for suspension (Duricef). Warner Chilcott has discontinued Duricef due to effective generic products available.

Humatin capsules (Paromomycin). King Pharmaceuticals has discontinued Humatin due to effective generic products available.—MK

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