safety of immunomodulation€¦ · – tb, pneumocystis carinii, ebv, opportunistic • severe...

Safety of Immunomodulation

Pia MunkholmHerlev University Hospital

Copenhagenwww.dccd-ibd.dk

Safety of AZA/6MP; Cy-A; MTX; IFX

• Adverse events– Allergy, liver cirrhosis, pancreatitis,

leucocytopenia• Infection

– TB, pneumocystis carinii, EBV, opportunistic• Severe adverse events: Cancer & Mortality• Pregnancy, fertility male/female, breastfeeding

Adverse reactions Prednisone AzathioprineMoonface 25%25%Hirsuitism 8%8% p<0.05p<0.05

Striae 7%7%Acne 19%Headache 19%Nausea Vomiting 29%Infection 8%Abdomominal pain 11%Pharyngitis 5%Muscle weakness 3%Athritis/arthralgia 16%Leucopenia 2%Trombocytopeneia 2%

2%0%2%

8%24%35%17%9%8%6%31%2%1% NCCD 1976

AZA or 6-MPside-effects

• Dose-independent, allergic-type reactions– Pancreatitis, fever, rash, arthralgias, diarrhea, nausea

Present D et al. Ann Int Med 1989;111:641-9.Garey K et al. Ann Pharmacother 1998;32:425-8.

• Dose-dependent, non-allergic-type reactions– Bone marrow suppression(2wks-11 years) cum.10%, reversed

by G-CSF –granulocyte colony stimulating factor– Infection(reactivation of latent EBV leading to lymphoma),

hepatitis Sandborn W. AJG 1996;91:423-33. Dayharsh GA. Gastro 2002;122.

15%

5%

AZA or 6-MPside-effects

• Dose-independent, allergic-type reactions– Pancreatitis, fever, rash, arthralgias, diarrhea, nausea

Present D et al. Ann Int Med 1989;111:641-9.Garey K et al. Ann Pharmacother 1998;32:425-8.

• Dose-dependent, non-allergic-type reactions– Bone marrow suppression(2wks-11 years) cum.10%, reversed

by G-CSF –granulocyte colony stimulating factor– Infection(reactivation of latent EBV leading to lymphoma),

hepatitis Sandborn W. AJG 1996;91:423-33. Dayharsh GA. Gastro 2002;122.

15%

5%

In situ hybridisation EBV nucleus positivityin the lymphoma(5pts lymphoma/7 EBV pos)

Epstein-Barr virus reactivation2 fold increased risk of lymphoma in EBV pos. PatientsShould we advise resection?

1200 pts treated AZARisk: 6/1200 ~ 0.5%

AZA/6MPcancer

• 3.1 % cancer. Present D. Ann Int Med 1989;111. Mt Sinai

• 755 pts(450 CD/ 282UC); 2mg/kg AZA. Median treatment: 12.5 mths(2 days-15 years). Connell WR. Lancet 1994;343. St. Marks

• Cancer (O:31) vs (E: 24.3)= 1.3 ns. • CRC (O: 13 rectal + 2 anal) vs (E: 2.27)= 6.7, p=0.00001

• Extensive UC 86 pts AZA vs 180 non-AZA sex, age +/-10 yrs; dur dis <1yr:

AZA-UC: 8 CRC vs 0.26 (E) non-AZA-UC: 15 CRC vs 0.63 (E)

O: 8 (AZA+) vs E: 15 (AZA-); 0.53 p=0.54 AZA treatment DO not cause the CRC

AZAMortality

• MortalityO: 67 vs E: 58.3, ratio 1.15(CI 0.89-1.46)

• Death from cancer • (6 CRC; 1 carcinomatosis, 1stomach, 1breast, 3

lung, 1cervix) O: 13 vs E: 16.4, ratio 0.79; p=0.459

• NO EXCESS MORTALITY

Cyclosporin

CyA and Tracolimus• Whole-blood through levels: 200-400 ng/ml,

Kornbluth A et al. AJG 1997;204-11• Common side-effects Cy-A:

– Paresthesias(51%), hypertension(43%), hypertrichosis(27%), nephrotoxicitiy(23%), gingivalhyperplasia(4%), seizures(3%), deaths(2%) tremor, nausea, vomiting, headaches, Steinhart A et al. APT 1996;10:729-36. SternthalM.Gastro 1996;110:A1019

• Increased risk of developing seizures: serum-cholesterol <120mg/dl & hypomagnesiemia

CyA and Tracolimus• Whole-blood through levels: 200-400 ng/ml,

Kornbluth A et al. AJG 1997;204-11• Common side-effects Cy-A:

– Paresthesias(51%), hypertension(43%), hypertrichosis(27%), nephrotoxicitiy(23%), gingivalhyperplasia(4%), seizures(3%), deaths(2%) tremor, nausea, vomiting, headaches, Steinhart A et al. APT 1996;10:729-36. SternthalM.Gastro 1996;110:A1019

• Increased risk of developing seizures: serum-cholesterol <120mg/dl & hypomagnesiemia

20% reduction in glomerular without creatinine change + tracolimus

Potential drug interactions of Cy-A and tacrolimus. Kornbluth et al. AJG 1997:92.

Inhibition of cytochrome P450 calcium channel blockersCy-A levels bromocriptine, imidazole,

metoclopramide, macrolidmethylprednisolone, protease inhib., grapefruitjuice

Induction of cytochrome P450 rifampicin, phenobarbital, Cy-A levels phenytoin, carbamazepine,

reverse transcriptase inhib.

CyA and AZA, GS Quan V et al. BMJ 1997;314:363-4

• Increased risk of opportunistic infections, pneumocystis carinii: risk 3% AZA+ GS or 3-10% at Cy-A+GS treatment (Case: 63 yr male pancolitis died from pc day 8 post CyA+GS)

• Recommendation: – Prophylaxis against pneumocystis carinii pneumonia -

trimoxasole 460mg twice daily(Trimethoprim-sulfamethoxazole), 3-6 mths. Sandborn W. IBD 1995;1:48.

– pc-mortality- in immunosupressed pts: 75-100%– pc-mortality in background population: 40%

CyA and AZA, GS Quan V et al. BMJ 1997;314:363-4

• Increased risk of opportunistic infections, pneumocystis carinii: risk 3% AZA+ GS or 3-10% at Cy-A+GS treatment (Case: 63 yr male pancolitis died from pc day 8 post CyA+GS)

• Recommendation: – Prophylaxis against pneumocystis carinii pneumonia -

trimoxasole 460mg twice daily(Trimethoprim-sulfamethoxazole), 3-6 mths. Sandborn W. IBD 1995;1:48.

– pc-mortality- in immunosupressed pts: 75-100%– pc-mortality in background population: 40% Typical bilateral air-space consolidation of

Pneumocystis carinii pneumoniain a patient with AIDS.

Methotrexate• Folate receptors bring MTX into cells

• High adenosine levels into bloodstream = anti-inflammatory

• Folate 5mg/wk reduces sideeffects– Reducing plasma MTX – increasing clearance. Cutulo M.

AnnRheumDis 2001;60

• Bioavailability: – 100% i.m. or s.c.– 50-90% oral. Egan LJ. Clin Pharmacol Ther 1999;65

MTXadverse effects

• 18 % stop treatment drug-related toxicity• Idiosyncratic allergic-hypersensitivity

reactions(rash+pneumonitis) 3-11%, transaminases (30%), cirrhosis 5 yr: 0.001%(1/1000)

• Risk factors cirrhosis: cumulative dosis >1.5 g debatable, alcohol, obesity, diabetes, old age. Walker AM. Arth Rheum 1993;36. Newmann M. Arch Dermatol 1989;125

MAYO-MTX Guidelines prevention & monitoring hepatotoxicity in IBD

Baseline withhold MTXLiver tests ast, alt, alp,bilirubin > 2 x normal

hep B & C if actively infected

Liver biopsy abnormal liver test hepatitis, fibrosis, if clinical suspicion LD cirrhosis

During treatment reduce/stop MTXAst 6th week >2 x normal

Liver biopsy progressive ast elevation hepatitis, fibrosis, >50% of all ast tests high cirrhosis

Sandborn W. In Kirsners IBD 2004;32

Routine liver biopsies are not warranted

Rutgeerts P et al. ATP 2003;17:1435-50

Infliximab Safety• Safety data collected in clinical trials with

infliximab >10 years• > 575,000 patients have received infliximab

commercially • > 1,350,000 patient-years of treatmentApproved Indications• Crohn’s disease 1999• Rheumatoid arthritis 2000 + early RA 2004, • Ankylosing spondylitis 2003• Psoriatic arthritis (Europe) 2004

Data on file, Centocor, Inc.

340.535

212.843

22.522

575.910

0

200.000

400.000

600.000

800.000

1.000.000

1.200.000

1.400.000

RA CD other all

Rheum† CD Other Total

633.807692.761

20.762

1.347.330

0

200.000

400.000

600.000

800.000

1.000.000

1.200.000

1.400.000

Rheum† CD Other Total

Number of Patients* Number of PYsfe*

Post–Marketing Patient Exposure by Indication

PSUR 10, Aug 04.*Cumulative from Launch, Aug 24, 1998 to Aug 23, 2004.†Rheum = RA + AS + PsA

RA CD ALL

Placebo Infliximab

Patients treated 486 2427Average wks follow-up 47.4 53.1Pts with ≥ 1 infection(s) 48.8% 58.5%Treated (%) 28.4% 35.8%

Serious (%) 3.9% 5.9%Pneumonia 0.2% 1.2%Abscess 0.2% 1.0%Cellulitis 0.4% 0.5%Sepsis 0.4% 0.5%Herpes zoster 0.0% 0.2%Tuberculosis 0.0% 0.2%

Infections in All Completed Clinical Trials

Data on file, Centocor, Inc.

Completed Clinical TrialsCompleted Clinical Trials

0,0

0,5

1,0

1,5

2,0

feb-00

aug-00

feb-01

aug-01

feb-02

aug-02

feb-03

aug-03

feb-04

aug-04

EU/Norway US

Feb 2000 – Aug 2004

Rat

e pe

r 1,0

00 E

IP P

atie

nts

Reporting Rate per 1,000 Patients ExposedReporting Rate per 1,000 Patients Exposed--inin--Period (EIP)Period (EIP)

Tuberculosis

PSUR 10, Aug 04.

PostPost––MarketingMarketing

Post–Marketing Tuberculosis Report

0

20

40

60

80

100

120

1 2 3 4 5 6 7 8 >8

Num

ber o

f TB

Cas

es

Number of Infusions

Only 60% of latency is known

Latency of TB After Infliximab InitiationLatency of TB After Infliximab Initiation

Data on File. Centocor, Inc.

Physicians must always be vigilant for TBor any infection regardless of dose number

Feb 2000 – Feb 2003


Turberculosis4 cases in Denmark, 2 RA died miliar TB• ENBREL:

– 1 case 77 F, RA in MTX, TB at 20 yrs age (died)– 1 Psoriasis artheritis case 40 M, never TB

• HUMIRA:– 1 RA case 56 M, in MTX, never TB, from Bosnia

(died)

• REMICADE:– 1 Crohn’s 35 M, in Immuran, never TB, Thamil

National concensus in 2005 awaited: L Andersen (RA)A Rosenvinge(Ped), P Munkholm(Gas), R Gniadecki(Der)N Seersholm(Lun), Å Bengaard Andersen(Inf)

Algorithm for TB Testing: European-based recommendations

New infliximab patient has office visit

PPD Test Positiveand active TB

Initiate latent TB treatment

Treat active TB to resolution

Initiate infliximab

Administer appropriate TB screening test(PPD skin test + chest x-ray +

detailed medical/exposure history)

Evaluate test results

Test Negative

Initiate infliximab

PPD Test Positiveand normal CXR

>5mm after 48-72 hrsDanish vaccinated until 1972

Pos. PPD test

Hepatotoxicity• 34 cases out of 576,000 patients treated (1.34 Million Pt-

yrs) in 6 year period & different indications & multiple co-medications

– 3 cases resulted liver transplantation for acute liver failure

– 2 cases resulted in death • 61 yr-old male with alcoholic hepatitis who also

received infliximab• 86 yr-old female with CHF and abnormal LFT’s who

had received infliximab


Hepatotoxicity

venlaxafine, nortriptyline, celecoxib, cyclosporine, AZA

Required liver transplant5 dosesAcute liver failure

34 yr oldFemale

CD

Naproxen, sulfamethoxazole, prednisone, Bactrim, AZA, calcium, calcifediol, codeine, MTX, IVIG, high-dose steroids, Cytoxan

Required liver transplant

15 d after 2nd doseAcute liver failure

28 yr oldFemale

Adult-onset Still's disease

Leflunomide, Antimalarials, NSAID’s

Required liver transplant

8 wks after ? dose (received at least 4 doses)

Acute liver failure, autoimmune picture?

37 yr oldFemale

RA

Current Concom MedsOutcomeIFX Time

Clinical ProblemPatient


Hepatotoxicity Recommendations

• caution in patients known to be chronic carriers of Hepatitis B virus. Prophylaxis with antivirals (e.g. lamivudine) may be considered

• jaundice or ALT > 5 times the upper limit infliximab should be discontinued

• Patients have improved with steroid therapy

Comparison with Infliximab Clinical Trials

Mayo TREAT TREATACCENT I ACCENT II Cohort IFX pts Non-IFX

Number of Patients 573 306 500 2850 2957

Infusion 17% 7% 3.8% 5.4% --Reactions

Serious Infusion 1.0% 0.3% 0.4% 0.16% --Reactions

Annual Serious Inf 4.0% 4.6% 2.1% 1.3% 0.9%

Annual Malignancy 1.0% 0% 0.4% 0.5% 0.5%

Annual Mortality 0.7% 0% 1.3% 0.5% 0.5%

Integrated Safety Summary, Aug 09, 2002; FDA Advisory Committee, March 4, 2003

Malignancies in All Infliximab Clinical Trials Compared with General Population

*Includes ASPIRE trial. **Excludes non-melanoma skin cancers because also excluded in SEER database

• 1 placebo and 9 infliximab reported through long-term F/U

Observed # inInfliximab Trials

(RA / CD)

Expected # FromSEER Database

General US Population

Patient-yearsof F/U

Infliximab

766

5,391

55.0

30.1 27

Placebo

Completed Clinical TrialsCompleted Clinical Trials

NIH: SEER Surveillance, Epidemiology, End Results

TREAT Registry

0.05735,225Not treated with infliximab

0.06246,417Infliximab

Incidence per 100 PtYrsLymphomas

PtYrs of follow-upTreatment

Lymphomas in Crohn’s Disease RegistryLymphomas in Crohn’s Disease Registry

RegistryRegistry

FDA Advisory Committee. March 04, 2003. Data on file. Centocor, Inc.

FDA Lymphoma warning 2005• “Malignancies have also been observed in open-label,

uncontrolled clinical studies at a rate several-fold higherthan expected in the general population.”

• Patients with Crohn's disease or rheumatoid arthritis, particularly patients with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several fold) than the general population for the development of lymphoma.

• FDA has recommended a warning:concerning malignancy be added to the labeling for all therapeutic agents that block TNF.

Pregnancysafety

PREGNANCY fetal drug toxicityCategory

• Vitamin pill A

• 5-asa, Infliximab, metoclopramide, Ciprofloxazine, antacids, Bcholestyramine, Loperamide

• Steroids, budesonide, CY-A, Tracolimus, PPI, NSAIDs, Codeine C

• Metronidazole (after 1.trimester safe B), tetracycline, Sulphonamides, DAzathioprine, 6MP, aspirin

• Methotrexate, Thalidomide X

”A”=controlled studies show no risk ”B”=no evidence of risk in humans

”C”=risk cannot be ruled out ”D”=positive evidence of risk

”X”=known danger, contraindicated in pregnancy

FDA recommendations

Safety in mothersMTX, CyA, IFX

• MTX(FDA ”X”) are abortifacient. Goldenberg M. Hum Reprod 1993;8• MTX in animals & humans:

– Spon. abortionrate 40%. Neural tube defects & congenital anomalies– Case reports successfully to term in RA. Kazlowski RD. Am J Med

1990;88• CyA(FDA ”C”) transplant population and rats: no neonatal

complications or congenital anomalies. Armenti V. Transplantation 1994;57– IBD population 6 case reports: no congenital abnormalities, no renal

toxicities. Marion JRP. AJG 1996;91 & Bertschinger P. AJG 1995;90. • Infliximab(FDA ”B”)

• A, B, C, D acceptable & seems to be safe during pregnancy

ECCO concensus 2005 Gut, in Press

36

Infliximab and Pregnancy

• 188 pregnant women in Centocor database

• 112 women with known dates of infliximab exposure

– 33% only exposed after conception

– 67% received infliximab within 3 months prior to conception

• 48% of women with more than one infusion (range 1-9 doses)

Infliximab and pregnancy

before conception

after conception

both before conception andduring 1. trimesteronly within 3 mths beforeconception

38

Expected vs. Observed Pregnancy Outcomes

67 69 69

17 17 131611

18

01020304050607080

Generalpopulation

Crohn'sdisease

Infliximab

Live births Miscarriages Therapeutic termination

1 2

1Ventura et al. National Center for Health Statistics Vital Health Stat 2000;21:1-592Hudson et al. Int J Gynaecol Obstet 1997;58:229-237.

Perc

enta

ge o

f Wom

en

Case I, Herlev University hospital 2005

• Male 33 years, UC since 1993 • 3 rd sterorid course within 1½ year

– supplementet with AZA 2½ mg/kg for 5 days– Wants to conceive– Should he stop AZA?– Why? – Should he go for a Colectomy and pouch?

– Save the sperms in a bank?

Animal study shows change in sperm DNA

No, there is a risk of ejaculatory problems <1%, impotence <0.1%

Not nescecarry - but recommended by oncologist friend

Light micrograph:Deformed sperm

”Hockey stick” spermatozoonwith abnormal residual

cytoplasm

BMJ 2002;325:28

Dejaco et al Gastro 2001;121:1048

Outcome of pregnancies whenfathers treated with 6MP in IBD

00,20,40,60,8

11,21,41,61,8

2

conceivedwithin<3mths

6MP use

conceived> 3mths

after 6MPstop

IBD fathers no 6MP

spon abortions malformations

P<0.002

P<0.013

n=13 n=37 n=90

Rajapakse R, et al. AJG 2000;95 Lennox

Anomalies:1. Missing thumb2. Acrania, multiple digital & limb abn

RetrospectiveSmall sampleNo controlMothers comorbid cond

• Women discontinue MTX >3 mths prior conception

• Males 4-6 mths prior conception• Males AZA, debatable-discuss

Attempting conception regarding IBD fathersand mothers treated with MTX

Breastfeeding child drug toxicityacceptable milk:serum ratios in child

• SAFE: Sulfasalazine, Topical mesalamine, Oral mesalamine(but not olsalazine), Corticosteroids

• PROBABLY SAFE: Budesonide, Azathioprine, 6-MP, (limited data) Infliximab

• CONTRAINDICATED: Methotrexate, Thalidomide, Cyclosporine, Diphenoxylate, Ciprofloxacin, Metronidazole, Loperamide

ECCO consensus. Riis L. Gut 2005 submitted

Fetal liver lack enzymes that convert AZA to active metabolites

FDA & AAP recommandationsFood and Drug Administation & American Academy of Pediatrics

Janssen NM. Arch Int Med 2000;160:610-19

Conclusions I Safety of immunomodulation(I)

• AE: can be managed• SAE: TB, PS might cause early death –

can be avoided by prophylaxis• CANCER: no increased cancer risk due to

IM only if > 2 immunosppresants• MORTALITY: no increased mortality due

to IM only if > 2 immunosuppressants

Conclusions II Safety of immunomodulation(IM)

• FDA fetal drug toxicities ”A-X”– Avoid MTX, Thalidomide during pregnancy– Males should probably avoid MTX, AZA >

3mths before conceiving-data lack • IM probably safe during breastfeeding-

data lack: probably avoid AZA, MTX, CyA• Therapeutic termination should never be

recommended but discussed with the couple on individual basis

INVITATION!

Opera

15-20 October 2005

1805 - 1875

Infertility

Light micrograph:

Deformed sperm

”Hockey stick” spermatozoonwith abnormal residual cytoplasm

BMJ 2002;325:28

AZA/6MPlymphoma & cancer

• No increase risk lymphoma. Lewis JD. Gastroent 2001;121

• 3.1 % cancer. Present D. Ann Int Med 1989;111. Mt Sinai• Median treatment: 12.5 mths(2 days-15 years). 2mg/kg AZA

in 755 pts(450 CD/ 282)UC. Connell WR. Lancet 1994;343. St. Marks

• Cancer (O:31) vs (E: 24.3)= 1.3 ns. • CRC (O: 13 rectal + 2 anal) vs (E: 2.27)= 6.7, p=0.00001

• UC 86 pts AZA vs 180 non-AZA sex, age +/-10 yrs; dur dis <1yr:AZA-UC: 8 CRC vs 0.26 (E) non-AZA-UC: 15 CRC vs 0.63 (E) O: 8 AZA+ vs E: 6.2 AZA-; p=0.54 AZA treatment DO not cause the CRC

Vader J-P, Michietti P et al. Gut 2005 submitted

EPACT: The European Panel on the Appropriateness of Crohn’s Disease Therapy RAND Appropriateness Method

Odds Ratio 95% CI

Current use of infliximab 1.088 0.578 – 2.048

Current use of 6MP/AZA/MTX 0.821 0.451 – 1.495

Current use of corticosteroids 2.315 1.563 – 6.06**

Current use of narcotic analgesics 3.079 1.227 – 4.368**

Serious InfectionsLogistic Regression Data (Multivariate)

TREAT

**p<.01

Odds Ratio 95% CI

Age > 40 years 1.012 0.992 - 1.032

Female 2.209 1.097 – 4.445*

Baseline moderate, severe

or fulminant CD 2.669 0.95 – 7.46

>10 years since diagnosis 1.042 1.016 – 1.068

Serious InfectionsLogistic Regression Data (Multivariate)

TREAT

*p<.05

TREAT Registry – Patient

• 5807 adult CD patients from community, (80%),academic (20%) practices have been enrolled in TREAT as of August 2003– 2850 patients have received infliximab– 2957 patients have not received infliximab

• Mean length of time in registry 0.9 years• Of patients who have received infliximab, 86%

have received ≥ 2 infusions, with concommittanttreatment

TREAT

Crohn’s Therapy Resource, Evaluation and Assessment ToolCrohn’s Therapy Resource, Evaluation and Assessment Tool

Lichtenstein G.Gastro; DDW 2004

Infusion Reactions

• Infliximab infusions: 11,504• Infusions with reactions: 5.4%• Infusions with serious reactions: 0.16%

TREAT

Malignancies

• Anal cancer (1)• Breast cancer (3)• Cervical cancer (1)• Colon cancer (2)• Lymphoma (4)• Lung cancer (2)• Non-melanoma skin

cancer (3)• Recurrent leukemia (1)

• Colon cancer (2)• Disseminated squamous

cell cancer (1)• Esophageal cancer (1)• Lung cancer (2)• Lymphoma (2)• Metastatic carcinoid

tumor (1)• Renal cancer (1)• Thyroid cancer (2)

Infliximab Other Treatments Only

TREAT

Malignancies

• Anal cancer (1)• Breast cancer (3)• Cervical cancer (1)• Colon cancer (2)• Lymphoma (4)• Lung cancer (2)• Non-melanoma skin

cancer (3)• Recurrent leukemia (1)

• Colon cancer (2)• Disseminated squamous

cell cancer (1)• Esophageal cancer (1)• Lung cancer (2)• Lymphoma (2)• Metastatic carcinoid

tumor (1)• Renal cancer (1)• Thyroid cancer (2)

Infliximab Other Treatments Only

TREAT

Infliximab Non-infliximab Oddspatients patients Ratio 95% CI

All Cancer* 0.53 0.49 1.05 0.53-2.08Lymphoma* 0.10 0.06 1.69 0.30-8.99Longer follow-up needed!

safety of immunomodulation€¦ · – tb, pneumocystis carinii, ebv, opportunistic • severe...

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