Download DSQ Fall 2013 - American College of Rheumatology

InsideThis Issue
DSQ
Wound Healing and AntiRheumatic Agents.........................1
Drug Safety Quarterly
Vo l . 4 ( 3 )
Fall 2013
Safety of Anti-Osteoporosis
Medications .................................1
TNF inhibitors and Severe
Hepatic Injury................................3
EULAR 2013 Safety Update..........4
an online publication of the ACR Drug Safety Committee
FDA MedWatch: Fall 2013 ...........5
Wound Healing and Anti-Rheumatic Agents
In the News: Fall 2013..................6
Safety Signals: Sept. 2013...........7
Susan M. Goodman1, Miguel Perez-Aso2 and Bruce N. Cronstein2
Hospital for Special Surgery, Department of Medicine; New York University School of Medicine, Department of Medicine, Division of Translational Medicine
1
2
Patients with rheumatoid arthritis (RA) are often on multiple
medications to control disease activity and these medications
may have significant toxicities, including effects on wound
healing. Deep surgical site infections are of particular concern
when prostheses such as arthroplasties are implanted,
given the morbidity, mortality, and expense associated with
prosthetic joint infection. Wound healing complications,
including prolonged drainage or superficial infection, are highly
associated with deep surgical site infection, so medications
which delay wound healing following elective surgery are
particularly worrisome(1). However, active RA also confers
an increased risk for infection(2) and slows post-operative
mobilization, so perioperative management strategies must
balance the risks. Because poor wound healing often leads to
infection (e.g. up to 50% of diabetic foot ulcers will become
infected(3), and infection often contributes to delayed wound
healing) it is often difficult to disentangle infection from
poor wound healing in the postoperative period. This review
will concentrate on the effects of anti-rheumatic therapy on
wound healing, and identify those effects which are well
documented versus those which are less well studied. This
review will not address the effects of therapy on fracture
healing.
Healthy wound healing proceeds through an inflammatory
phase, followed by wound remodeling and finally reepithelialization, normal stages of wound healing which
are blunted by systemic corticosteroids in both patients and
animal models(cf (4, 5)). Although the corticosteroid doses used
in RA are usually low, even low dose corticosteroid therapy
confers an increased infection risk, and duration of therapy,
frequently prolonged in RA, also contributes to infection risk(6).
The increase in risk of infection associated with corticosteroid
use has been demonstrated in multiple surgical contexts (7).
However, the clinical distinction between slowed wound
healing and surgical site infection can be difficult and the
clinical literature often makes little distinction between
poor wound healing and wound infections. Moreover, the
contribution of disease activity to infection risk in the postoperative period has not been studied.
Patients may be taking analgesic, anti-inflammatory,
biologic or synthetic disease-modifying antirheumatic drugs
(DMARDs) to manage their systemic disease-raising concerns
with respect to wound healing problems(8). With the exception
of methotrexate, there are few prospective controlled studies
addressing the effects of these medications on infection and
wound healing in the perioperative period. Recommendations
for medication management are frequently made based on
retrospective series(9) or large data base studies regarding
the incidence of infection rates and risk factors(10, 11). Here, we
provide a careful synthesis of the available data regarding
wound healing risk.
Methotrexate is the most commonly used DMARD in RA,
and its anti-inflammatory activity is likely due to multiple
mechanisms with the best documented being increased
extracellular adenosine levels(12). Currently methotrexate
is usually administered as the initial remittive agent and
patients tend to remain on methotrexate longer than other
DMARDs. The question of methotrexate safety during the
perioperative period has been addressed in prospective
studies which support the practice of continuing methotrexate
during the perioperative period without an increase in
infection or wound healing complications. In a prospective
randomized controlled trial of 388 MTX treated RA patients
undergoing orthopedic surgery, those who continued MTX
had an infection and orthopedic complication rate of 2%,
while those who discontinued MTX had an infection and
orthopedic complication rate of 15%. These cases were
additionally compared to 228 not on MTX at the time of
surgery, who had an infection and surgical complication ate
of 10.5%. Joint flares were also increased in the patients
who were not taking perioperative methotrexate(13). These
findings were confirmed in two small prospective studies(14-17).
see Wound Healing and Anti-Rheumatic Agents, page 2
Update on Drug Shortages...........8
Letter to the
Editors
Dear DSQ,
I was told that there were
reported anaphylactic
reactions to Prolia injections
recently. I spoke to our rep
and medical liasion who
could/would not answer two
specific questions: 1. How
many patients were reported
with this reaction? 2. How
many died?
- Joshua Stolow,M.D. San
Antonio Arthritis Care Centers
In July 2013 the FDA issued a
Medwatch update of
denosumab's (Prolia) labeling to
include clinically significant
hypersensitivity warnings,
including anaphylaxis. No
additional information was given
on the FDA website. Two other
sources (AdverseEvents.com and
DrugCite.com) noted that as of
8/27/12 there were 4230 reports
of serious adverse events
ascribed to Prolia; the top three
see Letter to the Editors, page 8
Send letters to
[email protected]
Safety of Anti-Osteoporosis Medications
Michael R. McClung; Oregon Osteoporosis Center, Portland, OR
Osteoporosis is a very common, chronic condition characterized by deterioration
of skeletal architecture, bone fragility and increased risk of fracture, most
importantly of the spine and hip. Drugs in several therapeutic classes effectively
reduce fracture risk. Raloxifene reduces spine but not non-spine fracture risk
and reduces risk of invasive breast cancer. Bisphosphonates and denosumab
reduce the risk of spine, hip and other non-spine fractures as quickly as 6
months after beginning therapy. Teriparatide and strontium ranelate protect
patients from spine and non-spine fracture. Bisphosphonates and especially
teriparatide are effective in patients receiving glucocorticoids. However, none
of our therapies restore and normalize skeletal structure and, with the exception
of bisphosphonates, the beneficial effects of treatment wane quickly when
treatment is stopped. Long-term therapy is necessary in most patients, raising
concern about both short and long-term safety of these agents.
Calcium and Vitamin D: (1)Little skeletal benefit is observed with total daily
see Safety of Anti-Osteoporosis Medicatins, page 4
D r u g
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1
DSQ
Wound Healing and Anti-Rheumatic Agents
continued from cover
In a retrospective review of 725 foot and ankle procedures in 104 patients
with RA with an overall complication rate of 32%, there was no statistical
association of wound or infectious complications with use of corticosteroids,
methotrexate, or hydroxychloroquine(18). Thus, the clinical data that address
wound healing in patients with RA treated with methotrexate suggests no
significant increase in healing complications although lack of a consistent
clinical definition for differentiation of pathologic wound healing from infection
hampers the interpretation of these studies. Taken together, current data
suggests that methotrexate can be continued in the perioperative period to
avoid flare, without impairing wound healing or increasing the infection risk.
2
In contrast to methotrexate there is relatively little information on the risks of
continuation of other DMARDs and the biological agents in the perioperative
period(8,19). There are no randomized studies addressing perioperative
complications in RA patients treated with other commonly used antirheumatic
drugs, including hydroxychloroquine, leflunomide, azathioprine or sulfasalazine.
Thus any and all recommendations on these agents are drawn from case
series and retrospective studies. Although not studied in a surgical setting,
hydroxychloroquine has an extremely
favorable toxicity profile and consensus Methotrexate does not affect
considers hydroxychloroquine to be wound healing after joint
safe to use in the perioperative period surgery. But there is minimal
as it is not a potent immunosuppressant.
information on the effect of
Two small, uncontrolled series describe
leflunomide patients undergoing DMARDs and biologics on
orthopedic surgery with different post-op wound healing.
results. While 41 leflunomide-treated
RA patients undergoing orthopedic surgery in one study suffered no increase in
post-operative infections(20), a second series of 32 leflunomide-treated patients
reported an increase in wound healing complications.(21) As no standard
definition has been applied, clinical differentiation of infection vs. wound healing
hampers our analysis, as noted above. As the concomitant use of corticosteroid,
leflunomide, and methotrexate has been reported to heighten infection risk(22),
leflunomide is often withheld prior to surgery. When patients on leflunomide
fall into a higher risk group due to other co-morbidities or medications,
cholestyramine can be given 8 grams BID-TID for 5 -11 days to accelerate drug
elimination, with the higher dose regimen effecting a more complete washout.
Although unstudied in this context, other immunosuppressant medications such
as azathioprine and mycophenolate mofetil are frequently withheld prior to
surgery as well.
The data assessing anti-TNF agents and wound healing are conflicting and
comprise a mixture of large database studies and small retrospective and
prospective studies in RA(8). Similar to DMARDs other than methotrexate, we
lack data on the perioperative safety of anti-TNF agents with regard to wound
healing. Moreover, animal and experimental studies reveal conflicting effects of
TNF-α on wound healing and only a few small studies address the use of TNF-α
antagonists in patients with RA [reviewed in(19)]. In one small prospective study
of foot and ankle surgery in patients with RA 31 patients were prospectively
followed; 16 patients in the study were treated with TNF inhibitors, and had
no increase in wound healing or infectious complications(23). However, as noted
above, delayed wound healing is associated with an increased risk of infection
and clinical studies rarely differentiate between wound healing and surgical site
infection. Unsurprisingly, given the paucity of high quality data, rheumatology
associations from different countries offer different recommendations, largely
basing the recommendations on the reduction of perioperative infection. The
French Society of Rheumatology has issued some extremely conservative
guidelines suggesting prolonged drug withdrawal for perioperative use
of TNF-α antagonists, with resumption of therapy after complete wound
healing assuming the absence of infection(24). Similarly, the British Society of
Rheumatology recommends that treatment with infliximab, etanercept, and
adalimumab should be withheld 2 to 4 weeks prior to major surgical procedures
and they recommend restarting treatment when wound healing is satisfactory
and there are no signs of infection(25). The American College of Rheumatology
recommends withholding TNFα antagonists for > 1 week (one drug dosing
cycle) before and after surgery until the wound has healed without signs of
infection, a recommendation which provides a practical framework permitting
vigilance in wound care without prolonged drug withdrawal which can increase
the risk of disease flares. The differing recommendations reflect the lack of clear
randomized control trial data on which to base recommendations and available
data do not allow permit more definitive conclusions about the use of TNF-α
antagonist perioperatively. This difficulty in developing accurate guidelines is
further complicated by the different risks of infection and poor wound healing
posed by different surgical procedures. As described above, there is significant
clinical difficulty in separating poor wound healing from wound infections.
There is surprisingly little data on the effect of NSAIDs on wound healing in
rheumatic diseases patients who have undergone surgery. A recent systematic
review on this subject suggests that there is little effect of NSAIDs on healing
of soft tissues after sports injury or surgery but that NSAIDs do interfere with
bone healing and should be avoided(26).
In summary, with the exception of methotrexate, there is a lack of data regarding
optimal practice for perioperative management of antirheumatic treatment in RA
patients undergoing surgery. Existing data, however, indicates that methotrexate
may be continued throughout the perioperative period for otherwise healthy
individuals. For the other anti-rheumatic drugs, while continuing medication
may hamper wound healing and predispose to infections, discontinuation may
lead to disease flare, which increases the need for corticosteroids or other
medications that may also increase the risk for inadequate wound healing and
infection to regain disease control. Moreover, there is no consensus among the
various rheumatic disease societies regarding optimal practice. Although there
are clear effects of anti-rheumatic therapy on wound healing and clear infection
risk, the role of RA inflammatory activity on wound healing, infection, and
rehabilitation should also be considered. For surgeries such as the implantation
of a prosthetic joint, where surgical site infection carries significant morbidity,
current practice favors a conservative approach. D S Q
Table 1. Drug Effects on Wound Healing
Effect on Wound Healing
Anti-rheumatic Rx
NSAIDs
No Effect
Unknown
X
Reference
(26)
X
Corticosteroids
(4-7)
X
Hydroxychloroquine
Methotrexate
Impaired
Healing
X
(13-15, 17, 18)
Leflunomide
X
TNF inhibitors
X
References
1. Berbari, E. F., Hanssen, A. D., Duffy, M. C., Steckelberg, J. M., Ilstrup, D. M., Harmsen, W. S., and
Osmon, D. R. (1998) Risk factors for prosthetic joint infection: case-control study. Clinical infectious
diseases : an official publication of the Infectious Diseases Society of America 27, 1247-1254.
PMID: 9827278
2. Au, K., Reed, G., Curtis, J. R., Kremer, J. M., Greenberg, J. D., Strand, V., Furst, D. E., and Investigators,
C. (2011) High disease activity is associated with an increased risk of infection in patients with
rheumatoid arthritis. Annals of the rheumatic diseases 70, 785-791. PMID: 21288960
3. Hobizal, K. B., and Wukich, D. K. (2012) Diabetic foot infections: current concept review. Diabetic foot
& ankle 3. PMID: 22577496
4. Li, J., Wang, X., Zhou, C., Liu, L., Wu, Y., Wang, D., and Jiang, H. (2012) Perioperative glucocorticosteroid
treatment delays early healing of a mandible wound by inhibiting osteogenic differentiation. Injury 43,
1284-1289. PMID: 22658419
5. David, D. J. (1972) Skin trauma in patients receiving systemic corticosteroid therapy. British medical
journal 2, 614-616. PMID: 4555652
Continued on next page
D r u g
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Vol. 4 (3)
drug safety quarterly
Wound Healing and Anti-Rheumatic Agents
Fall 2013
continued from previous page
6. Dixon, W. G., Abrahamowicz, M., Beauchamp, M. E., Ray, D. W., Bernatsky, S., Suissa, S., and Sylvestre,
M. P. (2012) Immediate and delayed impact of oral glucocorticoid therapy on risk of serious infection
in older patients with rheumatoid arthritis: a nested case-control analysis. Annals of the rheumatic
diseases 71, 1128-1133. PMID: 22241902
7.Ismael, H., Horst, M., Farooq, M., Jordon, J., Patton, J. H., and Rubinfeld, I. S. (2011) Adverse effects of
preoperative steroid use on surgical outcomes. American journal of surgery 201, 305-308; discussion
308-309. PMID: 21367368
8. Barnard, A. R., Regan, M., Burke, F. D., Chung, K. C., and Wilgis, E. F. (2012) Wound healing with
medications for rheumatoid arthritis in hand surgery. ISRN rheumatology 2012, 251962. PMID:
23251815
9. Giles, J. T., Bartlett, S. J., Gelber, A. C., Nanda, S., Fontaine, K., Ruffing, V., and Bathon, J. M. (2006)
Tumor necrosis factor inhibitor therapy and risk of serious postoperative orthopedic infection in
rheumatoid arthritis. Arthritis and rheumatism 55, 333-337. PMID: 16583385
10. Bongartz, T., Halligan, C. S., Osmon, D. R., Reinalda, M. S., Bamlet, W. R., Crowson, C. S., Hanssen,
A. D., and Matteson, E. L. (2008) Incidence and risk factors of prosthetic joint infection after total hip
or knee replacement in patients with rheumatoid arthritis. Arthritis and rheumatism 59, 1713-1720.
PMID: 19035425
11. Dixon, W. G., Symmons, D. P., Lunt, M., Watson, K. D., Hyrich, K. L., British Society for Rheumatology
Biologics Register Control Centre, C., Silman, A. J., and British Society for Rheumatology Biologics,
R. (2007) Serious infection following anti-tumor necrosis factor alpha therapy in patients with
rheumatoid arthritis: lessons from interpreting data from observational studies. Arthritis and
rheumatism 56, 2896-2904. PMID: 17763441
12. Chan, E. S., and Cronstein, B. N. (2010) Methotrexate--how does it really work? Nature reviews.
Rheumatology 6, 175-178. PMID: 20197777
13. Grennan, D. M., Gray, J., Loudon, J., and Fear, S. (2001) Methotrexate and early postoperative
complications in patients with rheumatoid arthritis undergoing elective orthopaedic surgery. Annals
of the rheumatic diseases 60, 214-217. PMID: 11171680
14. Sany, J., Anaya, J. M., Canovas, F., Combe, B., Jorgensen, C., Saker, S., Thaury, M. N., and Gavroy,
J. P. (1993) Influence of methotrexate on the frequency of postoperative infectious complications
in patients with rheumatoid arthritis. The Journal of rheumatology 20, 1129-1132. PMID: 8371204
15. Murata, K., Yasuda, T., Ito, H., Yoshida, M., Shimizu, M., and Nakamura, T. (2006) Lack of increase
in postoperative complications with low-dose methotrexate therapy in patients with rheumatoid
arthritis undergoing elective orthopedic surgery. Modern rheumatology / the Japan Rheumatism
Association 16, 14-19. PMID: 16622718
16. Jain, A., Witbreuk, M., Ball, C., and Nanchahal, J. (2002) Influence of steroids and methotrexate on
wound complications after elective rheumatoid hand and wrist surgery. The Journal of hand surgery
27, 449-455. PMID: 12015719
17. Carpenter, M. T., West, S. G., Vogelgesang, S. A., and Casey Jones, D. E. (1996) Postoperative
joint infections in rheumatoid arthritis patients on methotrexate therapy. Orthopedics 19, 207-210.
PMID: 8867548
18. Bibbo, C., Anderson, R. B., Davis, W. H., and Norton, J. (2003) The influence of rheumatoid
chemotherapy, age, and presence of rheumatoid nodules on postoperative complications in
rheumatoid foot and ankle surgery: analysis of 725 procedures in 104 patients [corrected]. Foot &
ankle international. / American Orthopaedic Foot and Ankle Society [and] Swiss Foot and Ankle
Society 24, 40-44. PMID: 12540080
19. Pieringer, H., Stuby, U., and Biesenbach, G. (2007) Patients with rheumatoid arthritis undergoing
surgery: how should we deal with antirheumatic treatment? Seminars in arthritis and rheumatism
36, 278-286. PMID: 17204310
20. Tanaka, N., Sakahashi, H., Sato, E., Hirose, K., Ishima, T., and Ishii, S. (2003) Examination of the risk of
continuous leflunomide treatment on the incidence of infectious complications after joint arthroplasty
in patients with rheumatoid arthritis. Journal of clinical rheumatology : practical reports on rheumatic
& musculoskeletal diseases 9, 115-118. PMID: 17041441
21. Fuerst, M., Mohl, H., Baumgartel, K., and Ruther, W. (2006) Leflunomide increases the risk of early
healing complications in patients with rheumatoid arthritis undergoing elective orthopedic surgery.
Rheumatology international 26, 1138-1142. PMID: 16736164
22. Jenks, K. A., Stamp, L. K., O'Donnell, J. L., Savage, R. L., and Chapman, P. T. (2007) Leflunomideassociated infections in rheumatoid arthritis. The Journal of rheumatology 34, 2201-2203.
PMID: 17937473
23. Bibbo, C., and Goldberg, J. W. (2004) Infectious and healing complications after elective orthopaedic
foot and ankle surgery during tumor necrosis factor-alpha inhibition therapy. Foot & ankle
international. / American Orthopaedic Foot and Ankle Society [and] Swiss Foot and Ankle Society
25, 331-335. PMID: 15134615
24. Pham, T., Claudepierre, P., Deprez, X., Fautrel, B., Goupille, P., Hilliquin, P., Masson, C., Morel, J.,
Puechal, X., Saraux, A., Schaeverbeke, T., Mariette, X., Sibilia, J., and Club Rhumatismes et
Inflammation, F. S. o. R. (2005) Anti-TNF alpha therapy and safety monitoring. Clinical tool guide
elaborated by the Club Rhumatismes et Inflammations (CRI), section of the French Society of
Rheumatology (Societe Francaise de Rhumatologie, SFR). Joint, bone, spine : revue du rhumatisme
72 Suppl 1, S1-58. PMID: 15978467
25. Ledingham, J., Deighton, C., British Society for Rheumatology Standards, G., and Audit Working, G.
(2005) Update on the British Society for Rheumatology guidelines for prescribing TNFalpha blockers
in adults with rheumatoid arthritis (update of previous guidelines of April 2001). Rheumatology 44,
157-163. PMID: 15637039
26. Chen, M. R., and Dragoo, J. L. (2013) The effect of nonsteroidal anti-inflammatory drugs on tissue
healing. Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA 21, 540-549.
PMID: 22744434
3
TNF inhibitors and Severe Hepatic Injury
Marked elevations of liver function tests are rarely encountered in patients
receiving TNF inhibitors. CORRONA analyzed 6861 rheumatoid arthritis patients
and found that 5.9% had any elevation of LFTs but <1% had greater than 2 fold
elevations of LFTs(1). In their cohort elevations were more likely with infliximab
and less likely with etanercept.
In a 2003 FDA arthritis advisory committee meeting the FDA reported its
review of 134 reports of liver failure seen with TNF inhibitors(2). While minor
elevations of AST/ALT were seen in 29-42% of patients in the ATTRACT (RA)
and ACCENT I (Crohns) trials, extreme elevation (>5 fold elevations) was rare.
The Medwatch AERS database revealed 134 reports of liver failure. Analyses
of 50 detailed cases showed 31 were due to infliximab and 19 etanercept.
When other potential confounders (eg, hepatitis, alcohol, MTX, hepatotoxic
agents, GVHD) are excluded, 7 of 50 cases pointed to the TNF inhibitor as the
offending agent.
A recent analysis of 34 cases of TNF inhibitor-induced severe liver injury,
disclosed that most of these were related to infliximab use (26/34) with
many being treated for psoriatic disorders (13 patients), inflammatory bowel
disease(12), rheumatoid arthritis (6), and ankylosing spondylitis (3). While most of
these occurred in patients receiving infliximab (26 cases), none were related to
natalizumab, golimumab, or certolizumab use. The onset occurred in the first 3-6
months of therapy for most (range 2-104 wks) and two-thirds of patients were
ANA+ and ASMA+. In many of the available liver biopsies showed a picture
of autoimmune induced hepatocellular injury, but a mixed non-autoimmune
pattern or predominant cholestasis pattern was also seen (3).
The prescribing information for most of the marketed TNF inhibitor details a
small risk of hepatic enzyme elevation – although there are reports of severe
hepatic reactions, acute liver failure, > 5 fold LFT elevations, hyperbilirubinemia
and liver transplantation from TNF inhibitor use. The product label includes
post-marketing reports of severe hepatic reactions, acute liver failure, jaundice,
hepatitis and cholestasis. Despite these rare reports, most patients showing
elevated hepatic enzymes are asymptomatic. As noted above, infliximab has
been the most implicated of these agents. Although it would be very unlikely
for such elevations to be due to muscle inflammation, the adalimumab package
insert states that 15% of children receiving ADA developed mild to moderate
creatine kinase (CK) elevations.
Elevated hepatic enzymes with TNF inhibitor use should prompt reassessment
and careful review of other medications and comorbidities. Those with marked
elevations tend to respond well to discontinuation of the TNF inhibitor. D S Q
Table. Package Insert Data on >3 fold ALT Elevations with TNF inhibitors
TNF inhibitor
RA, PsA, AS
TNFi
Crohn’s disease
Ulcerative Colitis
PBO
TNFi
PBO
TNFi
PBO
Adalimumab
3.5 %
1.5%
0.9%
0.9%
1.5%
1.0%
Infliximab
4-10%
0-3%
2%
0%
<1%
<1%
Golimumab
2%
2%
ND
ND
Certolizumab
“elevated liver enzymes and hepatitis” in post marketing
reports
Etanercept
“elevated transaminases” in post marketing reports
Abbreviations: TNFi -TNF inhibitor; PBO- Placebo; x ULN- times the upper limit of normal; ND- no
data included
References
1. Ghabril M, et al. Clin Gastroenterol Hepatol 2013; 11: 558-5642. Cote TR. Arthritis Advisory
Committee 2003. PMID: 23333219
2. FDA. Center for Drug Evaluation and Research. Arthritis Advisory Committee, March 4, 2003.
http://www.fda.gov/ohrms/dockets/ac/03/transcripts/3930T1.htm
3. Sokolove J, et al. Ann Rheum Dis 2010;69:1612-1617. PMID: 20448284
an online publication of the ACR Drug Safety Committee
DSQ
EULAR 2013 Safety Update
TNF inhibitor therapy lowers risk of type II diabetes. A CORRONA study
(Lillegraven OP0161) of 21,775 RA patients showed that TNF inhibitor therapy
was associated with a 65% reduced risk of type II DM (HR 0.35).
TB risk is even higher with TNFi + MTX. In a pooled analysis of 86 clinical
trials involving RA, PsA, psoriasis, IBD and AS patients treated with either
adalimumab, infliximab or certolizumab, 0.2% developed incident TB. TNFi alone
increased the odds ratio to 9.9, the combined use of TNFi and MTX increased
the OR to 49.8 (Bruzzese, et al #OP0070).
Safety of Anti-osteoporosis Medications
4
continued from page 1
intake of calcium above 800-1200 mg. Daily supplements of 1000 mg in patients
with dietary intake of 800-1000 mg have been associated with an increased
risk of kidney stones and a 30-40% increased risk of cardiovascular events in
some but not all studies. Vitamin D intake of >10,000 units daily may cause
hypercalcemia and hypercalciuria. Serum concentration of 25-hydroxyvitamin
D of more than 50 ng/mL has been associated with an increase overall in
cancer-related mortality. The Institute of Medicine suggests that 4000 units
daily is the upper limit of safety.
Salmon Calcitonin: Weak evidence linking therapy to cancer risk resulted in
the drug being withdrawn from European market.
Raloxifene: (2) Excess venous thrombotic events occurred in 0.7% of patients
over 3 years, usually within first months of therapy and perhaps more commonly
in women with previous thrombotic events. Discontinue therapy 72 hours before
episodes of immobilization. There was no effect on overall incidence of
cardiovascular disease, but increased risk of death following stroke was
observed. Muscle cramps may also occur.
Teriparatide: (3) Serum calcium increases transiently after dosing. Persistent
hypercalcemia is infrequent. Muscle cramps may occur. Treatment of patients
on glucocorticoids for up to 3 years was not associated with untoward effects.
(4)
However, therapy is limited by regulation to 24 months in the United States
(18 months in Europe). High dose, long term treatment induced osteosarcoma
in rats. Although a few patients who received teriparatide may have developed
osteosarcoma, the estimated incidence does not appear to exceed that expected
in untreated older adults. Avoid use in adolescents, Paget’s disease or skeletal
metastases or with history of radiation therapy to skeleton.
Denosumab: (5-7) This subcutaneously injected anti-RANK ligand monoclonal
antibody was associated with eczema (3% versus 1.2% with placebo) and
cellulitis requiring hospitalization during the 3 year FREEDOM study. These skin
disorders were not related to the injection site or to the timing of injection and
did not increase in frequency with longer therapy. Hypocalcemia can occur,
especially in patients with osteomalacia.
RANKL is expressed in dendritic cells, but its role in immune function is unknown.
No signals of immune dysfunction have occurred in RANKL-deficient animals
or humans. Numeric but statistically insignificant imbalances in the incidence
of neoplasm and of infections or inflammation associated with hospitalization
were observed in FREEDOM. Cases of opportunistic infection and immune-related
neoplasms were similar between treatment and control groups. No immune
problems were identified in 218 subjects with rheumatoid arthritis taking
methotrexate treated with denosumab 60 or 180 mg Q6 months 12 months. A
few patients received anti-TNF therapy and 28% took glucocorticoids during
the study without apparent untoward effects. However, the safety of denosumab
in patients immunosupressed by disease or drugs has not been evaluated. In
cancer-related bone diseases, osteonecrosis of the jaw (ONJ) occurs with a
frequency similar to that in patients receiving high-dose intravenous zoledronic
acid. A small number of cases of ONJ and atypical fracture of the femur have
been reported in the osteoporosis extension study, but the incidence is unknown.
Hypersensitivty reactions including anaphylaxis, facial swelling and urticaria
have been reported rarely.
D r u g
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Rheumatoid arthritis and Pregnancy outcomes. RA patients were shown
to have increased rates of miscarriage (Wallenius M, #SAT0532) and infertility,
with the latter being associated with high disease activity, NSAID and prednisone
use (Brouwer J, #FRI0145).
Tofacitinib and Severe Lymphopenia. van Vollenhoven (THU0252) showed that
lymphopenia with absolute lymphocyte counts < 1500 ALC occurred in 35-39% of
3252 patients in Phase 3 trials in RA. ALC of 500-1500 was not associated with
a risk of serious infections, although ALC <500 occurred in 0.2-0.3% of patients
and all developed infection but only one-third had serious or opportunistic
infections. D S Q
Bisphosphonates: (8-10) In clinical trials, oral and intravenous bisphosphonates
have been well tolerated. Upper GI intolerance, usually mild or moderate, is
observed in daily practice, especially if the tablets are taken incorrectly. GI
bleeding, esophageal ulceration or rupture, and inflammatory eye disease
(uveitis, iritis) have been reported very rarely. Acute phase reaction occurs with
IV or high dose oral dosing. Bone and muscle pain, not observed in the clinical
trials, has been reported. Both the incidence and mechanism of this potential
side effect is unknown. Hypocalcemia can occur, especially in patients with
osteomalacia. Renal failure is reported in clinical practice with intravenous
zoledronic acid which is contraindicated in patients with estimated GFR <35
cc/min. Atrial fibrillation associated with hospitalization but not temporally
related to the annual dose occurred more frequently (1.3%) with intravenous
zoledronic acid compared to placebo (0.5%) in the HORIZON Pivotal Fracture
Trial. However, the incidence of atrial fibrillation, other arrhythmias or cardiac
events and stroke was similar between treatment and control groups. After
review of all bisphosphonate studies, the FDA concluded that a causal link
between bisphosphonate therapy and atrial fibrillation has not been established.
Cases of esophageal cancer have been reported in patients who took oral
bisphosphonates. No evidence of this association was observed in placebocontrolled clinical trials or in several observational cohorts. One of two analyses
(but not the other) of the UK General Practice Research Database suggested
an increased risk of esophageal cancer (3% vs 2.3% in controls), and especially
with treatment for >5 years (relative risk 2.24, 1.47 to 3.43). The FDA has stated
that evidence is insufficient to evaluate this association. In contrast, decreased
mortality and risks of breast, prostate, colon and pancreatic cancer have been
reported with bisphosphonates in observational and, for mortality, in randomized
controlled trials.
ONJ is primarily observed in patients receiving high dose intravenous therapy
for cancer-related bone diseases. The incidence in patients treated for osteoporosis
is very low with estimates ranging from 1:4000 to 1:250,000. A causal link
between oral bisphosphonates and ONJ has not been established, and minimal
evidence exists suggesting a relationship between the risk and duration of therapy.
Fractures of the femoral shaft with “atypical” features suggesting a brittle
bone-type fracture are observed with long-term therapy (average duration 7
years). Two studies suggest that risk increases with long-term therapy, the risk
being 2, 20 and about 100 per 100,000 patients after 2, 5 and 8-10 years,
respectively. Atypical fracture risk appears to decrease within 1-2 years after
stopping therapy. Interruption of treatment for 1-3 years is recommended for
patients at modest fracture risk after 3-5 years of treatment. Patients still at
high risk of fracture after that interval of treatment benefit from continued
therapy. In my opinion, most patients may be candidates for a “drug holiday”
after 10 years of therapy.
Strontium ranelate: (11) This drug is widely available except in North America
and was associated with a modest increase in venous thrombotic events in
clinical trials. Rare but very serious skin disorders have been observed in
postmarketing surveillance. Recent evidence links strontium ranelate therapy
with increased cardiovascular risk, leading European regulatory authorities to
limit the use of this agent.
Continued on page 8
drug safety quarterly
Vol. 4 (3)
Fall 2013
FDA MEDWATCH: Fall 2013
Fluoroquinolones and Risk for Permanent Nerve Damage. The FDA required
drug labels of all oral and intravenous fluoroquinolone antibiotics updated to
reflect the serious side effects of peripheral neuropathy. The warnings came
after review of data from the FDA Adverse Event Reporting System (AERS). The
onset of neuropathy is rapid, occurring within days of starting the fluoroquinolone
and can occur at any time during treatment with the drug and can last months
to years after discontinuation, in some cases, the condition can be permanent.
About 23.1 million unique patients received an oral fluoroquinolone from retail
pharmacies in 2011. (posted 8/15/13)
Acetaminophen Associated with Risk for Serious Skin Reactions.
Through the FAERS database and medical literature, new information suggest
that Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and
acute generalized exanthematous pustulosis (AGEP) have been associated with
acetaminophen. These reactions are rare but can be fatal, occurring with first-time
use or at any time the drug is taken. Healthcare workers should be aware of
this rare risk associated with acetaminophen. Given the new information, the
FDA will require that a new warning be added to labels of OTC acetaminophen
drug products as well as prescription drug products containing acetaminophen.
(Posted 8/2/13)
Ketaconazole (Nizoral) tablets and Risk for Adrenal Insufficiency, Fatal
Liver Injury. The FDA warns that oral ketaconazole should not be a first line
treatment for any fungal infection and has taken several actions to limit the
drug's use, including a revised boxed warning stating the drug is contraindicated
in patients with liver disease and included new recommendations for monitoring
liver function. In addition, adrenal function should be monitored in patients who
are at risk for adrenal insufficiency (major surgery, intensive care, prolonged
steroid use, etc). Topical formulations have not been associated with the above
adverse effects. (Posted 7/26/13)
Olmesartan Medoxomil and Sprue-like Enteropathy. The FDA found
clear evidence that olmesartan, an angiotensin II receptor blocker (ARB) blood
pressure medicine marketed as Benicar, Azor, and Tribenzor can cause sprue-like
symptoms including, severe, chronic diarrhea and weight loss. 23 cases were
identified in the FAERS database; patients presented with late-onset diarrhea,
significant weight loss, and in some cases have intestinal villous atrophy on biopsy.
Symptoms develop months to years after starting olmesartan, some required
hospitalization. All patients improved after discontinuation of the drug, and in
10 cases, a positive re-challenge was seen. In 2012, the Mayo Clinic published
a case series of 22 patients with similar findings whose clinical symptoms
improved after discontinuation of olmesartan; 18 patients had follow-up intestinal
biopsies which showed clinical recovery. Another case series was reported in
May 2013, patients had negative serologies for celiac disease but were found
to have villous atrophy associated with olmesartan use. The signal of sprue-like
enteropathy was further investigated for ARB class effects by the Mini-Sentinel
and CMS Medicare database; olmesartan had a higher rate of association with
celiac disease than other ARBs. Mechanism for olmesartan-associated sprue-like
enteropathy is unknown but delayed symptom latency and findings of collagenous
colitis along with high association with HLA-DQ2/8 suggest a localized delayed
hypersensitivity or cell- mediated immune response to the drug. TGF-B inhibition
by ARB is being explored as a possible mechanism; as TGF-B is considered an
important mediator of gut homeostasis. (Posted 7/3/13)
speculated that oral sulfasalazine can inhibit the absorption and metabolism of
folic acid. A national survey evaluated the outcome of pregnancies associated
with inflammatory bowel disease (IBD). In a group of 186 women treated with
sulfasalazine, the incidence of fetal morbidity and mortality was comparable to
untreated IBD pregnancies and pregnancies in the general population. A study
of 1,455 pregnancies associated with exposure to sulfonamides indicated that
this group of drugs, including sulfasalazine, did not appear to be associated with
fetal malformation. No clinical studies have evaluated the effect of sulfasalazine
on the growth development of children whose mothers received the drug during
pregnancy. SSZ remains a pregnancy category B. (posted July 2013)
Immunoglobulin (IVIG, subcutaneous IG, intramuscular IG) - new boxed
warnings were added after more data indicated risk for thrombosis with
immunoglobulin products. Retrospective data analysis of a large health-claims
database and post-marketing events noted thrombosis regardless of route of
administration. Risk factors for thrombosis included: advanced age, prolonged
immobilization, hypercoagulable conditions, h/o venous/arterial thrombosis, use
of estrogens, indwelling vascular catheters, but can occur without these risk
factors. Adequate hydration is advised before administration (Posted June 2013)
Trimethoprim-Sulfamethoxazole (TMX-SMX, Bactrim)- The FDA published
new warnings that severe and symptomatic hyponatremia can occur, particularly
when using this drug for the treatment of Pneumocystis jirovecii pneumonia
(PJP) pneumonia. In addition, the label will also reflect a warning of increased
congenital malformations, particularly neural tube defects and cardiovascular
malformation, urinary tract defects, oral clefts, and club foot. Patients should
be advised of potential hazards during pregnancy. Pregnancy labeling: category
D. (Posted July 2013)
Editor’s note: Several studies have looked at hyponatremia and hyperkalemia
associated with TMP-SMX use and found that the drug can affect the distal renal
tubules affecting electrolyte balance. This effect has been described in granulomatosis
with polyangiitis (GPA) patients prophylactically given TMP-SMX for PJP prophylaxis.
Patients with renal dysfunction and those who receive higher doses of the drug have
greater risk for hyponatremia/hyperkalemia and should be regularly monitored for
electrolyte disturbances. PMID: 12924488
Lupron (leuprolide) - new warnings were added after the FDA reviewed
post-marketing reports of convulsion in patients receiving leuprolide. Those at
highest risk include patients with history of seizures, epilepsy, cerebrovascular
disorders, CNS anomalies or tumors, and patients taking concomitant buproprion/
SSRI. (Posted July 2013)
Nifedipine (Procardia) - label changes reflect that nifedipine is transferred
through breast milk and should be avoided in breast feeding women. The drug
remains a Pregnancy category C. (Posted July 2013)
Doxycycline - post-marketing reports of pseudotumor cerebri had been noted
by the FDA. (Posted July 2013)
Aldactone (spironolactone) - warnings and precautions added to the labeling
that concomitant administration of Aldactone with the following drugs may lead
to severe hyperkalemia: NSAIDs, heparin, ACE inhibitors, ARB, aldosterone
blockers. Hyperkalemia metabolic acidosis has been reported in patients who
receive aldactone concurrently with cholestyramine. (Posted June 2013) D S Q
Sulfasalazine (SSZ) and Neural Tube Defects – The FDA is reviewing
reports of babies with neural tube defects born to mothers who take SSZ during
pregnancy, though the role of this drug in these defects is not established, it is
an online publication of the ACR Drug Safety Committee
5
DSQ
IN THE NEWS: Fall 2013
Electronic Health Record (EHR) Identifies Drug Safety Issues Before
National Alerts Are Issued. Not all safety issues with new drugs are
identified before they are marketed due to small study sizes, heterogeneity
of study populations, and short duration of follow-up. Stanford University
recently published their success in a computer algorithm to allow doctors
to differentiate between drug adverse events (AE) from another illness. The
algorithm was tested on a database of patient and physician AE reports from
the FDA and confirmed with the EHR records of patients at Stanford. One
example analysis examined arrhythmias and deaths due to drug interactions
between SSRIs and thiazides and showed that patients on the combination
are more likely to experience prolonged QT intervals compared to those on
other combinations. With the new tool, 1300 AE from more than 59,000 pairs
of drugs were identified. Similar research from Vanderbilt University reviewed
lab results from patients receiving a particular medication compared to those
who did not. Results confirmed previously reported adverse drug reactions
and allowed for detection of new ones; their tool showed high correlation
with 77% precision and 61% recall. In addition, internet search patterns by
patients have also been used as means to flag drug interactions. Researchers
from Microsoft, Stanford, and Columbia University examined logs of patient
queries entered into Google, Microsoft, and Yahoo search engines looking
for side effects. They found strong signals for combination paroxetine with
pravastatin which later, the pair was reported to cause hyperglycemia.
(FierceEMR 2013)
6
Opioid Knowledge Lacking in Healthcare Providers. The Pennsylvania
Patient Safety Authority published a study looking at medication errors
related to knowledge deficits regarding opioids in prescribers. Serious AE
related to opioid errors ranged from allergic reactions, failure to control
pain, oversedation, respiratory depression, seizures and death. Morphine,
hydromorphone, meperidine, and fentanyl are drugs highly associated with
patient harm. To decrease these errors, an opioid knowledge assessment
tool was developed for prescribers, pharmacists, and nurses. The questions
covered differences between opioid naive vs. tolerant patients, indications
for long-acting opioids, comparative dosing between opioids, patient specific
conditions requiring lower starting doses, impact of concomitant medications
used in combination with opioids, and opioid monitoring. The assessment
tool was administered to 2000 practitioners; results indicated that lowest
scoring questions involved predictors of respiratory depression, defining the
opioid tolerant patients and drug interactions that can potentiate the effects
of opioids. The study findings suggest a greater need for education about
opioids among healthcare providers. The assessment tool can be found at:
http://www.patientsafetyauthority.org/EducationalTools/PatientSafetyTools/
opioids/Documents/assessment.pdf (Pa Patient Saf Advis 2013)
European Medicines Agency (EMA) Recommended Precautions with
Diclofenac. The EMA's Pharmacovigilance Risk Assessment Committee
(PRAC) concluded that diclofenac, particularly in high doses (e.g, 150 mg/
day) and in longterm treatment, has similar cardiovascular risk as selective
COX-2 inhibitors after reviewing data generated by independent academic
research, including one called The Safety of Non-Steroidal Anti-Inflammatory
Drugs (SOS), set up and funded by the European Commission's 7th Framework
Programme in 2012. The agency recommended precautions to minimize the
risk for arterial thrombotic events: a) patients who have serious underlying
cardiovascular diseases, such as heart failure, heart disease, circulatory
problems, previous heart attack or stroke, should not use diclofenac b) patients
with certain cardiovascular risk factors (e.g, hypertension, hyperlipidemia,
diabetes or smoking) should only use diclofenac after careful consideration.
Healthcare professionals were advised to periodically re-assess the need for
patients to continue taking the medicine. PRAC concluded that the benefits of
diclofenac still outweigh the risks. (European Medicines Agency June 2013)
D r u g
S a f e ty
Q u a r t e r ly
Fostamatinib Drug Development Halted. Astra-Zeneca announced it
would not pursue regulatory approval for the Syk-kinase inhibitor fostamatinib.
Although early trials showed promise, subsequent randomized clinical trials
failed to show competitive improvements in ACR20 response rates for
patients participating in the OSKIRA-2 (DMARD incomplete responders) and
the OSKIRA-3 (TNF inhibitor partial responder) trials. The toxicity profile was
consistent across several studies with diarrhea, hypertension, headache and
URI as the most common events reported. Astra Zeneca will return drug rights
to Rigel Pharmaceuticals (who originally developed the compound) for further
consideration. (NASDAQ.com June 2013).
Tofacitinib Application Denied by EMA. In April Pfizer announced that
its application for regulatory approval of Xeljanz (tofacitinib) was negatively
viewed by the European Medicines Agency (EMA) Committee for Medicinal
Products for Human Use (CHMP). CHMP noted concerns regarding safety
(serious infections, GI performations, lipid elevations, certain malignancies)
and the consistency of reductions in disease activity and structural damage
– especially for the 5 mg dose proposed. The EMA re-examined this decision
and on July 25, 2013 confirmed the refusal of the marketing authorization
of tofacitinib, stating its major concerns were over safety issues. (European
Medicines Agency July 26, 2013)
FDA Allows Updates of Generic Drug Warnings. Two years ago the
Supreme Court ruled that inadequate labeling of a generic drug was not just
cause for a lawsuit against the maker. Branded drugs are liable if the product's
safety label is inadequate. Given the regulatory gap, the watchdog group,
Public Citizen had lobbied for making generic and brand-name producers
equally responsible for updating safety labeling. Under current rules, brandname makers can update safety labels without FDA approval, while generics
are restricted from this activity unless certain criteria are met, such as when
ordered by the FDA or if the brand name equivalent has already made similar
changes. However, 434 generic drugs have no comparable brand-name
product, and 80% of prescriptions filled in the U.S. were for generic drugs
according to Public Citizen. The FDA announced in July 2013 that generic
drug manufacturers now have permission and responsibility to change safety
labels when new potential risks are uncovered. (USA Today July 2013)
Drug Safety Information for Pregnant Consumers Hard to Find. Women
often use the Internet to find answers related to medication safety during
their pregnancy, but a new study conducted by the Centers for Disease
Control and Prevention (CDC) examining 25 pregnancy related websites found
discrepancies in lists that were supposedly safe. Twenty-two products called
safe by one site were deemed risky by another. In addition, there was lack
of evidence to support the safety claims for 40% of drugs. The CDC noted
that medication use has increased 60% in the last 3 decades during the 1st
trimester, a time when developing fetal organs have the greatest vulnerability
for birth defects. The CDC is initiating a "Treating for Two" program to improve
pregnancy drug safety information; the FDA will also revamp prescription
drug labels with updated information on pregnancy and will tighten control
on drugs that pose pregnancy risks. Several barriers to accurate information
exist. Drug manufacturers shy from studying pregnant women, hence, safety
data can take years to accumulate; in addition, 1 in 33 babies will have some
type of birth abnormalities regardless of medication use. Unfortunately,
Clinicians and patients will have to balance risk to the mother for not taking
the medication vs. risk to the fetus off of medications given the limited
available data. (Associated Press Mar 2013)
Sleep Aids Will Have to Demonstrate Safety with Next Day Driving.
The FDA had taken interest in how safely sleep aids will allow people to
wake up. The effects of common sleep aids can last into the next day, and of
concern is how safely people can drive the next morning. The FDA recently
rejected an application by Merck for the new sleep drug, suvorexant, because
Continued on next page
drug safety quarterly
IN THE NEWS: Fall 2013 continued from previous page
tests showed that some people had trouble driving the next day. In May 2013
the agency warned patients taking common allergy drugs like Benadryl not to
drive, and in January, the FDA posted warnings that zolpidem dose should be
reduced by half in women. They are now taking a closer look at all sleep aids
on the market and will ask manufacturers to conduct extensive driving tests
for new sleep drugs and any drug that can cause drowsiness. Sixty million
prescriptions for sleep aids were distributed last year, almost 5% of daytime
drivers tested positive for prescription or over the counter drugs that can
impair attention. (New York Times Aug 13, 2013)
Quick Drug Approvals Do Not Impact Safety. In a new research study
published in Canadian Health Policy, data about the number of drug safety
Vol. 4 (3)
Fall 2013
warnings issued by regulators in Canada and U.S. were compared to number of
discontinuation of new drugs related to safety concerns. In the analysis, 454 new
drugs were approved in Canada and U.S. over a 20 year period (1992-2011); new
drug approval times were faster in the U.S. but were not linked to an increased in
issuance of regulatory safety warnings or withdrawal of drug. In addition, rates
of discontinuation were lower for expedited approval drugs than for standard
products, opposite of what would be expected if faster approvals led to more
dangerous drugs approved. The study strongly suggests that changes in the
regulatory behavior of drug approval agencies offer a better explanation for
the increased number of serious warnings than from expedited drug approval.
(Drug Discovery and Development 8/15/13) D S Q
Safety Signals: September 2013
Trends in the use of aspirin and nonsteroidal anti-inflammatory drugs
in the general U.S. population. Zhou Y, et al. Pharmacoepidemiol Drug Saf.
2013 May 30. [Epub ahead of print] PMID: 23723142. National Health Interview
Survey (NHIS) showed an increase in regular aspirin use to 43 million US adults
(19.0%) and NSAIDs to more than 29 million adults (12.1%), representing a
57% and 41% increase use (respectively) from 2005 to 2010.
GI-REASONS: a novel 6-month, prospective, randomized, open-label,
blinded endpoint (PROBE) trial. Cryer B, et al. Am J Gastroenterol. 2013;108:392400. PMID: 23399552. Prospective, open-label trial of 8,067 adults requiring
NSAIDs for OA demonstrated fewer clinically significant upper and/or lower
GI events in patients taking celecoxib (1.3%) versus nonselective-NSAIDS
(2.4%) (P= 0.0003).
Vascular and upper gastrointestinal effects of non-steroidal antiinflammatory drugs: meta-analyses of individual participant data from
randomised trials. Lancet 2013 May 29. [Epub ahead of print] PMID: 23726390.
Metanalyses of 754 clinical trials and 353,809 patients demonstrated that all
NSAIDs increased the risk of upper gastrointestinal complications and heart
failure. Compared to placebo, of 1000 patients treated with a coxib or diclofenac
(but not naproxen) for one year, three more had major cardiovascular events
(including one fatal). Vascular death was increased significantly by coxibs and
diclofenac, but not by ibuprofen or naproxen.
Nonsteroidal anti-inflammatory drugs and risk of cardiovascular
disease in patients with rheumatoid arthritis: a nationwide cohort
study. Lindhardsen J, et al. Ann Rheum Dis. 2013 Jun 8 [Epub]. PMID: 23749610.
Cardiovascular events were lower in RA patients receiving NSAIDs (compared
with non-RA on NSAIDS) in a Danish national registry of 17320 RA patients
and 69280 matched controls. However, higher CV event rates were seen with
rofecoxib and diclofenac.
Statin toxicity from macrolide antibiotic coprescription: a populationbased cohort study. Patel AM, et al. Ann Intern Med 2013; 158(12):869-76.
PMID: 23778904. Augmented statin toxicity is seen when elderly patients take
clarithromycin or erythromycin (but not azithromycin) with a statins metabolized
by CYP3A4. More hospitalizations for rhabdomyolysis, acute renal injury and
all-cause mortality were seen.
The risk of gastrointestinal perforations in patients with rheumatoid
arthritis treated with anti-TNF therapy: results from the BSRBR-RA.
Závada J, et al. Ann Rheum Dis. [Epub ahead of print]. PMID: 23644671.
Gastrointestinal perforations (GIP) were not increased in TNF inhibitor treated
RA (n=11881) patients in the British Society for Rheumatology Biologics Register.
However, steroids were shown to be a major risk factor for lower GIP (HR 8.0,
95% CI 2.6 to 24.1).
Use of glucosamine and chondroitin supplements and risk of colorectal
cancer. Kantor ED, et al. Cancer Causes Control, 2013; 24:1137-46. PMID:
23529472. Using surveys on supplement use in 75,137 Washington state residents
aged 50-76 yrs, the use of glucosamine + chondroitin on 4+ days/week for >3
years was associated with a trend towards a lower risk of colorectal cancer
(HR: 0.55; 95 % CI 0.30-1.01). The use of glucosamine alone was not protective.
Is cancer associated with polymyalgia rheumatica? A cohort study
in the General Practice Research Database. Muller S, et al. Ann Rheum
Dis Jul 2013, [Epub] PMID:23842460. The incident risk of cancer was shown
to be increased in PMR patients treated with corticosteroids only in the first
6 months after diagnosis; with an adjusted HR of 1.69 (95% CI 1.18 to 2.42).
Nonsteroidal antiinflammatory drugs in late pregnancy and persistent
pulmonary hypertension of the newborn. Van Marter LJ, et al. Pediatrics
2013;131:79-87. PMID: 23209104. A case controlled study of 377 women showed
no association between 3rd trimester exposure to NSAIDs and persistent
neonatal pulmonary hypertension of the newborn.
Clinical risk factors for adverse events in allopurinol users. Ryu HJ, et al.
J Clin Pharmacol 2013;53:211-6. PMID: 23436266. Retrospective, case-controlled
study of allopurinol users showed allopurinol toxicity to be significantly higher
in patients with chronic renal disease, hypertension, lower LFT levels, higher
cholesterol levels, and the use of angiotensin receptor blockers, colchicine or
statin drugs.
Primary care attitudes to methotrexate monitoring. Byng-Maddick R, et al.
Qual Primary Care 2012;20:443-7. PMID: 23540824. In a UK survey of general
practitioners about MTX use, 36/81 practices responded and showed that MTX
use occurred in 1/743 practice patients. All GPs wrote MTX prescriptions, but
only 77.4% monitored MTX. Roughly half were aware of local and national
guidelines and one-third claimed to not need further education on MTX use.
Non-viral opportunistic infections in new users of tumour necrosis
factor inhibitor therapy: results of the SAfety Assessment of Biologic
ThERapy (SABER) Study. Baddley JW, et al. Ann Rheum Dis. 2013 Jul 13. [Epub
ahead of print] PMID: 23852763. Using several administrative claims databases
and 33,324 new TNFI users - 80 non-viral opportunistic infections were found
with pneumocystosis (n=16) as the most common. Overall non-viral OI were
slightly increased by corticosteroids and new TNFI use, especially infliximab.
Improvement in safety monitoring of biologic response modifiers after the
implementation of clinical care guidelines by a specialty. Hanson RL, J
Manage Care Pharm 2013;19:49-67. PMID: 23383700. As standardized guidelines
for the monitoring of BRMs have not been established, the University of Illinois
developed multidisciplinary Clinical Care Guidelines for BRMs, which included
prebiologic TB test, HBsAg, LFTs, CBC, vaccination review and update, cancer
risk assessment, pregnancy testing, review of contraindications, concomitant
disease state risk assessment and patient education. Four of these (TB, HBsAg,
LFT, and CBC) were studied retrospectively and prospectively. Compliance rates
were studied in 2 different groups and rose significantly (52% →83% and 23%
→50%) from pre- to post-implementation. D S Q
an online publication of the ACR Drug Safety Committee
7
DSQ
Letter to the Editors
continued from page 1
were back pain, extremity pain and arthralgia. There were 12 reports of
anaphylaxis found - but not adjudicated, and outcomes and relatedness are
unknown. In response to these issues Amgen cited that anaphylaxis occurred
rarely, between 0.01-0.1% of people who received the drug, with no deaths
as of Nov 2012. As these are voluntary postmarketing reports, the incidence
Safety of Anti-Osteoporosis Medications
and prevalence of severe allergic reaction is unclear. Healthcare professionals
and patients are encouraged by the FDA to report adverse events or side effects
related to this and other drugs to the FDA's MedWatch Safety Information and
Adverse Event Reporting Program: www.fda.gov/MedWatch/report.htm
--DSQ Editors D S Q
continued from page 4
Intolerance and rare serious side effects occur in patients receiving osteoporosis
drugs. However, in patients at high risk for fracture, the risk to benefit ratio for
most therapies is very favorable, especially during the first 3-5 years of treatment.
DSQ
References
1. Institute of Medicine. Dietary reference intakes for calcium and vitamin D. http://www.iom.edu/
Reports/2010/Dietary-Reference-Intakes-for-calcium-and-vitamin-D.aspx Accessed August 20, 2013.
2. Evista® Prescribing Information. 2012.
3. Forteo® Prescribing Information. 2012.
4. Saag, K.G., et al. Effects of teriparatide versus alendronate for treating glucocorticoid-induced
osteoporosis: thirty-six-month results of a randomized, double-blind, controlled trial. Arthritis
Rheum. 2009, 60(11): p. 3346-55. PMID: 19877063
5. Cummings, S.R. et al., Denosumab for prevention of fractures in postmenopausal women with
osteoporosis. N Engl J Med. 2009. 361(8): p.756-65. PMID: 19671655
6. Watts, N.B., et al., Infections in postmenopausal women with osteoporosis treated with
denosumab or placebo: coincidence or causal association? Osteoporos Int. 2012. 23(1): p. 327-37.
PMID: 21892677
7. Cohen, S.B., et al., Denosumab treatment effects on structural damage, bone mineral density,
and bone turnover in rheumatoid arthritis: a twelve-month, multicenter, randomized, double-blind,
placebo-controlled, phase II clinical trial. Arthritis Rheum. 2008; 58(5): 1299-309. PMID: 18438830
8. McClung, M. et al., Bisphosphonate therapy for osteoporosis: benefits, risks, and drug holiday. Am J
Med. 2013. 126(1): p.13-20. PMID: 23177553
9. Green, J. et al., Oral bisphosphonates and risk of cancer of oesophagus, stomach, and colorectum:
case-control analysis within a UK primary care cohort. BMJ. 2010 Sep 1;341:c4444. PMID: 20813820
10. Vinogradova,Y., C. Coupland, J. Hippisley-Cox, Exposure to bisphosphonates and risk of common
non-gastrointestinal cancers: series of nested case-control studies using two primary-care
databases. Br J Cancer. 2013. 109(3): p. 795-806. PMID: 23868009
11. European Medicines Agency. Recommendation to Restrict the Use of Protelos/Osseor (strontium
ranelate).http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2013/04/
WC500142507.pdf Accessed August 20, 2013.
Update on Drug Shortages
Drug Shortage
8
Reason for shortage
Estimated Availability
Acyclovir IV
Manufacturing delays (note that oral acyclovir caps and tabs are now available)
Unknown
Aspirin Tablets (Buffered) 325 mg
Novartis voluntarily recalled and suspended manufacturing of multiple drugs at the Lincoln facility; 2
other manufacturers discontinued the product
Unknown
Bupivicaine HCl inj 0.25% (10, 20, 30, 50 mL)
Demand exceeded supply
Aug 2013
Cortisone Acetate Tabs
Manufacturing delays- note conversion to prednisone is 5:1 (e.g, 25 mg cortisone is 5 mg prednisone)
Oct 2013
Cyanocobalamin Inj 1000 mcg/mL, 1 mL
Manufacturing delays, increase demand
Unknown
Dexamethasone 4mg/mL (1, 5, 30 mL)
American Regent: voluntary recall due to particulate matter found in vials
Aug 2013
Doxycycline (50, 75 , 100, 150 mg)
Raw material shortage
Unknown
Epinephrine Inj 1 mg/mL (1, 10, 30 mL)
Manufacturing delays, increased demand
Unknown
Furosemide Inj
Increased demand and manufacturing delays
Aug 2013
Heparin Inj
FDA issued import bans against Chinese mfg due to inadequate manufacturing
Unknown
practices
Aug 2013
Aug 2013
Hydrocortisone 100 mg/2mL, 250 mg/2mL,
500 mg, 1000 mg
Increased demand
2014
Indomethacin Inj (lyophilized powder)
Nationwide backorder due to manufacturing issues
Aug 2013
Isoniazid tab (100, 300 mg)
Unknown
Sept 2013
Ketorolac Inj
Increase demand
Unknown
Leucovorin Calcium Inj 50, 100, 200, 350 mg
Manufacturing delays, increased demand. Note that leucovorin tablets are not affected
Unknown
Lidocaine (with and without Epi) 0.5%, 1%,
1.5%, 2%
Raw material shortage
2014
Mercaptopurine 50 mg
Increased demand
Unknown
Continued on next page
D r u g
S a f e ty
Q u a r t e r ly
drug safety quarterly
Update on Drug Shortages
Vol. 4 (3)
Fall 2013
continued from previous page
Drug Shortage
Reason for shortage
Estimated Availability
Mesna Inj
Manufacturing delays and increase demands
Unknown
Methotrexate Inj 25 mg/mL (2,4,8,10,40 mL
vials) AND
Manufacturing delays
MTX Inj - Unknown
tablets 2.5 mg
Manufacturing delays
MTX Inj - Unknown
MTX tabs – Aug 2013
NECC closed manufacturing site due to fungal meningitis outbreak related to
MTX Inj - Unknown MTX
tabs – June 2013
Methylprednisolone Inj 40 mg, 80 mg (1, 5,
10 mL vials)
NECC closed manufacturing site due to fungal meningitis outbreak related to
Product released as it
intrathecal use
Product released as it
Revised: Unknown
becomes available
Watson noted supply constraints, Teval discontinued product
Aug 2013
Morphine sulfate inj
Watson noted supply constraints, Teval discontinued product
Aug 2013
Nitroglycerin 2% ointment
Unknown
Unknown
Ondansetron Inj 2mg/mL
Manufacturing delays, increased demand
Oct 2013
Pantoprazole Tabs (20,40 mg)
Increased demand
Aug 2013
Prednisone 1, 5, 10, 20 mg tab
Raw materials shortage
Aug 2013
Promethazine Inj 25 mg/mL, 50 mg/mL
Increase demand, temporary suspension of mfg by Bedford
Unknown
Tetracycline caps 250 mg, 500 mg
Manufacturing delays, increase demand
Unknown
Tuberculin PPD, intradermal inj
Increase demand, low supply
Unknown
9
Resolved Drug Shortages
Acyclovir Tabs/Caps
Diphenhydramin Inj
Ibandronate sodium Inj (Boniva IV)
Meperidine Injx
Rifampin and Isoniazid Combination Tab (300/150)
DSQ
EDITORS:
Kathryn H. Dao, MD, Co-Editor
John J. Cush, MD: Clinical investigator for Genentech, Pfizer, UCB,
Celgene, CORRONA, Novartis; consultant to Centocor, UCB, Wyeth,
Amgen, Roche, BMS, Savient, Abbvie.
Catalina Orozco, MD, Co-Editor
Drs. Cush and Dao are with Baylor Research Institute – Dallas, TX.
Dr. Orozco is with Rheumatology Associates – Dallas, TX.
Susan M. Goodman, MD: None
John J. Cush, MD, Co-Editor
DISCLOSURES:
Miguel Perez-Aso, PhD: None
Bruce N. Cronstein, MD: holds patents on use of adenosine
A2A receptor agonists to promote wound healing and use of A2A
receptor antagonists to inhibit fibrosis, use of adenosine A1 receptor
antagonists to treat osteoporosis and other diseases of bone, use
of adenosine A1 and A2B Receptor antagonists to treat fatty liver
and use of adenosine A2A receptor agonists to prevent prosthesis
loosening. Bruce N. Cronstein is consultant for Bristol-Myers
Squibb, Novartis, CanFite Biopharmaceuticals, Cypress Laboratories,
Regeneron (Westat, DSMB), Endocyte, Protalex, Allos, Inc., Savient,
Gismo Therapeutics, Antares Pharmaceutical and Medivector.
Kathryn Dao, MD: Investigator: for Amgen, UCB, Celgene, Pfizer,
Novartis, Merck
Michael R.McClung, MD: Clinical investigator for Amgen and
Merck; Consultant and/or speaker for Amgen, GSK, Lilly, Merck,
Novartis and Warner-Chilcott.
Catalina Orozco, MD: Sub-investigator for: Abbvie, Amgen,
Amplimmune, Astellas, Astra Zeneca, Biogen, Celgene, Conversant,
Dynavax, Genzyme, Ignyta, Janssen, Lilly, Medimmune, Merck,
Nektar, Nodality, Novartis, Pfizer, Resolve, Rigel, Roche, Sanofi,
UCB, Xoma.
Drug Safety Quarterly is provided as a service to members from
the ACR Drug Safety Committee, and is committed to providing
news, insight and critical review of safety issues germane to
anti-rheumatic therapy and rheumatologic care. The information and
views contained herein represent those of the DSQ authors/editors,
and does not represent guidelines, official positions or statements
from the ACR.
The ACR is an independent professional medical and scientific
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© 2013 American College of Rheumatology – No part of this publication can be reproduced without the written permission of the ACR.