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Appendix 11:\
Expert Panel Recommendation for the Prevention,\
Diagnosis and Treatment of Osteonecrosis of the Jaw

Zometa^®^ (zoledronic acid) Injection

and

Aredia^®^ (pamidronate disodium) Injection

Submitted: February 1, 2005

Oncologic Drugs Advisory Committee Meeting

March 4, 2005

Property of Novartis Pharmaceuticals Corporation\
All rights reserved\
**Available for public disclosure without redaction**

Background

Osteonecrosis of the jaws is a rare potential complication in cancer
patients receiving radiation, chemotherapy, or other cancer treatment
regimens, or in patients with tumors/infectious embolic events.

Recently, there have been reports of osteonecrosis of the jaws in cancer
patients receiving concomitantanticancer therapy (chemotherapy, steroid
therapy, or head and neck radiotherapy) and an intravenous (IV)
bisphosphonate (Marx 2003, Migliorati 2003, Ruggiero 2004). There are
multiple recognized conditions and risk factors associated with the
development of osteonecrosis (not limited to the jaws) in cancer
patients. These factors include trauma, female sex, advanced age,
edentulous regions, combination cancer therapy (eg, head and neck
radiotherapy, chemotherapy, or steroid therapy), blood
dyscrasias/metastatic disease, anemia, coagulopathy, surgical dental
procedures, alcohol or tobacco use, and prior infection. In the cases
reported to date, the majority of patients were receiving long-term
hemotherapy and many were receiving short-term intermittent steroid
therapy with concomitant bisphosphonate therapy for their cancer and
symptom management. In the majority of cases, patients could be managed
in a pain-free state with continued exposed bone using anonsurgical
approach consisting of oral systemic antibiotics and 0.12% chlorhexidine
gluconate antisepticcontaining oral rinses. Surgical intervention was
counterproductive and often produced further exposed bone.
Bisphosphonates and other cancer therapies were continued in the
majority of patients. A causal relationship between bisphosphonate
therapy and osteonecrosis of the jaws has not been established. However,
to better understand the pathogenesis of and management of patients with
osteonecrosis of the jaws, a panel of experts\* representing oral
surgery, oral edicine/oral oncology, endocrinology, and medical oncology
convened recently to discuss identification of risk factors for
osteonecrosis of the jaws, and to develop clinical guidelines for
prevention, early diagnosis, management, and multidisciplinary treatment
of osteonecrosis of the jaws in patients with cancer. Additionally, the
panel developed recommendations to reduce the incidence of osteonecrosis
of the jaws in cancer patients receiving bisphosphonate therapy as well
as for patients with clinical osteonecrosis of the jaws who are already
receiving bisphosphonates and may require oral surgery. The panel's
recommendations are presented here to help guide physicians in patient
management.

Clinical presentation and diagnosis of osteonecrosis of the jaws

-   Osteonecrosis of the jaws may remain asymptomatic for many weeks or
    months and may only be recognized by the presence of the exposed
    bone in the oral cavity. These lesions are most frequently
    symptomatic when sites become secondarily infected or there is
    trauma to the soft tissues via the sharp edges of the exposed bone.

-   Typical signs and symptoms include pain, soft-tissue swelling and
    infection, loosening of teeth, drainage,

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-   Osteonecrosis of the jaws may remain asymptomatic for many weeks or
    months and may only be recognized by the presence of the exposed
    bone in the oral cavity. These lesions are most frequently
    symptomatic when sites become secondarily infected or there is
    trauma to the soft-tissues via the sharp edges of the exposed bone
    and exposed bone, which may occur spontaneously or, more commonly,
    at the site of previous tooth extraction. Some patients may present
    with atypical complaints, such as "numbness," the feeling of a
    "heavy jaw," and various dysesthesias

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-   Signs and symptoms that may occur before the development of clinical
    osteonecrosis include a sudden change in the health of periodontal
    or mucosal tissues, failure of the oral mucosa to heal, undiagnosed
    oral pain, loose teeth, or soft-tissue infection

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-   If osteonecrosis is suspected, panoramic and tomographic imaging may
    be performed to rule out other etiologies (eg, cysts or impacted
    teeth). Smaller intraoral films can also be used to demonstrate
    subtle bone changes.

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-   Microbial cultures may provide a differential diagnosis for comorbid
    oral infections.

Tissue biopsy should be performed only if metastatic disease is
suspected. If a biopsy is performed to rule out metastatic tumor,
microbial cultures (aerobic and anaerobic) may provide identification of
the pathogens causing secondary infections (Note: actinomyces organisms
are often seen microscopically or identified upon culture)

Potential risk factors for the development of osteonecrosis of the jaws

-   The precise risk factors for osteonecrosis of the jaws have not been
    identified. Risk factors may include

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-   Concomitant therapy with steroids, chemotherapy, and IV
    bisphosphonates (in few instances aftershort dosing)

-   Dental extraction, infectious disease, and/or trauma

-   Occasionally the concomitant risk factors may not be apparent

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-   Other risk factors that have been previously identified for
    osteonecrosis (not limited to the jaws) include

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-   Head and neck radiotherapy, chemotherapy, immunotherapy, or other
    cancer treatment regimens

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-   Female gender, coagulopathies, infections, periodontal disease, bony
    exostosis, previous invasive dental procedures, dental prostheses,
    arthritis, blood dyscrasias, vascular disorders, alcohol abuse,
    smoking, and malnutrition. Controversially, anesthetics with
    vasoconstrictors (ie, novocaine) have been reported as potentially
    contributing to some cases of osteonecrosis

Potential preventive measures prior to the initiation of IV
bisphosphonate therapy

-   Avoid any elective jaw procedure that will require bone to heal

-   Recommend a routine clinical dental exam that may include a
    panoramic jaw radiograph to detect potential dental and periodontal
    infections.

-   If bisphosphonate therapy can be briefly delayed without the risk of
    a skeletal-related complication, teeth with a poor prognosis or in
    need of extraction should be extracted and other dental surgeries
    should be completed prior to the initiation of bisphosphonate
    therapy. The benefit or risk of withholding bisphosphonate therapy
    has not been evaluated to date. Therefore, the decision to

-   withhold bisphosphonate treatment must be made by the treating
    oncologist in consultation with an oral maxillofacial surgeon or
    another dental specialist

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-   Suggested preventive dentistry before initiation of chemotherapy,
    immunotherapy, and/or bisphosphonate therapy may include:

1.  Remove abscessed and nonrestorable teeth and involved periodontal
    tissues.

2.  Functional rehabilitation of salvageable dentition, including
    endodontic therapy.

3.  Dental prophylaxis, caries control, and stabilizing restorative
    dental care.

4.  Examine dentures to ensure proper fit (remove dentures at night)

5.  Oral self-care hygiene education.

6.  Prophylactic antibiotics are not indicated before routine dentistry
    unless otherwise required for prophylaxis of bacteremia in those
    patients at risk (eg, those with an indwelling catheter).

-   Educate patients regarding the importance of good dental hygiene and
    symptom reporting

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-   Suggest regularly scheduled hard- and soft-tissue oral assessments,
    possibly every 3 to 4 months, depending on risk

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-   Oncologists should perform a brief visual inspection of the oral
    cavity at baseline and at every follow-up visit.

Dental treatment for patients currently receiving bisphosphonate therapy

-   Maintain excellent oral hygiene to reduce the risk of dental and
    periodontal infections

-   Check and adjust removable dentures for potential soft-tissue
    injury, especially tissue overlying bone.

-   Perform routine dental cleanings, being sure to avoid soft-tissue
    injury

-   Aggressively manage dental infections nonsurgically with root canal
    treatment if possible or with minimal surgical intervention.

-   Endodontic (root canal) therapy is preferable to extractions when
    possible. It may be necessary to carry out coronal amputation with
    subsequent root canal therapy on retained roots to avoid the need
    for tooth extraction and, therefore, the potential development of
    osteonecrosis.

Management of patients with osteonecrosis of the jaws

-   Consultation with an oral surgeon or dental oncologist

-   A nonsurgical approach may prevent further osseous injury

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-   Minimal bony debridement only to reduce sharp edges so as to reduce
    trauma to surrounding or opposing tissues (eg, lateral tongue where
    lingual mandibular bone is exposed)

-   A removable appliance may be used to cover and protect the exposed
    bone

-   A protective stint may be of benefit for patients with exposed bone
    that causes trauma to adjacent tissues and in patients where the
    osteonecrotic site is repeatedly traumatized during normal oral
    function. A thin, vinyl, vacuformed mouth guard or thin acrylic
    stint may be used, provided that the device does not further
    traumatize the osteonecrotic site and that it can be kept free of
    bacterial plaque and debris

-   Biopsy should be performed only if metastasis to the jaw is
    suspected. A portion of the biopsy should be submitted for microbial
    analysis as well as culture from the biopsy site.

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-   Intermittent or continuous antibiotic therapy may be beneficial
    (cultures should be collected to determine the appropriate
    antibiotic therapy). The goal of antibiotic therapy is to prevent
    secondary soft-tissue infection and, therefore, pain as well as to
    prevent osteomyelitis. At this time, the duration of antibiotic
    therapy and the benefit of oral antiseptic rinses have not been
    defined, but pain control and disease control have been observed
    with this management strategy. The decision to treat with an
    antibiotic is a clinical judgment that should be made by an oral
    maxillofacial surgeon or other dental specialist in consultation
    with the treating physician/oncologist. Cultures, including those
    for aerobic, anaerobic, viral, and fungal species, may be collected
    to determine the appropriate antimicrobial intervention Antibiotics
    that have been found useful for osteonecrosis include

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-   Penicillin VK 500 mg or amoxicillin 500 mg; both 4 times daily (QID)
    initially and twice daily (BID) for maintenance

-   If penicillin allergic:

1.  Clindamycin 150 to 300 mg QID

2.  Vibramycin 100 mg once daily (QD)

3.  Erythromycin ethylsuccinate 400 mg 3 times daily (TID)

4.  Antifungals when required:

5.  Nystatin oral suspension 5 to 15 mL QID or 100,000 IU/mL

6.  Mycelex troches (clotrimazole 10 mg) × 5/day

7.  Fluconazole 200 mg initially, then 100 mg QD

8.  Other potential systemic antifungals include itraconazole or
    ketoconazole

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9.  Antivirals, if required:

10. Acyclovir 400 mg BID

11. Valacyclovir hydrochloride 500 mg to 2 g BID

-   Suggested preventive dentistry before initiation of chemotherapy,
    immunotherapy, and/or bisphosphonate therapy may include

-   0.12% chlorhexidine gluconate (Peridex^®^) oral rinses or
    minocycline hydrochloride (Arestin^®^) periodontal pockets can be
    used

-   Dentures can be worn, but should be adjusted to minimize soft-tissue
    trauma or irritation, especially in light of ongoing antibiotic
    therapy, and should be removed at night.

-   All patients should be monitored every 3 months or sooner if
    symptoms continue or worsen.

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-   Cessation or interruption of bisphosphonate therapy may be
    considered in severe cases. However, close coordination between the
    dental specialist and the medical oncologist is recommended, taking
    into consideration the risk of skeletal complications (including
    hypercalcemia of malignancy) versus the risk of osteonecrosis. To
    date, cessation of bisphosphonate therapy appears to have no effect
    on established osteonecrosis. However, further study is needed.

-   If surgery is required in patients with established osteonecrosis,
    cessation or interruption of bisphosphonate therapy may be
    considered taking into account the potential risk of further
    osteonecrosis versus the risk of skeletal complications or
    hypercalcemia of malignancy. It is unknown whether or not there is
    benefit to cessation of bisphosphonate therapy. However, cessation
    of bisphosphonate therapy may be prudent in some patients if the
    risk of osteonecrosis outweighs the risk of skeletal complications
    or hypercalcemia of malignancy. Therefore, the decision to stop
    bisphosphonate therapy must be coordinated between the treating
    oncologist and an oral surgeon. Antibiotics following dental surgery
    may be appropriate in this patient population and should be
    continued postoperatively for at least 10 days. However, this is a
    clinical judgment that must be made in collaboration with the
    treating oncologist. Cultures taken from the extraction site at the
    time of oral surgery can provide guidance in making this decision.

-   Hyperbaric oxygen has not been shown to be effective and, therefore,
    is not recommended.

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-   Osseointegrated dental implants are contraindicated and may result
    in further osteonecrosis

References

Marx RE (2003) Pamidronate (Aredia) and zoledronate (Zometa) induced
avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac
Surg; 61:1115-1117.

Migliorati CA (2003) Bisphosphonates and oral cavity avascular bone
necrosis. J Clin Oncol; 21:4253-4254.

Ruggiero SL, Mehrotra B, Rosenberg TJ, et al (2004) Osteonecrosis of the
jaws associated with the use of bisphosphonates: a review of 63 cases. J
Oral Maxillofac Surg; 62:527-534.

\* The expert panel representatives were as follows: **Kathryn Damato,
RDH, MS, CCRP**, University of Connecticut Health Center, Farmington,
Conn; **Julie Gralow, MD**, University of Washington Medical Center,
Seattle, Wash; **Ana Hoff, MD**, University of Texas MD Anderson Cancer
Center, Houston, Tex; **Joseph Huryn, DDS**, Memorial Sloan-Kettering
Cancer Center, New York, NY; **Robert Marx, DDS**, University of Miami
School of Medicine, Miami, Fla; **Salvatore Ruggiero, DMD, MD**, Long
Island Jewish Medical Center, New Hyde Park, NY; **Mark Schubert, DDS,
MDS**, Seattle Cancer Care Alliance, Seattle, Wash; **Bela Toth, DDS,
MS**, University of Texas MD Anderson Cancer Center, Houston, Tex;
**Vicente Valero, MD, FACP**, The University of Texas MD Anderson Cancer
Center, Houston, Tex.