Reporting and Monitoring of Adverse Events of Cancer TreatmentRosalynn L. Pangan, RPhDepartment Manager for Pharmacy Dispensing & CompoundingSt. Luke’s Medical Center – Global City

Objectives

At the end of the presentation, the participant will be able to:▫Have a clear understanding of the

definition of adverse drug events;▫Value the importance of reporting

adverse events;▫Know common adverse events with

cancer treatment; ▫Learn about the FDA Philippines

process of ADR reporting; and,▫Appreciate how to assess ADRs

Outline

• DEFINITION OF TERMS

• COMMON ADVERSE EVENTS WITH CANCER

TREATMENT

• ADR REPORTING PROGRAM IN THE PHILIPPINES

• ASSESSING ADRS

• INTEGRATION

Patient Case•49/F diagnosed with breast CA•Patient presented erythema and dysesthesia on the hands and heels after the 5th session of chemotherapy•HPI:

• Patient underwent mastectomy and two months after patient was started chemotherapy with docetaxel, adriamycin, cylophopshamide

• On the 4th chemo session, patient presented erythema and dysesthesia of the burning sensation type on the hands which improved in 2 weeks

•Treatment given: prednisone 0.2 mg/kg/day for 7 days, mometasone cream and moisturizer

Donati, A. And Castro LGM. Cutaneous adverse reactions to chemotherapy with taxanes. The dermatologist's point of view. An. Bras. Dermatol. vol.86 no.4 Rio de Janeiro July/Aug. 2011

•Did the patient experience an adverse event?

•Is it an ADR?

•Which is the most likely causative agent?

Definition of Terms (WHO)

Adverse Event (AE)

•Any untoward medical occurrence that may present during treatment with a pharmaceutical product but which does not necessarily have a causal relationship with this treatment

Synonym: Adverse experience

Adverse Drug Reaction (ADR)

• A response which is noxious and unintended, and which

occurs at doses normally used in humans for the

prophylaxis, diagnosis, or therapy of disease, or for the

modification of physiological function. (WHO, 1972).

• An adverse drug reaction, contrary to an adverse event, is

characterized by the suspicion of a causal

relationship between the drug and the occurrence,

i.e. judged as being at least possibly related to treatment

by the reporting or a reviewing health professional.

Serious Adverse Drug Reaction (ADR)

- any untoward medical occurrence that at

any dose:

results in death

requires inpatient hospitalisation or

prolongation of existing hospitalisation

results in persistent or significant

disability/incapacity

is life-threatening

Side Effect

•Any unintended effect of a

pharmaceutical product occurring at

normal dosage which is related to

the pharmacological properties of

the drug

Unexpected Adverse Reaction

•An adverse reaction, the nature or

severity of

which is not consistent with domestic

labelling

or market authorization, or expected from

characteristics of the drug

Common Adverse Events with Cancer Treatment

Common ADRs

• Alopecia• Nausea and vomiting• Myelosuppression• Haemorrhagic cystitis• Mucositis• Increased toxicity with

impaired renal function• Cardiac toxicity• Hot flushes• Electrolyte imbalance• Deep vein thrombosis

Beers, M.H. and Berko, R. 1999. The Merck Manual. 17th ed. USA. pp 990-993

ADRs identified in the RADAR Project and no. of reports contained in the database (1998-2007)

RADAR – RESEARCH ON ADVERSE DRUG EVENTS AND REPORTS

Chemotherapy-Induced Dermatological Toxicity

• Alopecia

• Hyperpigmentation

• Nail changes

• Palmar-plantar

erythrodysesthesia

• Extravasation

• Radiation reactionsCassagnol, M. Dermatologic Toxicities of Chemotherapeutic Agents. US Pharm 2008; 33(1):10-

18

Chemotherapy-Induced Dermatological Toxicity

Berger A, Karakunnel J. Adverse effects of treatment. In: DeVita V, Hellman S, Rosenberg S, eds. Cancer: Principles & Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams &

Wilkins; 2005:2556. line B. Prevention of chemotherapy-induced alopecia: a review of the literature. Cancer

Nurs. 1984;7:221-228.

Chemotherapy-Induced Dermatological Toxicity

Alley E, Green R, Schuchter L. Cutaneous toxicities of cancer therapy. Curr Opin Oncol. 2002;14:212-216.

Lindley C. Adverse effects of chemotherapy. In: Koda-Kimble MA, Young LY, Kradjan W, eds. Applied Therapeutics: The Clinical Use of Drugs. 8th ed. Philadelphia, PA: Lippincott

Williams & Wilkins; 2005.

Chemotherapy-Induced Dermatological Toxicity

Lindley C. Adverse effects of chemotherapy. In: Koda-Kimble MA, Young LY, Kradjan W, eds. Applied Therapeutics: The Clinical Use of Drugs. 8th ed. Philadelphia, PA: Lippincott

Williams & Wilkins; 2005.

Chemotherapy-Induced Nausea and Vomiting (CINV)

• Risk factors: ▫ Patient-related: age, sex▫ Drug-related chemotherapy dose, emetogenicity

Hesketh, PJ. Chemotherapy-Induced Nausea and Vomiting. N Engl J Med 2008; 358:2482-2494

Chemotherapy-Induced Peripheral NeuropathySymptoms Drugs linked to CPN• Pain (may be there all the time or come and go, like

shooting or stabbing pain) • Burning • Tingling (“pins and needles” feeling) or

electric/shock-like pain • Loss of feeling• Trouble using your fingers to pick up or hold things;

dropping things • Balance problems • Trouble with tripping or stumbling while walking • Pressure may hurt more than usual • Temperature may hurt more than usual (mostly

cold; this is called cold sensitivity) • Shrinking muscles • Muscle weakness • Trouble swallowing • Constipation • Trouble passing urine • Blood pressure changes • Decreased or no reflexes

• Platinum drugs like cisplatin, carboplatin, and oxaliplatin

• Taxanes including paclitaxel docetaxel and cabazitaxel

• Plant alkaloids, such as vinblastine, vincristine, vinorelbine, and etoposide (VP-16)

• Bortezomib• Eribulin

http://www.cancer.org/acs/groups/cid/documents/webcontent/002908-pdf.pdf

Importance of Monitoring and Reporting ADR

Why is there a need to Watch Out for ADRs?•44,000 to 98,000 deaths occur annually

from medical errors. Of this total, an estimated 7,000 deaths occur due to ADRs (IOM, Jan 2000)

•In a meta-analysis of 39 prospective studies from US hospitals, the overall incidence of serious ADRs was 6.7% and fatal ADRs was 0.32% of hospitalized patients

*Lazarou, J., Pomeranz, BH., Corey, PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies.JAMA. 1998 Apr 15;279(15):1200-5.

Misconceptions about ADR Reporting

• It is ALREADY DOCUMENTED

• It is DIFFICULT TO ESTABLISH CAUSAL RELATIONSHIP WITH THE DRUG

• Report ADRs IF ABSOLUTELY CERTAIN

• One case report CAN’T MAKE A DIFFERENCE

NOT ALL ARE DOCUMENTED

TEMPORAL RELATIONSHIP MAY BE USEFUL

ANY SUSPICION SHOULD BE REPORTED

ONE REPORT CAN MAKE A DIFFERENCE

1Figueiras A, Tato F, Fontainas J, Gestal-Otero JJ. Influence of physicians’ attitudes on reporting adverse drug events: a case-control study. Med Care 1999;37(8):809-814. 2Eland IA, Belton KJ, van Grootheest AC, Meiners AP, Rawlins MD, Stricker BH. Attitudinal survey of voluntary reporting of adverse drug reactions. Br J Clin Pharmacol 1999;48(4):623–627. 3Chyka PA, McCommon SW. Reporting of adverse drug reactions by poison control centres in the US. Drug Saf  2000;23(1):87–93.

ADR Monitoring Program in the Philippines

ADR Reporting System

www.fda.gov

ADR Reporting System

ADR Report Form

Submit on a quarterly basisSerious ADRs to be submitted within 48 hours

Assessing ADRs

REACTION TYPE

•Exaggerated pharmacological action

▫Exaggerated, but otherwise normal

pharmacological action of a drug given in the

usual therapeutic doses

•Unpredicted/unexpected reaction

▫not expected from the known pharmacological

actions of a drug given in usual therapeutic doses

SEVERITY

• 0 – Reaction required little or no treatment, no change in therapy, did

not require significant reduction in dosage or discontinuation of the drug

and did not cause harm or extend the stay in the facility

• 1 – Reaction caused no harm to the patient but required significant

reduction in dosage or discontinuation of the drug

• 2 – Reaction contributed or resulted in temporary harm to the patient

and required initial or prolonged hospitalization

• 3 – Reaction contributed to or resulted in permanent patient harm or

disability

• 4 – Reaction required intervention necessary to sustain life

• 5 – Reaction contributed to or resulted in the patient’s death

AVOIDABLE/PREVENTABLE

Likelihood of ADRs according to Edwards and Aronson• Certain

▫ Time frame of the reaction can be linked to the drug▫ Patient responds positively to the removal of the drug

• Probable▫ No rechallenge info is available

• Possible▫ Time frame is reasonably related to the administration

of the drug in question▫ Occurrence might also be the result of other drugs or

diseases• Unlikely

▫ Other chemicals, drugs, and diseases provide likely explanationsEdwards, IR, Aronso, JK. Adverse drug reactions: definitions, diagnosis and management. Uppsala Monitoring

Centre, WHO Collaborating Centre for International Drug Monitoring, Sweden. The Lancet (Impact Factor: 39.06). 11/2000; 356(9237):1255-9. DOI: 10.1016/S0140-6736(00)02799-9

PROBABILITY (NARANJO ALGORITHM)

Six Types of ADR (Edwards and Aronso, 2000)

• dose-related • non-dose-related

•dose-related and time-related

•time-related•withdrawal•failure of therapy

AugmentedBizarreChronic

DelayedEnd of useFailure

Edwards, IR, Aronso, JK. Adverse drug reactions: definitions, diagnosis and management. Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring, Sweden. The Lancet (Impact Factor: 39.06). 11/2000; 356(9237):1255-9. DOI: 10.1016/S0140-6736(00)02799-9

INTEGRATION

Patient Case•49/F diagnosed with breast CA•Patient presented erythema and dysesthesia on the hands and heels after the 5th session of chemotherapy•HPI:

• Patient underwent mastectomy and two months after patient was started chemotherapy with docetaxel, adriamycin, cylophosphamide

• On the 4th chemo session, patient presented erythema and dysesthesia of the burning sensation type on the hands which improved in 2 weeks

•Treatment given: prednisone 0.2 mg/kg/day for 7 days, mometasone cream and moisturizer

Donati, A. And Castro LGM. Cutaneous adverse reactions to chemotherapy with taxanes. The dermatologist's point of view. An. Bras. Dermatol. vol.86 no.4 Rio de Janeiro July/Aug. 2011

Accomplish the ADR Report Form

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Patient developed erythema and dysesthesia of burning sensation on the hands and heels after the 5th session of chemotherapy

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Details of ADR

Docetaxel

Suspect Drugs

Adriamycin

Cylophosphamide

Suspect Drug: Docetaxel

•ADR (based on lit): Neurosensory symptoms characterized by paresthesia, dysesthesia or pain including burning sensation) were reported in 49% of patients treated with docetaxel as a single agent for various tumor types and in 38% of patients treated for recurrent and/or metastatic SCCHN. Severe reactions were observed in less than 4% of the patients.

Source: Taxotere Package insert

Suspect Drug: Adriamycin/Doxorubicin

•Peripheral neurotoxicity in the form of local-regional sensory and/or motor disturbances have been reported in patients treated intra-arterially with doxorubicin, mostly in combination with cisplatin

Source: Cytoxan package insert

Suspect Drugs: Docetaxel, Adriamycin, Cyclophos-phamide

Slade, JH. Neurological Toxicities Associated with Cancer Chemotherapeutic Agents. US Pharm.2005;4(Onc suppl):3-18.

Management of ADR

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prednisone 0.2 mg/kg/day for 7 days, mometasone cream and moisturizer

ADR Assessment

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ADR Assessment

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ADR Assessment

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Pharmacy Dispensing & Compounding

THANK YOU!