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13.1.3 preparation and administration

Drug will be administered only to eligible patients under the supervision of the investigator or identified subinvestigator(s). Patients may be treated on an outpatient basis, if possible. The drug will be prepared under the supervision of a pharmacist, or appropriately qualified and trained personnel. The amount (in mg) of drug to be administered will be determined based on body surface area. Body surface area is to be calculated based on body weight using a standard calculation. The dose should be calculated on Day 1 of each cycle; the dose administered should remain the same throughout each cycle but should be recalculated at the start of the next cycle. If a patient experiences a notable change in weight within a cycle, as determined by an unscheduled weight assessment, then the patient's dose should be recalculated at that time based on clinical judgment. The appropriate amount of bortezomib will be drawn from the injection vial and administered as an IV push over 3 to 5 seconds followed by a standard saline flush or through a running IV line. Vials are for single-use administration. There must be at least 72 hours between each dose of bortezomib. 13.1.4 Product Destruction For commercially-labeled bortezomib for IND-exempt studies, please contact your Millennium Clinical Operations representative to arrange for return of study drug procedures. Any unused or expired bortezomib must be returned to Millennium. Be sure to document drug return on your drug accountability logs. 13.1.5 Potential Risks of Bortezomib To date, more than 436,000 patients have been treated with bortezomib in both clinical trials investigating its use in hematological malignancies and solid tumors, and in patients who were treated with commercially available bortezomib. Prescribing physicians and health care practitioners are referred to their locally approved product label for bortezomib regarding Indications and Usage, Contraindications, Warnings, and Precautions. The known anticipated risks of bortezomib therapy are presented in Table 11-1 and Table 11-2. These risks are grouped according to the combined frequency observed in an integrated analysis of AEs in sponsored clinical studies of single-agent bortezomib dosed at 1.3 mg/m2 twice weekly on a 21-day schedule, in patients with multiple myeloma and mantle cell lymphoma. 13.1.6 Precautions and Restrictions It is not known what effects bortezomib has on human pregnancy or development of the embryo or fetus. Therefore, female patients participating in this study should avoid becoming pregnant, and male patients should avoid impregnating a female partner. Nonsterilized female patients of reproductive age and male patients should use effective methods of contraception through defined periods during and after study treatment as specified below. Female patients must meet 1 of the following:  
Postmenopausal for at least 1 year before the screening visit, or Surgically sterile, or If they are of childbearing potential, agree to practice 2 effective methods of contraception from the time of signing the informed consent form through 30 days after the last dose of bortezomib, or agree to completely abstain from heterosexual intercourse.  
| Highly effective methods                                                                                                                         | Other effective methods (barrier methods)     |
|--------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------|
| Intra-uterine devices (IUD)                                                                                                                      | Latex condom                                  |
| Hormonal contraceptives (birth control pills/oral  contraceptives, injectable contraceptives,  contraceptive patches, or contraceptive implants) | Diaphragm with spermicide Cervical cap Sponge |
| If one of the highly effective methods cannot be used, using 2 effective methods at the same time is  recommended.                               |                                               |  
It is strongly recommended that at least 1 of these 2 methods highly effective (see examples below) be used. Male patients, even if surgically sterilized (i.e., status post-vasectomy) must agree to 1 of the following:  
Practice effective barrier contraception during the entire study treatment period and through a minimum of 30 days after the last dose of study drug or completely abstain from heterosexual intercourse.  
| Table 13-1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Known Anticipated Risks of BORTEZOMIB by MedDRA System Organ Class,   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------|
| Observed Incidence, and Preferred Term System Organ Class Observed Incidence Preferred Term Blood and Lymphatic System Disorders Most common Thrombocytopenia*, anemia* Very common Neutropenia* Common Lymphopenia, pancytopenia*, leukopenia*, febrile neutropenia Cardiac Disorders Common Tachycardia, atrial fibrillation, palpitations, cardiac failure  congestive* Cardiogenic shock*, atrial flutter, cardiac tamponade*,  bradycardia, atrioventricular block complete, arrhythmia, cardiac  arrest, cardiac failure, arrhythmia, pericardial effusion,  pericarditis, pericardial disease, cardiopulmonary failure Ear and Labyrinth Disorders Uncommon Deafness, hearing impaired Eye Disorders Common Blurred vision, conjunctivitis, conjunctival hemorrhage  Gastrointestinal Disorders Most common Constipation, diarrhea*, nausea, vomiting* Very common abdominal pain (excluding oral and throat) Uncommon Dyspepsia, pharyngolaryngeal pain, gastroesophageal reflux,  abdominal distension, gastritis, stomatitis, mouth ulceration,  dysphagia, gastrointestinal hemorrhage*, lower gastrointestinal  hemorrhage*± rectal hemorrhage Common  Eructation, gastrointestinal pain, tongue ulceration, retching, upper  gastrointestinal hemorrhage*, hematemesis*, oral mucosal  petechiae, ileus paralytic*, ileus, odynophagia, enteritis, colitis,  esophagitis, enterocolitis, diarrhea hemorrhagic, acute  pancreatitis*, intestinal obstruction General Disorders and Administration Site Conditions Most common Fatigue, pyrexia Very common Chills, edema peripheral, asthenia Common Neuralgia, lethargy, malaise, chest pain, mucosal inflammation* Uncommon Injection site pain, injection site irritation, injection site phlebitis,  Uncommon general physical health deterioration*, catheter-related  complication Hepatobiliary Disorders Uncommon Hyperbilirubinemia, hepatitis* Immune System Disorders Uncommon Drug hypersensitivity, angioedema Infections and Infestations |                                                                       |  
| Version Date: 11/08/2021 Table 13-1 Known Anticipated Risks of BORTEZOMIB by MedDRA System Organ Class,  Observed Incidence, and Preferred Term System Organ Class Observed Incidence Preferred Term Very common Upper respiratory tract infection, nasopharyngitis, pneumonia*,  Herpes zoster* Lower respiratory tract infection*, sinusitis, pharyngitis, oral  Common  candidiasis, urinary tract infection*, sepsis, bacteremia*,  cellulitis, Herpes simplex, bronchitis, gastroenteritis*, infection Septic shock*, catheter-related infection*, skin infection*, Herpes  zoster disseminated*, lung infection, infusion site cellulitis,  catheter site cellulitis, infusion site infection, urosepsis*,  Aspergillosis*, tinea infection, Herpes zoster ophthalmic, Herpes  simplex ophthalmic, meningoencephalitis herpetic, varicella,  empyema, fungal esophagitis Injury, Poisoning, and Procedural Complications  Common Fall Uncommon Subdural hematoma Investigations Uncommon Weight decreased, alanine aminotransferase (ALT) increased,  aspartate aminotransferase (AST) increased, blood alkaline  phosphatase increased, liver function test abnormal, blood  creatinine increased* Common  Uncommon Gamma-glutamyltransferase (GGT) increased, oxygen saturation  decreased*, blood albumin decreased, ejection fraction decreased* Metabolism and Nutritional Disorders Very common Decreased appetite, anorexia, dehydration* Common Hyperglycemia, hypoglycemia, hyponatremia, hypokalemia,  hypercalcemia* Musculoskeletal and Connective Tissue Disorders Very common Bone pain, myalgia, arthralgia, back pain Common Muscular weakness Uncommon Limb discomfort Neoplasms, Benign, Malignant, and Unspecified (including cysts and polyps) Uncommon Tumor lysis syndrome* Nervous System Disorders Most common Peripheral neuropathy (including all preferred terms under the  MedDRA High-level term Peripheral neuropathy NEC) Very common Paresthesia, dizziness excluding vertigo, headache Common Polyneuropathy, syncope, dysesthesia, dysgeusia, postherpetic  neuralgia Convulsion, loss of consciousness, ageusia, encephalopathy,  paralysis*,autonomic neuropathy, reversible posterior  leukoencephalopathy syndrome, posterior reversible  encephalopathy syndrome Uncommon   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Table 13-1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Known Anticipated Risks of BORTEZOMIB by MedDRA System Organ Class,   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------|
| Observed Incidence, and Preferred Term System Organ Class Observed Incidence Preferred Term Psychiatric Disorders Very common Anxiety, insomnia  Common Confusional state  Uncommon Delirium Renal and Urinary Disorders Common Renal impairment*, renal failure*, hematuria Uncommon Micturition disorder Respiratory, Thoracic, and Mediastinal Disorders Very common Cough, dyspnea  Common Epistaxis, dyspnea exertional, pleural effusion*, rhinorrhea,  hypoxia*, pulmonary edema Hemoptysis*, acute respiratory distress syndrome*, respiratory  failure*, pneumonitis*, lung infiltration, pulmonary alveolar  hemorrhage*, interstitial lung disease*, pulmonary hypertension*,  pleurisy, pleuritic pain Skin and Subcutaneous Tissue Disorders Very common Rash Common Rash pruritic, rash erythematous, urticaria, petechiae Uncommon Cutaneous vasculitis, leukocytoclastic vasculitis Vascular Disorders Common Hypotension*, orthostatic hypotension Uncommon Cerebral hemorrhage* Source: VELCADE® Investigator's Brochure Edition 16. Most common =  30%, Very common = 10% to 29%, Common = 1% to 9%, Uncommon = < 1%. Uncommon |                                                                       |  
| Table 113-2                                                                                    | Reports of Adverse Reactions From Postmarketing Experience   |      |
|------------------------------------------------------------------------------------------------|--------------------------------------------------------------|------|
| System Organ Class                                                                             | Observed                                                     |      |
| Preferred Term                                                                                 | Incidencea                                                   |      |
| Blood and lymphatic system disorders Disseminated intravascular coagulation                    | Rare                                                         |      |
| Cardiac Disorders Atrioventricular block complete                                              | Rare                                                         |      |
| Cardiac tamponade                                                                              | Rare                                                         |      |
| Ear and labyrinth disorders Deafness bilateral                                                 | Rare                                                         |      |
| Eye Disorders Ophthalmic herpes                                                                | Rare                                                         |      |
|                                                                                                | Optic neuropathy                                             | Rare |
|                                                                                                | Blindness                                                    | Rare |
| Gastrointestinal Disorders Acute pancreatitis                                                  | Rare                                                         |      |
| Ischemic colitis                                                                               | Rare                                                         |      |
| Hepatobiliary disorders Hepatitis                                                              | Uncommon                                                     |      |
| Liver failure                                                                                  | Unknown                                                      |      |
| Infections and infestations Herpes meningoencephalitis                                         | Rare                                                         |      |
| Septic shock                                                                                   | Rare                                                         |      |
| Progressive multifocal leukoencephalopathy                                                     | Very rare                                                    |      |
| Immune System Disorders Angioedema                                                             | Rare                                                         |      |
| Nervous System Disorders Autonomic neuropathy                                                  | Rare                                                         |      |
| Dysautonomia                                                                                   | Unknown                                                      |      |
| Encephalopathy                                                                                 | Rare                                                         |      |
| Respiratory, thoracic and mediastinal disorders: Acute diffuse infiltrative pulmonary diseaseb | Rare                                                         |      |
| Acute respiratory distress syndrome (ARDS)                                                     | Rare                                                         |      |
| Interstitial pneumonia                                                                         | Rare                                                         |      |
| Lung infiltration                                                                              | Rare                                                         |      |
| Pneumonitis                                                                                    | Rare                                                         |      |
| Pulmonary hypertension                                                                         | Rare                                                         |      |
| Skin and subcutaneous system disorders                                                         |                                                              |      |  
| Table 113-2                                                                                                                                                                                                                                                                                                                                                                                                                              | Reports of Adverse Reactions From Postmarketing Experience   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------|
| System Organ Class                                                                                                                                                                                                                                                                                                                                                                                                                       | Observed                                                     |
| Preferred Term                                                                                                                                                                                                                                                                                                                                                                                                                           | Incidencea                                                   |
| Acute febrile neutrophilic dermatosis                                                                                                                                                                                                                                                                                                                                                                                                    | Unknown                                                      |
| Toxic epidermal necrolysis                                                                                                                                                                                                                                                                                                                                                                                                               | Unknown                                                      |
| Source: VELCADE® Investigator's Brochure Edition 16. a Incidence is assigned using the following convention: very common ( 1/10); common  ( 1/100 and  1/10); uncommon ( 1/1000 and  1/100); rare ( 1/10,000 and  1/1000  ); very rare ( 1/10,000, including isolated reports). b Acute diffuse infiltrative pulmonary disease is a MedDRA Lower Level Term which  corresponds to a Preferred Term of Interstitial lung disease. |                                                              |  
Other medical events of interest that are considered not causally related to bortezomib include hepatic failure and QT prolongation. Fatal outcomes have been reported. Women of childbearing potential should avoid becoming pregnant while being treated with bortezomib. Genotoxicity testing has shown that bortezomib is negative in the in vitro Ames assay and in the in vivo micronucleus assay, but it is a clastogen in the in vitro chromosomal aberration assay. Additional details on the potential risks of bortezomib may be found in the current Investigator's Brochure.
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13.1.7 product complaints

A product complaint is a verbal, written, or electronic expression which implies dissatisfaction regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who identify a potential product complaint situation should immediately contact MedComm Solutions (see below) and report the event. Whenever possible, the associated product should be maintained in accordance with the label instructions pending further guidance from a Millennium quality representative. A medication error is a preventable event that involves an identifiable patient and that leads to inappropriate medication use, which may result in patient harm. While overdoses and underdoses constitute medication errors, doses missed inadvertently by a patient do not. Individuals who identify a potential medication error situation should immediately contact MedComm Solutions (see below) and report the event.
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for product complaints or medication

Product complaints and medication errors in and of themselves are not AEs. If a product complaint or medication error results in an SAE, an SAE form should be completed and sent to PPD (refer to Section 8.5). Bortezomib should be given prior to the rituximab infusion.
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13.2 rituximab

Refer to the FDA approved package insert for complete product information.
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13.2.1 supply

Commercially available in single-use vials containing 10 mL (100 mg) or 50 mL (500 mg) of rituximab solution at a concentration of 10 mg/mL. 13.2.2 Storage Rituximab vials should be stored in a secure refrigerator at 2º to 8°C. 13.2.3 Preparation Rituximab will be diluted to a final volume of 0.9% Sodium Chloride or 5% Dextrose Injection to prepare a standard product with concentration of 2 mg/ml. Caution should be taken during the preparation of the drug, as shaking can cause aggregation and precipitation of the antibody. 13.2.4 Stability After dilution, rituximab is stable at 2-8 degrees C (36-46 degrees F) for 24 hours and for an additional 24 hours at room temperature. 13.2.5 Administration A peripheral or central intravenous line will be established. During rituximab infusion, a patient's vital signs (blood pressure, pulse, respiration, temperature) should be monitored according to the standard of care. Medications readily available for the emergency management of anaphylactoid reactions should include: epinephrine (1:1000, 1 mg/mL) for subcutaneous injection, diphenhydramine hydrochloride for intravenous injection, and resuscitation equipment. Prophylaxis against hypersensitivity and infusion-related reactions associated with rituximab will include acetaminophen 650 mg and diphenhydramine hydrochloride 50-100 mg administered 30 to 60 minutes prior to starting rituximab. Patients will also receive their first dose of prednisone 60 mg/m2 (or a glucocorticoid equivalent dose of an alternative steroid) at least 60 minutes before rituximab treatment commences.  
Rituximab will be administered as an intravenous infusion at 375 mg/m2 on day 1 of each cycle of EPOCH after bortezomib (when both drugs are given on the same day) and before starting etoposide + doxorubicin + vincristine administration. Rituximab infusions will be administered to patients primarily in an outpatient clinic setting.
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first dose

The initial dose rate at the time of the first rituximab infusion should be 50mg/hour (25 mL/hr) for the first 30 minutes. If no toxicity is seen, the dose rate may be escalated gradually in 50 mg/hour (25 mL/h) increments at 30 minute intervals) to a maximum of 400 mg/hour (maximum rate = 200 mL/h).
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second and subsequent doses (select

If the first dose of rituximab was well tolerated, subsequent doses may be administered over 90 minutes with 20% of the total dose given in the first 30 minutes, and remaining 80% of the total dose administered over the subsequent 60 minutes; e.g.:
Two-Step Rate Escalation Volume to administer (X mL)  
| Total                         |       |
|-------------------------------|-------|
| Dose                          |       |
| (mg)                          |       |
|                              |       |
| 0.2                           |       |
|                              |       |
| X                             |       |
| mL                            |       |
| (over                         |       |
| 30                            |       |
| min)                          |       |
| 2                             |       |
| 1st portion (0 - 30 minutes)  | Total |
| Dose                          |       |
| (mg)                          |       |
|                              |       |
| 0.8                           |       |
|                              |       |
| X                             |       |
| mL                            |       |
| (over                         |       |
| 60                            |       |
| min)                          |       |
| 2                             |       |
| 2nd portion (30 - 90 minutes) |       |  
Special Note: The 90-minute infusion scheme is not recommended for patients with clinically significant cardiovascular disease or high circulating lymphocyte counts (≥5000/mcL).
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standard administration for second &

Patients who tolerate initial treatment without experiencing infusion-related adverse effects but for whom the 90-minute infusion scheme during subsequent treatments is considered inappropriate, may receive subsequent rituximab doses at the Standard Rate for Subsequent Infusions, which is as follows:
Begin at an initial rate of 100 mg/hour (50 mL/h) for 30 minutes. If administration is well tolerated, the administration rate may be escalated gradually in 100-mg/hour (50-mL/h) increments at 30-minute intervals to a maximum rate of 400 mg/hour (maximum rate = 200 mL/h). CAUTION: DO NOT ADMINISTER RITUXIMAB AS AN INTRAVENOUS PUSH OR BOLUS.
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13.2.6 toxicities

Common toxicities include fever, chills, nausea, asthenia, headache, angioedema, pruritis and rash. Leukopenia occurs in approximately 10% but grade 3 or 4 neutropenia is uncommon. Hypotension occurred in 10% of patients during rituximab infusion, and serious bronchospasm and urticaria associated with rituximab infusion each occurred in fewer than 10% of patients. Less common toxicities include abdominal pain, vomiting, thrombocytopenia, anemia, myalgia, arthralgia, dizziness, and rhinitis. Recently, in patients receiving Rituximab, there have been reports of hepatitis B virus reactivation with fulminant hepatitis, hepatic failure and death in some patients with hematological malignancies.
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13.3 cyclophosphamide 13.3.1 supply

Commercially available as a lyophilized powder for reconstitution in vials containing 100 mg, 200 mg, 500 mg, 1gm, and 2 gm of cyclophosphamide. 13.3.2 Storage and preparation Intact vials should be stored at room temperature (not to exceed 30oC). Reconstitute with appropriate amounts of 0.9% NaCl to produce a final concentration of 20 mg/ml. Discard solution after 24 hours at room temperature. Stable up to 6 days if refrigerated (2º-8ºC).  
13.3.3 Administration Cyclophosphamide will be diluted in D5W or 0.9% NaCl and administered as an intravenous infusion over 30minutes. Patients will be instructed to drink an adequate amount of fluids and empty their bladders frequently during cyclophosphamide administration.
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13.3.4 hydration guidelines

All patients should receive 0.9%NS at the following volumes (based on cyclophosphamide dose levels) and rates with half the specified volume given before starting cyclophosphamide administration and half the volume given after completing the cyclophosphamide administration.  
| Cyclophosphamide Dosage Levels   | Fluid Volume and Administration Rate   |
|----------------------------------|----------------------------------------|
| 1 & 2                            | 1000 mL 0.9%NS @ 300 - 500 mL/h        |
| Levels 3, 4, & 5                 | 2000 mL 0.9%NS @ 300 - 500 mL/h        |
| Levels 6                        | 2500 mL 0.9%NS @ 300 - 500 mL/h        |
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13.4 doxorubicin

Refer to the FDA approved package insert for complete product information.
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13.4.1 supply

Commercially available as a lyophilized powder for reconstitution in 10, 20, 50, and 100 mg vials. Also available as 2 mg/ mL solution for injection in 10, 20, 50, and 200 mg vials. 13.4.2 Preparation and stability Intact vials of doxorubicin solution for injection should be stored in the refrigerator (2º-8ºC). Intact vials of doxorubicin lyophilized powder for reconstitution should be stored at room temperature (not to exceed 30ºC). Reconstitute vials of doxorubicin powder with appropriate amounts of 0.9% NaCl to produce a final concentration of 2 mg/ml. Reconstituted solutions are stable for 7 days at room temperature and 15 days under refrigeration when protected from light. 13.4.3 Toxicities Myelosuppression, stomatitis, alopecia, nausea and vomiting, and acute and chronic cardiac toxicity, manifested as arrhythmias or a congestive cardiomyopathy, the latter uncommon at total cumulative doses less than 500 mg/m2. The drug causes local necrosis if infiltrated into subcutaneous tissue. Please refer to the package insert for a complete listing of all toxicities.
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13.5 vincristine

Refer to the FDA approved package insert for complete product information. 13.5.1 Supply Commercially available as a 1 mg/mL solution for injection in 1 mg, 2 mg, and 5 mg vials. 13.5.2 Stability Vials should be stored at 2º-8ºC and should be protected from light. 13.5.3 Toxicities Peripheral neuropathy, autonomic neuropathy, alopecia. Local necrosis if injected subcutaneously. Please refer to the package insert for a complete listing of all toxicities.
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13.6 etoposide 13.6.1 supply

Commercially available as a concentrate for parenteral use in 100 mg vials; each ml contains 20 mg etoposide, 2 mg citric acid, 30 mg benzyl alcohol, 80 mg polysorbate 80, 650 mg of polyethylene glycol 300, and 30.5% alcohol. 13.6.2 Toxicities Myelosuppression, nausea, vomiting, anaphylactoid reactions, alopecia, and hypotension if infusion is too rapid. Please refer to the package insert for a complete listing of all toxicities.
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13.7 administration of vincristine/doxorubicin/etoposide

Stability studies conducted by the Pharmaceutical Development Section, Pharmacy Department, NIH Clinical Center, have demonstrated that admixtures of vincristine, doxorubicin, and etoposide in 0.9% Sodium Chloride Injection, USP (0.9%NS) at concentrations, respectively, of 1, 25, and 125 mcg/mL; 1.4, 35, and 175 mcg/mL; 2, 50, and 250 mcg/mL; and 2.8, 70, 350 mcg/mL are stable for at least 36 hours at room temperature when protected from light. Also, admixtures containing vincristine, doxorubicin, and etoposide concentrations of 1.6, 40, and 200 mcg/mL are stable for at least 30 hours at 32°C. For this study, etoposide, doxorubicin, and vincristine comprising a daily dose (a 24-hour supply) will be diluted in 0.9%NS. Product containers will be replaced every 24 hours to complete the planned duration of infusional treatment. Product volumes will be determined by the amount of etoposide present in a 24-hour supply of medication. For daily etoposide doses ≤130 mg, admixtures will be diluted in approximately 500 mL 0.9%NS. For daily etoposide doses >130 mg, admixtures will be diluted in approximately 1000 mL 0.9%NS. Etoposide + doxorubicin + vincristine admixtures will be administered by continuous IV infusion over 96 hours with a suitable rate controller pump via a central venous access device. Temporary PICC lines or permanent lines may be used. Extravasation of these diluted agents has not caused local tissue damage due to their low concentrations in the solution.
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13.8 prednisone 13.8.1 supply

Commercially available in a large number of oral dosage strengths including pills and liquid formulations. 13.8.2 Storage Tablets should be stored in well-closed containers at temperatures between 15-30oC.  
13.8.3 Administration Prednisone utilization will be simplified by using only 20- and 50-mg tablets to produce individual doses and by stratifying prednisone doses by a patient's body surface area (BSA), according to the chart below. These are recommendations and not requirements.  
  
| 1.5 - 1.83   | 100 mg   |
|--------------|----------|
| 1.84 - 2.16  | 120 mg   |
| 2.17 - 2.41  | 140 mg   |
| 2.42 - 2.6   | 150 mg   |
| 2.61-2.69    | 160 mg   |
| 2.7 - 3      | 170 mg   |
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13.8.4 toxicities

Proximal muscle weakness, glucose intolerance, thinning of skin, redistribution of body fat, Cushingoid facies, immunosuppression, propensity to gastrointestinal ulceration. Please refer to the package insert for a complete listing of all toxicities.
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13.9 filgrastim (g-csf/neupogenr)

Refer to the FDA approved package insert for complete product information. 13.9.1 Supply Commercially available in single use vials containing 300 mcg (1 mL/vial) and 480 mcg/vial (300 mcg/ml, 1.6 mlvial). 13.9.2 Storage Should be stored at 2º-8ºC (do not freeze and do not shake) and is stable for at least 1 year at this temperature. 13.9.3 Administration Filgrastim will be given by subcutaneous injection; patient or other caregiver will be instructed on proper injection technique. 10.8.2 Toxicities Rare anaphylactic reactions with the first dose; bone pain at sites of active marrow with continued administration. Local reactions at injection sites. Constitutional symptoms, increased alkaline phosphatase, LDH, uric acid; worsening of pre-existing inflammatory conditions. Please refer to the package insert for a complete listing of all toxicities.
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14 administrative requirements 14.1 good

The study will be conducted in accordance with the International Conference on Harmonization (ICH) for Good Clinical Practice (GCP) and the appropriate regulatory requirement(s). The investigator will be thoroughly familiar with the appropriate use of the drug as described in the protocol and Investigator's Brochure. Essential clinical documents will be maintained to demonstrate the validity of the study and the integrity of the data collected. Master files should be established at the beginning of the study, maintained for the duration of the study and retained according to the appropriate regulations.
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14.2 ethical considerations

The study will be conducted in accordance with ethical principles founded in the Declaration of Helsinki. The IRB/IEC will review all appropriate study documentation in order to safeguard the rights, safety and well-being of the patients. The study will only be conducted at sites where IRB/IEC approval has been obtained. The protocol, Investigator's Brochure, informed consent, advertisements (if applicable), safety updates, annual progress reports, and any revisions to these documents will be provided to the IRB/IEC by the investigator. Informed consent documents will be provided to Millennium for their review.
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14.3 patient information and informed

After the study has been fully explained, written informed consent will be obtained from either the patient or his/her guardian or legal representative prior to study participation. The method of obtaining and documenting the informed consent and the contents of the consent will comply with ICH-GCP and all applicable regulatory requirement(s).
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14.4 patient confidentiality

In order to maintain patient privacy, all data capture records, drug accountability records, study reports and communications will identify the patient by name and/or initials and the assigned patient number. The investigator will grant monitor(s) and auditor(s) from Millennium or its designees and regulatory authority(ies) access to the patient's original medical records for verification of data gathered on the data capture records and to audit the data collection process. The patient's confidentiality will be maintained and will not be made publicly available to the extent permitted by the applicable laws and regulations.
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14.5 protocol compliance

The investigator will conduct the study in compliance with the protocol given approval/favorable opinion by the IRB/IEC and the appropriate regulatory authority(ies). Changes to the protocol will require approval from Millennium and written IRB/IEC approval/favorable opinion prior to implementation, except when the modification is needed to eliminate an immediate hazard(s) to patients. The IRB/IEC may provide, if applicable regulatory authority(ies) permit, expedited review and approval/favorable opinion for minor change(s) in ongoing studies that have the approval /favorable opinion of the IRB/IEC. The investigator will submit all protocol modifications to Millennium and the regulatory authority(ies) in accordance with the governing regulations.
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14.6 on-site audits

Regulatory authorities, the IEC/IRB and/or Millennium's clinical quality assurance group may request access to all source documents, data capture records, and other study documentation for on-site audit or inspection. Direct access to these documents must be guaranteed by the investigator, who must provide support at all times for these activities.
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14.7 drug accountability

Accountability for the drug at all study sites is the responsibility of the principal investigator. The investigator will ensure that the drug is used only in accordance with this protocol. Drug accountability records indicating the drug's delivery date to the site (if applicable), inventory at the site (if applicable), use by each patient, and return to Millennium or disposal of the drug (if applicable and if approved by Millennium) will be maintained by the clinical site. Accountability records will include dates, quantities, lot numbers, expiration dates (if applicable), and patient numbers. All material containing bortezomib will be treated and disposed of as hazardous waste in accordance with governing regulations.
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14.8 record retention

The investigator will maintain all study records according to ICH-GCP and applicable regulatory requirement(s).
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15 references

1. Campo E, Raffeld M, Jaffe ES. Mantle-cell lymphoma. Semin Hematol. 1999;36:115-127 2. Velders GA, Kluin-Nelemans JC, De Boer CJ, Hermans J, Noordijk EM, Schuuring E, Kramer MH, Van Deijk WA, Rahder JB, Kluin PM, Van Krieken JH. Mantle-cell lymphoma: a populationbased clinical study. J Clin Oncol. 1996;14:1269-1274 3. Hiddemann W, Unterhalt M, Herrmann R, Woltjen HH, Kreuser ED, Trumper L, Reuss-Borst M, Terhardt-Kasten E, Busch M, Neubauer A, Kaiser U, Hanrath RD, Middeke H, Helm G, Freund M, Stein H, Tiemann M, Parwaresch R. Mantle-cell lymphomas have more widespread disease and a slower response to chemotherapy compared with follicle-center lymphomas: results of a prospective comparative analysis of the German Low-Grade Lymphoma Study Group. J Clin Oncol. 1998;16:1922-1930 4. Samaha H, Dumontet C, Ketterer N, Moullet I, Thieblemont C, Bouafia F, Callet-Bauchu E,
Felman P, Berger F, Salles G, Coiffier B. Mantle cell lymphoma: a retrospective study of 121 cases. Leukemia. 1998;12:1281-1287 5. Teodorovic I, Pittaluga S, Kluin-Nelemans JC, Meerwaldt JH, Hagenbeek A, van Glabbeke M, Somers R, Bijnens L, Noordijk EM, Peeters CD. Efficacy of four different regimens in 64 mantle-cell lymphoma cases: clinicopathologic comparison with 498 other non-Hodgkin's lymphoma subtypes. European Organization for the Research and Treatment of Cancer Lymphoma Cooperative Group. J Clin Oncol. 1995;13:2819-2826 6. Zucca E, Fontana S, Roggero E, Pedrinis E, Pampallona S, Cavalli F. Treatment and prognosis of centrocytic (mantle cell) lymphoma: a retrospective analysis of twenty-six patients treated in one institution. Leuk Lymphoma. 1994;13:105-110 7. J A. A clinical evaluation of the International Lymphoma Study group classification of nonHodgkin's lymphoma. Blood. 1997;89:3909-3918 8. Khouri IF, Romaguera J, Kantarjian H, Palmer JL, Pugh WC, Korbling M, Hagemeister F,
Samuels B, Rodriguez A, Giralt S, Younes A, Przepiorka D, Claxton D, Cabanillas F, Champlin R. Hyper-CVAD and high-dose methotrexate/cytarabine followed by stem-cell transplantation: an active regimen for aggressive mantle-cell lymphoma. J Clin Oncol. 1998;16:3803-3809 9. Mangel J, Leitch HA, Connors JM, Buckstein R, Imrie K, Spaner D, Crump M, Pennell N,
Boudreau A, Berinstein NL. Intensive chemotherapy and autologous stem-cell transplantation plus rituximab is superior to conventional chemotherapy for newly diagnosed advanced stage mantlecell lymphoma: a matched pair analysis. Ann Oncol. 2004;15:283-290 10. Freedman AS, Neuberg D, Gribben JG, Mauch P, Soiffer RJ, Fisher DC, Anderson KC,
Andersen N, Schlossman R, Kroon M, Ritz J, Aster J, Nadler LM. High-dose chemoradiotherapy and anti-B-cell monoclonal antibody-purged autologous bone marrow transplantation in mantlecell lymphoma: no evidence for long-term remission. J Clin Oncol. 1998;16:13-18 11. Baldwin AS. Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB. J Clin Invest. 2001;107:241-246 12. Baldwin AS, Jr. The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol. 1996;14:649-683 13. Ghosh S, May MJ, Kopp EB. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol. 1998;16:225-260 14. Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-[kappa]B
activity. Annu Rev Immunol. 2000;18:621-663 15. Siebenlist U, Franzoso G, Brown K. Structure, regulation and function of NF-kappa B. Annu Rev Cell Biol. 1994;10:405-455 16. Gugasyan R, Grumont R, Grossmann M, Nakamura Y, Pohl T, Nesic D, Gerondakis S.  
Rel/NF-kappaB transcription factors: key mediators of B-cell activation. Immunol Rev. 2000;176:134-140 17. Staudt LM. The molecular and cellular origins of Hodgkin's disease. J Exp Med. 2000;191:207-212 18. Bargou RC, Emmerich F, Krappmann D, Bommert K, Mapara MY, Arnold W, Royer HD,
Grinstein E, Greiner A, Scheidereit C, Dorken B. Constitutive nuclear factor-kappaB-RelA activation is required for proliferation and survival of Hodgkin's disease tumor cells. J Clin Invest. 1997;100:2961-2969 19. Bargou RC, Leng C, Krappmann D, Emmerich F, Mapara MY, Bommert K, Royer HD,
Scheidereit C, Dorken B. High-level nuclear NF-kappa B and Oct-2 is a common feature of cultured Hodgkin/Reed-Sternberg cells. Blood. 1996;87:4340-4347 20. Krappmann D, Emmerich F, Kordes U, Scharschmidt E, Dorken B, Scheidereit C. Molecular mechanisms of constitutive NF-kappaB/Rel activation in Hodgkin/Reed-Sternberg cells. Oncogene. 1999;18:943-953 21. Cahir-McFarland ED, Davidson DM, Schauer SL, Duong J, Kieff E. NF-kappa B inhibition causes spontaneous apoptosis in Epstein-Barr virus-transformed lymphoblastoid cells. Proc Natl Acad Sci U S A. 2000;97:6055-6060 22. Fracchiolla NS, Lombardi L, Salina M, Migliazza A, Baldini L, Berti E, Cro L, Polli E,
Maiolo AT, Neri A. Structural alterations of the NF-kappa B transcription factor lyt-10 in lymphoid malignancies. Oncogene. 1993;8:2839-2845 23. Neri A, Chang CC, Lombardi L, Salina M, Corradini P, Maiolo AT, Chaganti RS, DallaFavera R. B cell lymphoma-associated chromosomal translocation involves candidate oncogene lyt-10, homologous to NF-kappa B p50. Cell. 1991;67:1075-1087 24. Joos S, Otano-Joos MI, Ziegler S, Bruderlein S, du Manoir S, Bentz M, Moller P, Lichter P.  
Primary mediastinal (thymic) B-cell lymphoma is characterized by gains of chromosomal material including 9p and amplification of the REL gene. Blood. 1996;87:1571-1578 25. Lu D, Thompson JD, Gorski GK, Rice NR, Mayer MG, Yunis JJ. Alterations at the rel locus in human lymphoma. Oncogene. 1991;6:1235-1241 26. Hirama T, Koeffler HP. Role of the cyclin-dependent kinase inhibitors in the development of cancer. Blood. 1995;86:841-854 27. Chiarle R, Budel LM, Skolnik J, Frizzera G, Chilosi M, Corato A, Pizzolo G, Magidson J,
Montagnoli A, Pagano M, Maes B, De Wolf-Peeters C, Inghirami G. Increased proteasome degradation of cyclin-dependent kinase inhibitor p27 is associated with a decreased overall survival in mantle cell lymphoma. Blood. 2000;95:619-626 28. Pham LV, Tamayo AT, Yoshimura LC, Lo P, Ford RJ. Inhibition of constitutive NF-kappa B activation in mantle cell lymphoma B cells leads to induction of cell cycle arrest and apoptosis. J Immunol. 2003;171:88-95 29. Bogner C, Ringshausen I, Schneller F, Fend F, Quintanilla-Martinez L, Hacker G, Goetze K, Oostendorp R, Peschel C, Decker T. Inhibition of the proteasome induces cell cycle arrest and apoptosis in mantle cell lymphoma cells. Br J Haematol. 2003;122:260-268 30. A G. Report of a Phase II Study of Proteasome Inhibitor Bortezomib in Patients with Relapsed or Refractory Indolent or Aggressive Lymphomas. Amer Soc Hematol: Blood; 2003 31. Assouline S et al. A Phase II study of Bortezomib in patients with Mantle Cell lymphoma. Proc Amer Soc of Hematol: Blood; 2003 32. Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV,
Srkalovic G, Alsina M, Alexanian R, Siegel D, Orlowski RZ, Kuter D, Limentani SA, Lee S, Hideshima T, Esseltine DL, Kauffman M, Adams J, Schenkein DP, Anderson KC. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003;348:2609-2617 33. Wilson WH et al. Idiotype Vaccine and Dose-Adjusted EPOCH-Rituximab Treatment in Untreated Mantle Cell Lymphoma: Preliminary Report on Clinical Outcome and Analysis of Immune Response. American Soc of Hematol: Blood; 2003:102(111) \#358 34. Rosenwald A, Wright G, Wiestner A, Chan WC, Connors JM, Campo E, Gascoyne RD,
Grogan TM, Muller-Hermelink HK, Smeland EB, Chiorazzi M, Giltnane JM, Hurt EM, Zhao H, Averett L, Henrickson S, Yang L, Powell J, Wilson WH, Jaffe ES, Simon R, Klausner RD, Montserrat E, Bosch F, Greiner TC, Weisenburger DD, Sanger WG, Dave BJ, Lynch JC, Vose J, Armitage JO, Fisher RI, Miller TP, LeBlanc M, Ott G, Kvaloy S, Holte H, Delabie J, Staudt LM. The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma. Cancer Cell. 2003;3:185-197 35. Liotta, L.A., et al., Protein microarrays: Meeting analytical challenges for clinical applications. Cancer Cell, 2003. 3(4): p. 317-25. 36. Espina, V., et al., Protein microarrays: Molecular profiling technologies for clinical specimens. Proteomics, 2003. 3(11): p. 2091-100.  
37. Zha, H., et al., Similarities of prosurvival signals in Bcl-2-positive and Bcl-2-negative follicular lymphomas identified by reverse phase protein microarray. Lab Invest, 2004. 84(2): p. 235-44. 38. Adams, J., The proteasome: structure, function, and role in the cell. Cancer Treat Rev, 2003. 29 Suppl 1: p. 3-9.  
39. Goy, A., et al., Phase II study of proteasome inhibitor bortezomib in relapsed or refractory Bcell non-Hodgkin's lymphoma. J Clin Oncol, 2005. 23(4): p. 667-75.  
40. Richardson PG, et al., N Engl J Med 2005; 352:2487-98. 41. Blade J, Samson D, Reece D, Apperley J, Bjorkstrand B, Gahrton G et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by highdose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT.  
European Group for Blood and Marrow Transplant. Br J Haematol 1998; 102 (5):1115-23.
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16 appendix a procedure for

This procedure is for use with blood tubes or syringes containing no anticoagulant. In some cases the blood will be received in vacutainer tubes containing a serum separator. Use of these serum separator tubes (SST) simplifies the recovery of serum after centrifugation since the gel separator will be found between the cell layer and the serum. Complete all required data entry. Prepare transmittal form to accompany sample. Assign each sample a unique Sample Accession Number. Contact the Clinical Support Laboratory at (301) 8465125 to receive one or more Sample Accession Numbers for use. Laboratory staff can also be contacted by email:
To: Theresa Burks - burkst@mail.nih.gov CC: Helen Rager (Supervisor) - ragerh@mail.nih.gov CC: Dr. Mingzhu Zhu (Lab Head) - zhum@mail.nih.gov The sample should be allowed to clot at room temperature for approximately 30 minutes. If possible the sample should be processed immediately after clotting. If it is not possible to proceed immediately the sample should be refrigerated or placed in a sealed bag on wet ice until processing can be performed. Both the draw time and time when processing was completed should be recorded.  
Set the centrifuge temperature to 4C. Centrifuge the sample for 10 minutes at 2000 rpm (approx.  
1170 x g) in the RC-3B centrifuge with no brake (2300 rpm Sorvall RT6000B). The centrifugation time does not include the time required for the rotor to reach the target speed. To determine centrifugation speed for different centrifuge/rotor combinations see the centrifuge manual or visit the following website: http://researchlink.labvelocity.com/tools/conversionTools/CentrifugationTool.jhtml Prior to initiating sample processing or during the centrifugation step label 2 ml Nunc cryovials (NUNC 368632 1.8 ml round bottom cryovial or equivalent) with the sample Accession Number. If multiple blood tubes have been received for a single patient/timepoint also label a 15 or 50 ml polypropylene tube depending on expected recovery volume. Carefully remove the serum layer (*the translucent first layer of fluid)* without disturbing the clot. Do not attempt to recover serum from the side of the retracted clot as doing so will result in contamination of the serum. If it is noted that the serum has not been cleanly removed transfer the recovered serum to a 15 ml polypropylene tube and repeat centrifugation. If only a single tube of blood was received for serum recovery aliquot directly to the labeled Nunc cryovials at 1ml per vial (1 10ml tiger top (SST) or red top vacutainer = approximately 4 vials, 2 tubes = >6 vials). If multiple blood tubes are received for a single patient/timepoint, transfer the serum from each tube into a single 15 or 50 ml centrifuge tube. Mix the contents by repeated pipetting or by replacing the lid and inverting the tube at least 6 times prior to aliquoting.  
Transfer filled vials to the -70C freezer. If the laboratory does not have access to a -70C freezer (or colder storage such as vapor phase LN2) the serum should be frozen solid on dry ice before transfer to the -20C freezer. If samples are held at temperatures outside the range of –60 to -86C please note the storage temperature on the transmittal form. Include any comments concerning adequacy of the specimen (e.g., gross hemolysis) on the transmittal form.
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17 appendix b epoch admixtures

All 3-in-1 admixtures dispensed from the Pharmacy will contain a 24-hour supply of etoposide, doxorubicin, and vincristine, *PLUS* 40 mL overfill (excess) fluid and a proportional amount of drug to compensate for volume lost in parenteral product containers and administration set tubing.  
| Etoposide Dose          | Volume of Fluid   | Volume of Overfill   | Total Volume in the Product   |
|-------------------------|-------------------|----------------------|-------------------------------|
| Containing a Daily Dose | (fluid + drug)    | (including overfill) |                               |
| ≤ 130 mg                | 528 mL            | 40 mL                | 568 mL                        |
| > 130 mg                | 1056 mL           | 40 mL                | 1096 mL                       |  
Before dispensing 3-in-1 admixtures, Pharmacy staff will:
[1] Purge all air from the drug product container,
[2] Attach an administration set appropriate for use with a portable pump,
[3] The set will be primed close to its distal tip, and [4] The set will be capped with a Luer-locking cap.  
Pre-printed product labeling will identify the 'Total Volume To Infuse' and the 'Volume of Overfill (fluid + drug)'. Bags will be exchanged daily for four consecutive days to complete a 96-hour drug infusion (unless treatment is interrupted or discontinued due to un-anticipated events).
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administration

Portable pumps used to administer etoposide + doxorubicin + vincristine admixtures will be programmed to deliver one of two fixed volumes at one of two corresponding fixed rates based on the amount of etoposide and fluid that is ordered (see the table, below).  
| Total Volume  to Infuse per  24 hours   |                    |                |            |
|-----------------------------------------|--------------------|----------------|------------|
| Etoposide  Dose                         | Volume of Overfill | Administration |            |
| (drug-containing fluid)*                | Rate               |                |            |
| ≤ 130 mg                                | 528 mL             | 40 mL          | 22 mL/hour |
| > 130 mg                                | 1056 mL            | 40 mL          | 44 mL/hour |  
*DO NOT attempt to infuse the overfill.  
At the end of an infusion, some residual fluid is expected because overfill (excess fluid and drug) was added; however, nurses are asked to return to the Pharmacy for measurement any drug containers that appear to contain a greater amount of residual drug than expected. Example at right: The amount of fluid remaining in a bag after completing a 24-hour infusion (1056 mL delivered).
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18 appendix c pregnancy reporting

Report Type:
( Follow-up Date of Report:
IN
REPORTER INFORMATION: (Please forward if an alternative physician is more appropriate)
Reporter name:
Title:  
| Adress:               |
|-----------------------|
| City, State/Province: |  
Telephone No.:  
  
Fax No.  
Postal Code:
Country:
FATHER'S INFORMATION
Initials:
Date of Birth:  
  
  
years
- Father Unknown Participating in an MPI clinical study?  
口 Yes  
  
If no, what company product was taken:
If yes, please provide:  Study drug:  
  
Protocol Not  
  
Center No:  
  
Patient No:  
  
  
Medical / Familial / Social History  
(i.e. Include chronic illnesses: specify, familal bith defects/genetic/chromosomal disorders; habbual exposure;
specify, alcoholtobacco; drug exposure; specify, substance abu  
  
prior to or around the time of conception and/or during pregnancy).  
MOTHER'S INFORMATION:
Initials:
Date of Birth:
or Age:
.years  
| Participating in an MPI clinical study?                                                                           | □ Yes                               | Race:          |                 |
|-------------------------------------------------------------------------------------------------------------------|-------------------------------------|----------------|-----------------|
| If no, what company product was taken:                                                                            | Occupation:                         |                |                 |
| If yes, please provide:  Study drug:                                                                              | Protocol No:                        |                |                 |
| Center No:                                                                                                        | Patient No:                         |                |                 |
| Number of previous pregnancies: Full term                                                                         | Pre-term                            |                |                 |
| Medical / Familial / Social History                                                                               |                                     |                |                 |
| (i.e. Include alcoholtobacco and substance abuse complications of particles).
pregnancy, labordelivery, fetusbaby, linesses during this pregnancy,
assisted conception, specif                                                                                                                   | Outcomes of previous pregnancies:   |                |                 |
| (Please indicate number of occurrences)                                                                           |                                     |                |                 |
| detects/genetic/chromosomal_disorders_method of diagnosis                                                         | - Normal live birth;                |                |                 |
| orsanguinity, etc.)                                                                                               | - Spontaneous abortion;             |                |                 |
| - Therapeutic abortion:                                                                                           | - Children bom with defects:        |                |                 |
| - Elective abortion:                                                                                              | - Stillbirth:                       |                |                 |
| - Other:                                                                                                          | - Outcome unknown;                  |                |                 |
| MOTHER'S DRUG EXPOSURE INFORMATION                                                                                |                                     |                |                 |
| Please include medical prescriptions, vaccinations, medical devices, OTC products, pregnancy supplements (such as |                                     |                |                 |
| folic acid, multivitamins)                                                                                        | Date of first                       |                |                 |
| Product                                                                                                           | Route                               | Date of end    | Contraindicated |
| Dosage                                                                                                            | administered                        | Indication     |                 |
| USE                                                                                                               | treatment
(DD/MM/Yr)                                     |                |                 |
| Name                                                                                                              | (DD/MM/Yr)                          | to pregnancy   |                 |
| to patient                                                                                                        | OYesONoOUnk                         |                |                 |
|                                                                                                                   | )                                   | O YesO NoO Unk |                 |
| /                                                                                                                 | )                                   |                |                 |
| /                                                                                                                 | l                                   | t              | O YesO NoO Unk  |
| (                                                                                                                 | )                                   | O YesO NoO Unk |                 |
|                                                                                                                   | e-Pregnancy Form (27 November 2013) |                |                 |  
  
Pregnancy Form  
  
Page 2 of 2 CURRENT PREGNANCY INFORMATION
Period at exposure:
. weeks Trimester Date of last menstrual period:
M
Pregnancy Status
( ) Pregnancy Ongoing O Live Birth 1 Still birth 1 Early Termination  
  
) Spontaneous abortion* O Therapeutic abortion*
- Elective abortion* O Other*:
Additional Details:
- Ultrasound  
  
  
Estimated date of delivery:  
  
* box is checked, please note reason in "Additional Details" section below Is there evidence of a defect from a prenatal test?  
I yes, indicate which test(s) showed evidence of birth defect:  
  
- Chorionic Villi Sampling
Please specify details of defect(s), disorder(s), and/or other anomaly(ies);
What are the defect(s) attributed to:
Infant Information:
Gestational weeks at birth or at termination:
weeks Date of birth or termination:
DL MY  
  
If multiple births (e.g. twins), indicate number:
(Please complete separate form for each child)
Birth Order (1, 2, 3, etc.)
Breast-fed:
□ Yes
❏ Unk Method of delivery:  
Sex:   Male    Female Length:
- cm Weight:
ll
□ lbs Head circumference: _
□ cm Apgar score (0-10) at 1 minute:
□ Unk Apgar score (0-10) at 5 minute:
- Unk Resuscitation required:    Yes Admission to intensive care required:
❏ Yes ❏ No   ◾ Unk Additional Notes:
Please attach RELEVANT LABORATORY TESTS AND PROCEDURES (e.g. results of ultrasounds, amniocentesis, chorionic villi sampling, or miscellaneous testing as applicable). In the case of an abnormal evolution or outcome, please send copies of results of all
evant laboratory testing and procedur Please submit any additional relevant information on a separate sheet.  
Investigator signature:
Date:
Investigator Name:  
| ( 3 )     |
|-----------|
| - Unknown |  
Fetal/Neonatal Status e-Pregnancy Form (27 November 2013)