# Presentation: 873978

##  Vaccinia Immune Globulin and Cidofovir 

**Centers for Disease Control and Prevention**
**Department of Health and Human Services**

**Smallpox Vaccine Adverse Event Workshop**
**January 22-23, 2003**

## Vaccinia Immune Globulin (VIG)Formulations

**Intravenous (IV) - Cangene**
**Newly produced**
**More abundant **
**Potential licensure**
**Intramuscular (IM) - Baxter**
**Older product**
**Limited**
**No licensure**
**All VIG used under Investigational New Product (IND) protocols currently**

## Vaccinia Immune Globulin (VIG)Formulations

**Intravenous VIG - Cangene**
**Sterile solution of gamma globulin (IgG) fraction containing antibodies to vaccinia obtained from persons vaccinated  with vaccinia vaccine**** **
**Protein content meets standards for IV administration**
**Intramuscular VIG - Baxter**
**Isotonic sterile solution of the immunoglobulin fraction of plasma from persons vaccinated with vaccinia vaccine**
**Protein content does **_**not **_**meet standards for IV administration**

## Vaccinia Immune Globulin (VIG)Indications

**Eczema vaccinatum**
**Vaccinia necrosum (progressive vaccinia)**
**Severe generalized vaccinia**
**Serious inadvertent inoculation**
**Some ocular vaccinia infections**

## Vaccinia Immune Globulin (VIG)Contraindications **

**History of prior severe reaction associated with the IV or IM administration of human immunoglobulin preparations**
**Selective immunoglobulin A deficiency (potential for developing antibodies to IgA with anaphylactic reactions to subsequent administration of blood products containing IgA)**
**Vaccinia keratitis (in absence of other complication)**
***** Attending physician can make risk-benefit assessment in cases of severe vaccinia infection and administer VIG if benefit outweighs risk***

## Vaccinia Immune Globulin (VIG)Precautions**

**Severe thimerosal allergy (IM preparation only)**
**Pregnancy**
**Breastfeeding**
***** Attending physician can make risk-benefit assessment in cases of severe vaccinia infection and administer VIG if benefit outweighs risk***

## Vaccinia Immune Globulin (VIG)Adverse Events

**Mild**
**Pain at injection site (mostly IM)**
**Moderate **
**Joint pain, headache, muscle aches, chills and/or fever, back or abdominal pain, pruritis, dizziness, etc.**
**Severe* - Rare**
**Anaphylaxis and anaphylactoid systemic reactions (IM and IV)**
**Renal dysfunction (IV)**
**Aseptic meningitis syndrome (AMS) (IV)**
**** Not seen in limited clinical trials of IVVIG but possible based on historical experience with other immunoglobulin products***

## Vaccinia Immune Globulin (VIG)Adverse Events -Treatment

**Mild and moderate AEs **
**Monitor or slow infusion rate (as with other IVIG products)**
**Symptomatic treatment if needed (acetaminophen, diphenhydramine, etc.) **
**Severe AEs**
**Discontinue infusion for **_**all**_** serious AEs**
**Administer appropriate treatment and supportive care for anaphylaxis**
**AMS usually resolves within several days**
**Renal dysfunction **

## Vaccinia Immune Globulin (VIG)Dosages

**VIG – IM **
**Formulation potency about 10,000U/ml **
**Dose is 0.6 ml/kg**** = 6000 U/kg = 100mg/kg (adult and pediatric dose)**
**VIG – IV (Cangene)**
**Formulation potency similar to IM product**
**Starting dose is 6000 U/Kg**** (adult and pediatric dose)**
**Starting infusion rate of 0.01-0.02 mL/kg/min for 30 min.  If no adverse reactions, the rate of infusion may be gradually increased to a maximum of 0.06 mL/kg/min**** **
**Repeat dosing may be given every 2-3 days if needed**

## Cidofovir

**Nucleotide analogue of cytosine **
***In vitro *****and *****in vivo***** activity against broad spectrum of herpesviruses**
**Anti-orthopoxvirus activity in cell-based *****in vitro***** and animal model studies **
**Licensed for treatment of Cytomegalovirus (CMV) retinitis in patients with AIDS**
**Associated with renal dysfunction and toxicities**
**IND for use as **_**second-line**_** treatment to VIG for vaccinia vaccine adverse reactions **
**drug can have serious adverse reactions **
**effectiveness in treating vaccinia virus infections in humans is **_**unknown/unproven**_

## CidofovirIndications

_**Only**_** used if:**
**Failure to respond to VIG treatment **
**Additional therapy in severely ill patient (near death)**
**All stores of VIG are exhausted**
**Same vaccinia virus adverse event indications as VIG (EV, GV, VN, etc.)**

## CidofovirContraindications*

**Receiving drugs known to compete with the active renal tubular secretion of other compounds **
**Receiving therapy within one week prior with any drug known to be nephrotoxic **
**Pre-existing renal impairment (serum creatine > 1.5 mg/dL; calculated creatinine clearance ******** 55 mL/min or a urine protein ******** 100 mg/dL (******** 2+ proteinuria)**
**Hypersensitivity to cidofovir**
**History of clinically severe hypersensitivity to probenecid or other sulfa-containing medications**
**** Contraindications valid except in possible cases of imminently lethal vaccinia infection unresponsive to all other treatment. Attending physician (in consultation with CDC) should make risk-benefit assessment***
** **

## CidofovirAdverse Reactions

**Nephrotoxicity **
**Proteinuria**
**Elevated creatinine**
**Irreversible renal failure**
**Anterior uveitis/iritis**
**Neutropenia, proteinuria, decreased intraocular pressure/ocular hypotony, and metabolic acidosis**
**Nausea, vomiting, fever, headache, rash, diarrhea**
_**Probenicid **_**associated with headache, anorexia, nausea, vomiting, urinary frequency, hypersensitivity reactions, anemia, hemolytic anemia, nephritic syndrome, hepatic necrosis, gout, uric acid stones, and renal colic **

## CidofovirDosages

**5 mg/kg one-time dose over 60 minutes**
**Second dose 1 week later may be considered if clinically indicated**
**Pre- and post infusion IV hydration and probencid therapy given according to IND protocol **
**Monitor renal function **
**Pediatric dose not known**

## Obtaining VIG or Cidofovir for Treatment of Adverse Event

**Consultation call to CDC SME through:**
**Clinical consultant hotline**
**	****	****        ****or**
**CDC Emergency Response**
**Consultations from State/local PH or physician**
**Physicians encouraged to consult through State Health Department (SHD)**
**SHD notified if not already involved **
**Review of case, if treatment indicated:**
**Obtain information needed prior to release **
**Delivery of VIG or Cidofovir and IND protocols through NPS**

## Information Needed for Shipment of VIG or Cidofovir

_**From Consulting Physician or Health Department**_
_**Patient Information**_**:  *****name, DOB, gender, patient weight, adverse reaction and brief clinical narrative, exposure history, etc. (CDC Drug Service Drug Release Form)***
_**Physician Information**_**:  *****attending physician name and phone number (pager, cell, etc)***
_**Hospital Information**_**:  *****address of receiving hospital and pharmacy contact information***
_**CDC Information**_
_**CDC Authorizer**_**:  *****name of authorizing CDC physician, contact phone number(s)***
_**Shipment Information**_**:  *****time/date of initial VIG/Cidofovir request; time/date VIG/Cidofovir released; transportation courier name and tracking information (NPS) ***

## State Roles for VIG or Cidofovir IND

**IND not considered research so local IRB can defer to CDC IRB**
**State based Co-Investigators **
**Assure CV and completed Form 1572 (will accompany protocol) from treating physician to register as co-Investigator for IND protocol ****	****	****	****	****	****or **
**State PH physician registered as co-Investigator who “supervises” treating physician**
**Assist with follow-up of clinical disposition and assure completion of IND reporting forms**

## Federal Responsibilities

**Obtain designation as “non-research” by HHS, FDA, and CDC (IRB)**
**Obtain approval of IND by CDC IRB **
**Obtain FDA review and allowance of IND**
**Delivery of product (VIG or Cidofovir) after release **
**Delivery of IND protocol for product and appropriate forms to register State co-Investigator**
**Phone follow up (CDC clinical team) to determine disposition and assure completion of IND reporting forms**
**Monitoring of adverse events associated with product by medical monitor and DSMB**

## Questions and Discussion