Ohio Opioid Prevention & Reduction Pilot Proposal

“We are still losing people all over the state of Ohio who are dying from overdoses.”

THE HONORABLE MIKE DEWINE

DripFusion Enterprises, Inc. is a Georgia Corporation

Table of Contents

Overview

Proposal

Ohio Pilot Coalition Centers of Excellence (Chronic/Arthritic)

Executive Summary

Budget

Formulation Design

Partners

Bethune Academic Curriculum Kit (B.A.C.K.)

Pro-Fast Construction Group

Eco Tech Solutions

Resource Partners, LLC

Weber Solutions

Freedom 365

Cost Justification

Ohio Strategy Overview

Gov. Mike DeWine announced he wants the state to spend $200 million on new initiatives aimed at addiction and mental health. Around 13 people in Ohio die a day from drug overdoses, as the state’s opioid epidemic rages on. the overall death rate is up because people are overdosing and dying due to fentanyl and Carfentanil being mixed into cocaine and methamphetamine.

Overdose deaths have risen in recent years. • In 2016, 4,050 people died, • In 2015, 3,050 people died, • In 2014, 2,531 died.

Ohio is spending around $1 billion to fight the drug problem, including $600 million on treatment. In 2014, Kasich expanded Medicaid, which covers many people in treatment.

DripFusion Enterprises, Inc., a Georgia Corporation and subsidiary Pro-IV have developed to date, the only solution in the US which is non opioid, non steroid, non addictive, 97% all natural AND accepted by ALL MAJOR US INSURANCE CARRIERS. This treatment is in utilization in the market nationwide.

In addition to safety, efficacy and successful outcomes, this investigation will demonstrate the exponential savings to government and payers utilizing the consolidated DripAmerica Patient Platform. This comprehensive strategy includes establishing state of the art facilities where required in partnership with Eco Tech Solutions.

The proposal consist of treating 2000 patients across the state of Ohio: Protocol is 6 treatments

1000 Prevention Patients (Post Op - Hospitals will treat patient post operatively 1 TIME. Subsequent treatment conducted at a cross section of existing sites listed below. 6000 Combined Treatments.

1000 Chronic (Weening off opioids) 6000 Combined Treatments

In addition to the hospital(s), the scope of treatment in the pilot will span across the state with a coalition of strategic partnerships, which include: • State Clinics • Senior/Community Centers • Homeless Facilities • Churches • Mobile Education & Treatment • Veteran Centers

The DripAmerica platform will demonstrate a streamline process integrating participating Physicians, Clinics & Sites (Chiropractor, Dentist) while demonstrating significant savings.

Operational Summation:

We Verify Insurance Collect Intake Data Bill Patient Provide Drugs

Govenor Dewine 12 Drug Addiction Action Plan

Point 1: Pass legislation to give the Governor the ability to declare a public health emergency statewide or in specific areas. The Governor should have more flexibility and tools to face this emergency, including the ability to do the following: • Distribute money and other resources to local entities that are facing

unexpected emergency conditions, like overdose spikes. • Create an accelerated process for state licenses in critical professions such as

the medical or social work fields as well as expedited licensing reciprocity with other states.

Point 2: Create a 21st Century law enforcement data infrastructure. This will allow real- time, statewide data-sharing and brings state-of-the-art data analytics and crime prediction to every Ohio law enforcement agency. Point 3: Expand proven drug task force models. This will specifically target and disrupt the flow of money and drugs from Mexican drug cartels. Point 4: Create at least 60 more specialized drug courts. Drug courts are a proven way to hold those with substance use disorder accountable and ensure participation in effective drug treatment. There are more than 20 counties without a drug court and hundreds of municipalities without one. Point 5: Implement Proven K-12 grade drug prevention education in all Ohio schools. The single most effective tool Ohio has in this fight is prevention, and our best opportunity to provide it is to require that every student in Kindergarten through 12th grade receive age- and environmentally appropriate, evidence-based substance use prevention education. Point 6: Double substance use treatment capacity in Ohio. According to a new study by The Ohio State University, Ohio has treatment capacity for only 20 to 40 percent of Ohioans suffering from opioid addiction. The shortage is even worse in poor and rural areas of the state. Utilizing funding from the drug companies who made billions of dollars creating this problem, Ohio must develop, incentivize or repurpose treatment options to double our treatment capacity. This can be accomplished in a number of ways, including: • Better utilizing Ohio hospitals’ existing capacity. We have existing capacity in

Ohio at the hundreds of hospitals around the state. However, current funding

mechanisms or rules don’t allow most of that capacity to be used for treatment.

• Driving more money to local addiction and mental health boards to pay for new treatment. By block-granting millions of additional dollars to local Alcohol, Drug and Mental Health boards, treatment and recovery providers can expand most where they’re needed and be more responsive to local needs.

Point 7: Expand workforce of critical specialists. Ohio has a shortage of addiction specialists, social workers, and other professionals who are needed now and in the future to help those with substance use disorder. To incentivize these workers, Ohio should develop a student loan forgiveness program for those in drug treatment fields who complete their studies at Ohio universities and spend a specified time working in the addiction field in Ohio. Point 8: Empower employers to help employees with substance abuse disorder to seek treatment while remaining employed. Working through the Bureau of Workers Compensation (BWC) Safety Grants program, Ohio should create a pilot project aimed at existing employees who are willing to go to their employer and acknowledge that they have a substance use problem. To keep that person in the job, BWC’s program would work with the employer to pay for a portion of the healthcare costs associated with an appropriate treatment program that would allow that employee to return to work when they’re drug free. Point 9: Help business owners hire employees in recovery by offering employers incentives and reducing risks. The BWC should start a pilot project incentivizing employers to hire applicants who have completed appropriate treatment programing. The pilot program would reimburse the employer for a certain percent of the employee’s wages, provide necessary training to the employee, and indemnify the employer from any BWC rate increases should the employee relapse and cause a work-related accident. Point 10: Roll-out a statewide drug prevention media campaign. Point 11: Create a special position reporting directly to the Governor. This position will work every day with the single-minded focus of fighting the opioid epidemic. Point 12: Expand early intervention programs that target Ohio families and children in foster care. Ohio should expand and extend to all 88 counties quality programs that emphasize intervention with the whole family such as Ohio START (Sobriety, Treatment and Reducing Trauma). This is an 18-county pilot program that helps local governments offer concentrated, critical services to not only those who struggle with substance use disorder, but to their children who find themselves in foster care and are equally traumatized and damaged by opioids.

Proposal

Opioid Investigation Study Design

Co-Principle Investigators

Dr. Puneet Sindhwani

ProMedica Designee

VA Designee

Dr. Kevin Jackson

Dr. Kevin Wiltz II

Dr. Eric Nepute

Contributors

Dr. Archie Roberts (Research)

Dr. Donald Boles (Pharmacy)

Parameters: Intent is to propose state of Ohio investigate the benefits of Opioid alternative therapy: • PREVENTION: 1000 Post-Op Treatment • REDUCTION OR ELIMINATION: 1000 Chronic/Arthritic   Our Position Statement: Positive patient outcomes are the centerpiece of this proposal.  We have data from existing practitioners that suggests the Dripfusion Chronic Pain product has statistically significant benefits for patients undergoing procedures when used prior-to and post procedure.  One of the primary benefits is the ability to avoid the use of opioids, which have been demonstrated to have significant deleterious effects when perpetuated over a long period of time.  These benefits require further investigation to quantify the evidence suggestive of decreased reliance on pain medication, increased healing, and faster recovery.  By accomplishing these three elements the patient experience is enhanced while completely avoiding opioids altogether.  

Veteran Study 2017 - St. Louis MO

PI: Dr. Eric Nepute

Note: (Raw Data Available Upon Request)

Patient Criteria: Veteran, M/F, Chronic Sufferer, VAS measured 6 or Higher

Dr. Nepute “notes” from our Pro-IV Base therapy. ( VAS | SF 36- We have an enhanced formulation which we made for professional athletes)

▪ The pain numbers moved on average 3 points down after the initial treatment was rendered. Some where higher some were lower. But all patients showed some level of improvement after the initial treatment.

▪ The pain levels dropped An additional 2 points on average for the majority of the participants over the next three week on the study showing a compounding effect of the drug.

▪ The vast majority of the participants in the study showed long term pain relief with the majority of the participants showing a residual reduction in pain up to 4 weeks. None of the pain levels returned fully back to there initial pain level during the refractory period (4 weeks of no IV)

▪ The majority of the patients saw a drop in pain after the initial treatment and it’s stayed the same the entire observation period.

▪ The subjective improvements on top of pain included. ! improved energy ! better sleep ! felt emotionally balanced ! Improved neuropathy symptoms in feet ! blood pressure lowered

▪ The only side offers we noticed were ! Feeling of warmth in the crotch or rectal area during treatment. ! dizziness on occasion most likely do to drop in blood sugar and or drop in blood

pressure. feeling of tired hours after infusion most likely do to detox from vit c chelation effects. two participants noticed slight GI irritation hours after there infusion. Most likely to vit c chelation and disbyosis in the GI track

   

Study Design for Hospital Trial

Abstract: Basic theory:  By utilizing this product combination, we should see pain control sufficient to avoid opiate usage, and an improvement in recovery time for patients.   Key outcomes: Patient Reported Outcomes - VAS scale pre/post op. Morphine equivalent doses reduced ---? ·         Need data regarding opiate usage in the hospital now.  Where is it given most?  ED? Post-Op? ·         Need data on number of opioid generating operations related to the study. o    What kinds of operations would be absolutely contraindicated to utilize something less powerful? o    Are there any operations whereby opiates provide specific benefit? ·         Need data on number of patients seen by the hospital. ·         Is there any longitudinal data regarding these procedures, particularly whether opiates were part of discharge orders.

·          Target is Post-Op??  Why is post op routinely excluded?  Too much variability? ·         Basic question:  "By giving this therapy instead of opiate therapy, how many doses can we reduce that would have ordinarily been done via opiates?"   Measurement (each of these with a baseline , midpoint, and possible post treatment): ·         VAS ·         SF-36 ·         Specific pain assessment: Include locale, activity, exacerbating or mitigating factors, duration of exacerbation or relief, character. ·         Labs needed: CBC w/LFT, Chemistries, Spectracel nutritional assessment pre/post.   Inclusion: ·         Hemodynamically stable patients experiencing painful procedures in the hospital that would otherwise be on opiates. ·         Fibromyalgia ·         Ages 18+   Exclusion: ·         Type of pain not within the scope of review: (WHAT ARE THESE?) ·         Juvenile populations ·         Psychiatric conditions   Basic design:

·         Provide to all patients meeting criteria for a predetermined period of time to assess for pain relief. ·         Patients that are not achieving efficacy using the product will be crossed over into an opiate. o    Do we need to consider breakthrough pain management?  What methodology/what product? ·         Duration: 6 week treatment assessment (challenge that number, why 6?) o    What is the normal post-op followup for the categories of procedures we are going to attempt this on? ·         Follow-up for 6 months - 1 year to establish any long term treatment benefits (improvements in labs, improvements in ADL, improvements in vitals)   Endpoints: ·         Procedure recovery (as a surrogate endpoint) -- at what point would the patient vs practitioner consider themselves recovered? ·         Patient perception via VAS and SF-36.  "do you feel that you have recovered from your procedure?" ·         Surrogate endpoint, to see whether the patient perception of procedure recovery matches that of the practitioner. ·         Complications after surgery or no complications. ·         Laboratory parity or nonimpact ·         Morphine Sparing effect ·         General health followup   Statistical analysis: p=<.05      

EXECUTIVE SUMMARY

Opioid addiction is one of the largest and most devastating epidemics in United States history. According to the Centers for Disease Control and Prevention, opioids (including prescription opioids, heroin, and fentanyl) killed more than 42,000 people in 2016 more than any year on record, an increase from 33,000 people in the previous year Nearly half of all opioid overdose deaths involve a prescription opioid which makes drug overdose the leading cause of accidental death in the nation. According to the American Society of Addiction Medicine, in 2012, 259 million prescriptions were written for opioids, enough for each American adult to have their own bottle of prescription opioids. Furthermore, and more recently, the Society reported that four out of every five new heroin users started by abusing prescription painkillers and 94% of respondents to a 2014 survey switched to heroin because it was a cheaper alternative to prescription opioids. In 2015, 276,000 adolescents were non-medical users of pain relievers with 122,000 of those admitting to having an addiction.

On October 26, 2017, President Donald Trump declared the opioid crisis a public health emergency under federal law. The declaration provides a critical step in confronting the causes and devastating effects of this crisis on a national scale. On November 1, 2017, the President’s Commission on Combating Drug Addiction and the Opioid Crisis issued its report comprising numerous, urgent recommendations. According to the Commission’s report, 175 American lives are lost every day from the opioid abuse epidemic. Fentanyl is the strongest opioid available for medical use by humans, with approximately 100 times the potency of morphine A startling trend has emerged in which fentanyl and fentanyl analogues are combined with inert substances and pressed into pill form and are being sold as counterfeit prescription opioid pills. A recent Centers for Disease Control and Prevention study found that of 5,152 opioid overdose deaths examined, 3,700 tested positive for fentanyl or a fentanyl analog.

In a November 2017 report titled The Underestimated Cost of the Opioid Crisis, the United States Council of Economic Advisors found that the 33,000 Americans who died in 2015 due to opioid related overdose represented 63% of all reported drug overdose deaths in the United States. The Council estimated economic costs of the crisis were over $500 billion in 2015 alone, equal to 2.8% of National Gross Domestic Product. A survey by the Substance Abuse and Mental Health Services Administration indicates that 2.4 million Americans have an opioid use disorder. Within the overall economic impact of this crisis, the non-fatal costs of treatment for an overdose is an estimated $58 billion nationally. The increasing economic burden and the compounding effect of lost human life caused by the opioid epidemic have presented systemic issues throughout the country that must be addressed through a multifaceted and collaborative approach. The Committee is hopeful that the recommendations put forth by the President’s Commission will lead to sweeping changes, increased funding, and heightened

national awareness to opioid use disorder, further strengthening the ability and capacity of the states to address these issues locally.

In addition to the economic impact in terms of cost, there is a deeper and more serious effect on productivity in the workplace, school classroom, playing fields for sports from athletes at all playing levels and the control of pain resulting from the above activities.

• Opioid abuse cost employers nationally $16.3 billion in 2013, due to reduced productivity and increased disability.

• A 2016 survey by the International Foundation of Employee Benefit Plans indicated that a third of employers in the survey reported that prescription drug addiction is at least somewhat prevalent among their workforce and that more than two-thirds believe that substance abuse challenges are greater now than five years ago.

• The average employer medical costs were nearly twice as much for opioid abusers, $19,450, than non-abusers, $10,583, in 2015, according to a 2016 study by San Francisco-based health care information firm Castlight Health Inc. ("The opioid crisis in America's workforce," U.S. Centers for Disease Control and Prevention)

• The average opioid abuser is older, lower-income and in pain, according to the Castlight study. Opioid prescribing peaks in the 45-64 age group, due in part to increasing prevalence of chronic pain with age, according to a recent CDC report.

• 11 percent, or 1 in 9 young people aged 12-25 used prescription drugs non-medically within the past year. According to the National Institute on Drug Abuse (NIDA), Vicodin, a commonly prescribed opioid pain reliever tops the list at 8 percent.

• The Centers for Disease Control and Prevention (CDC) reported that the number of people seen in hospital emergency departments for opioid overdoses jumped by about 30 percent in just a 14-month period between the third quarter of 2016 and the third quarter of 2017. Substantial increases were found among women and men, all age groups and all regions of the country.

• Chronic pain affects an estimated 100 million Americans, and between 5 to 8 million use opioids for long-term pain management.

• In February 2015, the NIH published its findings in the Annals of Internal Medicine, detailing a lack of research into better treatment methods and poor preparedness among physicians. “The prevalence of chronic pain and the increasing use of opioids have created a ‘silent epidemic’ of distress, disability, and danger to a large percentage of Americans,”

• For better care, the NIH suggests the medical community needs to start applying individualized treatment for chronic pain, and a multi-disciplinary approach should be used. Since pain is both physical and emotional and can affect all aspects of a person’s life, there should be more than one specialty involved in patient management.

• The NIH says there’s a lack of data that favors long-term use of opioids, and that other treatments like physical therapy and alternative and complementary medicine should be considered.

The root issue creating the need for opioid initial use is pain that is the result of numerous activities or stations of life from sports related injuries; repetitive activity during work; injuries from accidents and the ageing process. Pain can affect all segments of society. The most predominant treatment for pain has been the use of chemical compounds which contain opioids. Research indicates that opioids create patient addiction to the pain-relieving aspects to the chemicals.

DISCUSSION

Drip América and Pro IV are citizen-led initiatives in which we are taking real action to prevent the damages caused by opioids as well as other dangers such as concussions. DripFusion Enterprises, Inc. has developed non-opioid, non-steroid, safe, nonaddictive solutions for chronic pain and acute concussion. Pro-IV combinatory intravenous therapies open a new era in drug design and manufacturing as DripFusion technology merges trace minerals, micronutrients, and small-yet-effective dosages of synthetic drugs. At a minimum, 97.3% of these components are found in nature. Presently, all individual elements are FDA approved or manufactured by an FDA approved registrant. Pro-IV Chronic Pain Therapy is the Prevention Solution for the opioid crisis. Pro-IV is also the solution for anyone living with inflammation and chronic pain. PRO-IV is a collaboration of world renowned athletes and world-renowned physicians that create therapies to improve the safety, performance and quality of life for anyone living an active lifestyle. Pro-IV is administered intravenously which allows maximum effectiveness.

Pro-IV therapy is non-opioid, non-steroid, non-addictive, 97% all natural and extremely effective alternative treatment for chronic pain. The utilization of Pro IV equals 0% chance of opioid addiction. Objectives:

• Reduce inflammation which will allow for better outcomes • Eliminate Opioid Addiction

Pro-IV has proven to be effective in the treatment of chronic pain based on results of a test group composed of Professional Athletes and Military Veterans. All elements of the Pro-IV therapy utilizes micronutrients, trace minerals and a low dose synthetic drug that are approved by the Food & Drug Administration (FDA) or created by an FDA approved registrant as this therapy reduces inflammation; mitigates targeted chronic pain and has been documented to address other chronic health issues.

Pro-IV is administered intravenously which allows maximum effectiveness. Pro-IV therapy is non-opioid, non-steroid, non-addictive, 97% all natural and extremely effective alternative treatment for chronic pain. The utilization of Pro IV equals 0% chance of opioid addiction. This project will focus on the therapy administered to 1,000 (One thousand) Senior Citizens whose progress will be monitored by the Grantee and the results will be reported to the State of South Carolina to determine the applicability of this compound to:

• Reduce inflammation which will allow for better health outcomes with this segment of population

• Reduce and eliminate Opioid Addiction

We are proposing a double focused approach in that we proceed in a field study parameter with each participant group and the Hospital consider utilizing the compound as an alternate pain reliever, as the product has been accepted by most of the insurers in the South Carolina Marketplace.

Who we are:

DripAmerica is a citizen-led initiative whereby real action is taken to prevent the damages caused by opioid addiction as well as other dangers such as concussions. An affiliated company, DripFusion Enterprises, Inc., has developed non-opioid, non-steroid, safe, non-addictive solutions for chronic pain and acute concussion. Pro-IV combinatory intravenous therapies open a new era in drug design and manufacturing as DripFusion technology merges trace minerals, micronutrients, and small-yet-effective dosages of synthetic drugs. At a minimum, 97.3% of these components are found in nature. Presently, all individual elements are FDA approved or manufactured by an FDA approved registrant.

Our People

DripFusion Enterprises, Inc. Clinical Directors

Dr. Mark M. Beaty - Double Board-Certified Surgeon

Dr. Jackie Walters - OBGYN& Surgeon

Dr. Kevin Jackson - Board Certified Neurosurgeon

Dr. Terrence Fullum - Board Certified Surgeon

Dr. Eric Nepute - Chiropractor/Neurology Certs.

Dr. Kevin Dennis - Pharmacy/Trauma Physician

Dr. Melvin Forbes - Forbes Consulting

Dr. Thomas Coleman - Criminal Justice

Dr. Kevin Wiltz - Pharm D - PUYDF BOD - Pharmacy (Formulation Design)

Steven Hall - Water Specialist

Dr. Jerlunder Clark MD - Integrated Pain Management

Dr. Jake VanLandingham - Bimolecular Engineer

Health Industry Experts

Dr. Lori Wilson - Board Certified Surgical Oncologist

Dr W. John Martin - M I Hope, Inc.

The History (Current Activities)

Clinical Trials and Case Studies

1. Pre & Post “Cranial” - Dr. Mark Beaty

2. Pre & Post Bariatric- Dr. Terrence Fullum

3. C-Drip Stage

4. Cancer Dripfusion (Dot-42) - Dr. Lori Wilson

5. 4. Pro-IV Acute & Refractory – Dr. Kevin Jackson

6. Veterans Chronic Pain - Dr. Eric Nepute, Dr. Kevin Wiltz - CMO

Dripfusion Institute Research Partners

Howard University Hospital

Animal Model Research - Florida State University College of Medicine

Pro-IV Chronic Pain Therapy is the Prevention Solution for the opioid crisis. Pro-IV is also the solution for anyone living with inflammation and chronic pain. PRO-IV is a collaboration of world renowned athletes and world-renowned physicians that created therapies to improve the safety, performance and quality of life for anyone living an active lifestyle. Pro-IV is administered intravenously which allows maximum effectiveness. Pro-IV therapy is non-opioid, non-steroid, non-addictive, 97% all natural and extremely effective alternative treatment for chronic pain. The utilization of Pro IV equals 0% chance of opioid addiction.

Outcomes:

• Reduce inflammation which will allow for better outcomes

• Reduce and eliminate Opioid Addiction

DRIPFUSION ENTERPRISES, INC.

Pro-IV has proven to be effective in the treatment of chronic pain based on results of a test group composed of Professional Athletes and Military Veterans. All elements of the Pro-IV therapy utilizes micronutrients, trace minerals and a low dose synthetic drug that are approved by the Food & Drug Administration (FDA) or created by an FDA approved registrant as this therapy reduces inflammation; mitigates targeted chronic pain and has been documented to address other chronic health issues.

DripFusion/Pro-IV Chronic Pain Formulation: Combination Product:

Experimental IV Treatment of Chronic Pain Base formula micronutrients including a saline solution, Vitamin B1, B2, B3, and B9, Magnesium, Vitamin C and Ketorolac.

Novelty and Success: DripFusion Institute treated 110 veterans with the Pro-IV chronic

pain infusion as part of a study in St. Louis, Missouri.

Results

• Most of the pain numbers moved an average 3 points down after the initial treatment was administered. All patients showed some level of improvement after the initial treatment.

• The pain levels dropped an additional 2 points on average for most of the participants over the next three weeks on the study showing a compounding effect of the drug.

• The majority of the participants in the study showed long term pain relief with a residual reduction in pain up to 4 weeks after treatment. None of the pain levels returned fully back to the initial pain level during the refractory period (4 weeks of no IV)

• The subjective improvements on top of pain included:

o Improved energy

o Better sleep

o Improved emotional balance

o Improved neuropathy symptoms in feet

o Lower blood pressure

Side Effects:

• Feeling of warmth in the crotch or rectal area during treatment.

• Dizziness on occasion most likely do to the drop-in blood sugar and or drop in blood pressure.

• Short term fatigue after infusion most likely a result of the detox from Vitamin C chelation effects.

• Two participants noticed slight GI irritation hours after the infusion resulting from Vitamin C chelation and dysbiosis in the GI track

BUDGET

DFE CURRENTLY bills $1,100.00 per treatment to All Major insurance carriers. DFE to provide: $700 Per Treatment

• Program Administrator • All Pharmaceuticals 15,000 Infusions • DFE Treatments (see coalition below) • All Educational/Promotional Treatments (Health Fairs, Veteran, Town Hall &

Municipal meetings) • Collect Data

• Preventions • VAS • SF 36 • Labs • Epigenetics • BP, Diabetes, Heart Disease, Other conditions • Counseling Solutions

• Manage Data • Publish Data • Patient Intake (Informed Consent) • Education (Town Halls, Schools, Prison’s, Jails, Clinics, Homeless Shelters) • Marketing (Radio, TV, Digital) • B.A.C.K. Set Up • Site Renovation/Construction

Pro-IV Solution Design

Warnings Pro-IV is a combination product that requires clinicians be familiar with the administration of the individual components to achieve optimal effects.

Ketamine used for Anesthesia has caused emergence reactions in approximately 12 percent of patients. Dosages used for Pro-IV Refractory Concussion are sub-anesthetic and thusly not anticipated to cause these reactions. Patients are advised to be under observation during the treatment.

Description The Pro-IV Suite of products is a prescription only sterile, nonpyrogenic combination of established pharmaceutical products including Methylcobalamin, Ascorbic Acid, B Complex (Thiamine, Riboflavin, and Niacinamide), Folic Acid, and Magnesium Sulfate collectively known a Pro-IV Edge. Pro-IV Commercial and Pro-IV Elite include all the components of the Pro-IV Edge with injectable ketorolac tromethamine, USP for the relief of inflammatory conditions and pain where there is a therapeutic need. Pro-IV FiRe includes all components of Pro-IV Edge with 1000mg of Acetaminophen for first response treatment of concussive events. Pro-IV Refractory Concussion includes all components of Pro-IV Edge with ketamine HCl (CIII) for treatment of refractory concussive events.

Each kit contains single-moiety vials of the sterile solutions which are combined at the point of care in s compatible solution according to the treatment protocol.

Methylcobalamin1 Methylcobalamin, or vitamin B12, is a B-vitamin. It is found in a variety of foods such as fish, shellfish, meats, and dairy products. Although methylcobalamin and vitamin B12 are terms used interchangeably, vitamin B12 is also available as hydroxocobalamin, a less commonly prescribed drug product (see Hydroxocobalamin monograph), and methylcobalamin. Methylcobalamin is used to treat pernicious anemia and vitamin B12 deficiency, as well as to determine vitamin B12 absorption in the Schilling test. Vitamin B12 is an essential vitamin found in the foods such as meat, eggs, and dairy products. Deficiency in healthy individuals is rare; the elderly, strict vegetarians (i.e., vegan), and patients with malabsorption problems are more likely to become deficient. If vitamin B12 deficiency is not treated with a vitamin B12 supplement, then anemia, intestinal problems, and irreversible nerve damage may occur. The chemical formula is below:

The most chemically complex of all the vitamins, methylcobalamin is a water-soluble, organometallic compound with a trivalent cobalt ion bound inside a corrin ring which, although similar to the porphyrin ring found in heme, chlorophyll, and cytochrome, has two of the pyrrole rings directly bonded.  The central metal ion is Co (cobalt).  Methylcobalamin cannot be made by plants or by animals; the only type of organisms that have the enzymes required for the synthesis of methylcobalamin are bacteria and archaea.  Higher plants do not concentrate methylcobalamin from the soil, making them a poor source of the substance as compared with animal tissues. 

Ascorbic Acid2 Ascorbic Acid (vitamin C) is a water-soluble vitamin. It occurs as a white or slightly yellow crystal or powder with a light acidic taste. It is an antiscorbutic product. On exposure to air and light it gradually darkens. In the dry state it is reasonably stable in air, but in solution it rapidly oxidizes. Ascorbic Acid is freely soluble in water; sparingly soluble in alcohol; insoluble in chloroform, ether, and benzene. The chemical name of Ascorbic Acid is L-ascorbic acid. The molecular formula is C6H806 and the molecular weight is 176.13. The structural formula is as follows:

Ascorbic Acid injection is a clear, colorless to slightly yellow sterile solution of Ascorbic Acid in Water for Injection, for intravenous, intramuscular or subcutaneous use. Each ml contains : Ascorbic Acid 500 mg, Disodium Edetate 0.25 mg, Sodium Hydroxide 110 mg, in Water for Injection q.s. pH (range 5.5 to 7.0) adjusted with Sodium Bicarbonate and Sodium Hydroxide. Contains no preservatives.

B Complex (Thiamine, Riboflavin, Niacinamide)3

Vitamin B-Complex 100 Injection is a sterile solution for intramuscular or slow intravenous injection comprised of vitamins which may be categorized as belonging to the vitamin B complex group.

Each mL contains: Thiamine Hydrochloride 100 mg, Riboflavin 5’ Phosphate Sodium 2 mg, Niacinamide 100 mg, with Benzyl Alcohol 2% as preservative, in Water for Injection. Sodium Hydroxide and/or Hydrochloric Acid may have been used to adjust pH.

Folic Acid4 Folic Acid Injection, USP is a sterile, nonpyrogenic solution of sodium folate (prepared by the addition of sodium hydroxide to folic acid) in Water for Injection intended for intramuscular (IM), intravenous (IV) or subcutaneous (SC) use.

Folic Acid is a complex organic compound present in liver, yeast and other substances, which may be prepared synthetically. It is a yellow or yellowish orange, odorless crystalline powder. It is very slightly soluble in water, insoluble in alcohol, chloroform, ether; readily dissolves in dilute solutions of alkali hydroxides and carbonates. It is chemically designated as: L-Glutamic acid, N-[4-[[(2-amino-1-4-dihydro-4-oxo-6-pteridinyl) methyl] amino]benzoyl]-, and has the following structural formula:

Each mL contains: Sodium folate (equivalent to 1 mg folic acid); edetate disodium 2 mg; benzyl alcohol 15 mg (added as preservative); Water for Injection q.s. Hydrochloric acid and/or sodium hydroxide for pH adjustment (8.0 to 11.0).

Magnesium Sulfate5

Magnesium Sulfate Injection, USP is a sterile solution of magnesium sulfate heptahydrate in Water for Injection, USP administered by the intravenous or intramuscular routes as an electrolyte replenisher or anticonvulsant. Must be diluted before intravenous use. May contain sulfuric acid and/or sodium hydroxide for pH adjustment. The pH is 6.0 (5.5 to 7.0). The 50% concentration has an osmolarity of 4.06 mOsmol/mL (calc.).

The solution contains no bacteriostat, antimicrobial agent or added buffer (except for pH adjustment) and is intended only for use as a single-dose injection. When smaller doses are required the unused portion should be discarded with the entire unit.

Magnesium Sulfate, USP heptahydrate is chemically designated MgSO4 • 7H2O with molecular weight of 246.48 and occurs as colorless crystals or white powder freely soluble in water.

Multitrace 56

MULTITRACE - 5 CONCENTRATE (TRACE ELEMENTS INJECTION 5, USP) is a sterile nonpyrogenic CONCENTRATED solution containing five Trace Elements.

Each mL Contains: Zinc Sulfate Heptahydrate 22 mg (equivalent to 5 mg Zinc); Cupric Sulfate Pentahydrate 3.93 mg (equivalent to 1 mg Copper); Manganese Sulfate Monohydrate 1.54 mg (equivalent to 0.5 mg Manganese); Chromic Chloride Hexahydrate 51.3 mcg (equivalent to 10 mcg Chromium); Selenious Acid 98 mcg (equivalent to 60 mcg Selenium); and Water for Injection q.s. pH of the solution may have been adjusted with Sulfuric Acid. The 10 mL Multiple Dose Vial contains 0.9% Benzyl Alcohol as an antimicrobial preservative.

Ketorolac7 Ketorolac tromethamine is a member of the pyrrolo-pyrrole group of nonsteroidal anti-inflammatory drugs (NSAIDs). The chemical name for ketorolac tromethamine is (±)-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, compound with 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1), and the structural formula is below:

Ketorolac tromethamine is a racemic mixture of [-]S and [+]R ketorolac tromethamine. Ketorolac tromethamine may exist in three crystal forms. All forms are equally soluble in water. Ketorolac tromethamine has a pKa of 3.5 and an n-octanol/water partition coefficient of 0.26. The molecular weight of ketorolac tromethamine is 376.40.

Ketorolac Tromethamine Injection USP is available for intravenous (IV) or intramuscular (IM) administration as: 15 mg in 1 mL (1.5%) and 30 mg in 1 mL (3%) in sterile solution; 60 mg in 2 mL (3%) and 300 mg in 10 mL (3%) of ketorolac tromethamine in sterile solution is available for IM administration only. The solutions contain 10% (w/v) alcohol, USP, and 6.68 mg, 4.35 mg, 8.70 mg, and 43.5 mg respectively, of sodium chloride in sterile water. The pH range is 6.9 to 7.9 and is adjusted with sodium hydroxide and/or hydrochloric acid. The sterile solutions are clear and slightly yellow in color.

Ketamine Hydrochloride8

Ketamine hydrochloride is a nonbarbiturate anesthetic chemically designated (±)-2-(o-Chlorophenyl)-2-(methylamino) cyclohexanone hydrochloride. It is formulated as a

slightly acid (pH 3.5 to 5.5) sterile solution for intravenous or intramuscular injection in concentrations containing the equivalent of either 50 or 100 mg ketamine base per milliliter and contains not more than 0.1 mg/mL benzethonium chloride added as a preservative. Ketamine hydrochloride has a molecular formula of C13H16ClNO • HCl, a molecular weight of 274.19 and the following structural formula:

Clinical Pharmacology Methylcobalamin1 Vitamin B12 is used in the body in two forms, methylcobalamin and 5-deoxyadenosyl cobalamin.  The enzyme methionine synthase needs methylcobalamin as a cofactor.  This enzyme is involved in the conversion of the amino acid homocysteine into methionine which is, in turn, required for DNA methylation.  The other form, 5-deoxyadenosylcobalamin, is a cofactor needed by the enzyme that converts L-methylmalonyl-CoA to succinyl-CoA.  This conversion is an important step in the extraction of energy from proteins and fats. Furthermore, succinyl CoA is necessary for the production of hemoglobin, the substance that carries oxygen in red blood cells.

Vitamin B12, or methylcobalamin, is essential to growth, cell reproduction, hematopoiesis, and nucleoprotein and myelin synthesis. Cells characterized by rapid division (epithelial cells, bone marrow, myeloid cells) appear to have the greatest requirement for methylcobalamin. Vitamin B12 can be converted to coenzyme B12 in tissues; in this form it is essential for conversion of methylmalonate to succinate and synthesis of methionine from homocysteine (a reaction which also requires folate). In the absence of coenzyme B12, tetrahydrofolate cannot be regenerated from its inactive storage form, 5-methyl tetrahydrofolate, resulting in functional folate deficiency. Vitamin B12 also may be involved in maintaining sulfhydryl (SH) groups in the reduced form required by many SH-activated enzyme systems. Through these reactions, vitamin B12 is associated with fat and carbohydrate metabolism and protein synthesis. Vitamin B12 deficiency results in megaloblastic anemia, GI lesions, and neurologic damage (which begins with an inability to produce myelin and is followed by gradual degeneration of the axon and nerve head). Vitamin B12 requires

an intrinsic factor-mediated active transport for absorption, therefore, lack of or inhibition of intrinsic factor results in pernicious anemia.

Pharmacokinetics

Methylcobalamin is administered intranasally, orally, and parenterally, while hydroxocobalamin is administered only parenterally. Once absorbed, vitamin B12 is highly bound to transcobalamin II, a specific B-globulin carrier protein and is distributed and stored primarily in the liver as coenzyme B12. The bone marrow also stores a significant amount of the absorbed vitamin B12. This vitamin crosses the placenta and is distributed into breast milk. Enterohepatic recirculation conserves systemic stores. The half-life is about 6 days (400 days in the liver). Elimination is primarily through the bile; however, excess methylcobalamin is excreted unchanged in the urine.

Intravenous Route: Peak plasma levels of cyanocobalamin are attained within 1 hour for parenteral doses. Methylcobalamin is expected to behave the same.

Ascorbic Acid2

In humans, an exogenous source of ascorbic acid is required for collagen formulation and tissue repair. Ascorbic acid is reversibly oxidized to dehydroascorbic acid in the body. These two forms of the vitamin are believed to be important in oxidation-reduction reactions. The vitamin is involved in tyrosine metabolism, conversion of folic acid to folinic acid, carbohydrate metabolism, synthesis of lipids and proteins, iron metabolism, resistance to infections, and cellular respiration. Ascorbic acid deficiency results in scurvy. Collagenous structures are primarily affected, lesions develop in bones and blood vessels. Administration of ascorbic acid completely reverses the symptoms of ascorbic acid deficiency.

B Complex (Thiamine, Riboflavin, Niacinamide)

Folic Acid4 In man, an exogenous source of folate is required for nucleoprotein synthesis and maintenance of normal erythropoiesis. Folic acid, whether given by mouth or parenterally, stimulates specifically the production of red blood cells, white blood cells and platelets in persons suffering from certain megaloblastic anemias.

Magnesium Sulfate5

Magnesium (Mg++) is an important cofactor for enzymatic reactions and plays an important role in neurochemical transmission and muscular excitability.

As a nutritional adjunct in hyperalimentation, the precise mechanism of action for magnesium is uncertain. Early symptoms of hypomagnesemia (less than 1.5 mEq/liter) may develop as early as three to four days or within weeks.

Predominant deficiency effects are neurological, e.g., muscle irritability, clonic twitching and tremors. Hypocalcemia and hypokalemia often follow low serum levels of magnesium. While there are large stores of magnesium present intracellularly and in the bones of adults, these stores often are not mobilized sufficiently to maintain plasma levels. Parenteral magnesium therapy repairs the plasma deficit and causes deficiency symptoms and signs to cease.

Magnesium prevents or controls convulsions by blocking neuromuscular transmission and decreasing the amount of acetylcholine liberated at the end plate by the motor nerve impulse. Magnesium is said to have a depressant effect on the central nervous system (CNS), but it does not adversely affect the woman, fetus or neonate when used as directed in eclampsia or pre-eclampsia. Normal plasma magnesium levels range from 1.5 to 2.5 mEq/liter.

As plasma magnesium rises above 4 mEq/liter, the deep tendon reflexes are first decreased and then disappear as the plasma level approaches 10 mEq/liter. At this level respiratory paralysis may occur. Heart block also may occur at this or lower plasma levels of magnesium. Serum magnesium concentrations in excess of 12 mEq/L may be fatal.

Magnesium acts peripherally to produce vasodilation. With low doses only flushing and sweating occur, but larger doses cause lowering of blood pressure. The central and peripheral effects of magnesium poisoning are antagonized to some extent by intravenous administration of calcium.

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ZINC has been identified as a cofactor for over 70 different enzymes, including alkaline phosphatase, lactic dehydrogenase and both RNA and DNA polymerase. Zinc facilitates wound healing, helps maintain normal growth rates, normal skin hydration and senses of taste and smell. Providing zinc during TPN prevents development of the following deficiency symptoms: Parakeratosis, hypogeusia, anorexia, dysosmia, geophagia, hypogonadism, growth retardation and hepatosplenomegaly. At plasma levels below 20 mcg zinc/100 mL, dermatitis followed by alopecia has been reported for TPN patients.

COPPER is essential as a cofactor for serum ceruloplasmin, an oxidase necessary for proper formation of the iron carrier protein, transferrin. Copper also helps maintain normal rates of red and white blood cell formation. Scorbutic type bone changes seen in infants fed exclusively with copper poor cow's milk are believed due to decreased activity of ascorbate oxidase, a cuproenzyme. Providing copper during TPN prevents development of the following deficiency symptoms: leukopenia, neutropenia, anemia, depressed ceruloplasmin levels, impaired transferrin formation and secondary iron deficiency.

MANGANESE is an activator for enzymes such as polysaccharide polymerase, liver arginase, cholinesterase and pyruvate carboxylase. Providing manganese during TPN prevents development of the following deficiency symptoms: nausea and vomiting, weight loss, dermatitis, and changes in growth and color of hair.

CHROMIUM (trivalent) is part of glucose tolerance factor, an activator of insulin-mediated reactions. Chromium helps to maintain normal glucose metabolism and peripheral nerve function. Providing chromium during TPN prevents development of the following deficiency symptoms: impaired glucose tolerance, ataxia, peripheral neuropathy and a confusional state similar to mild/moderate hepatic encephalopathy.

SELENIUM is part of glutathione peroxidase which protects cell components from oxidative damage due to peroxides produced in cellular metabolism. Prolonged TPN support in humans has resulted in selenium deficiency symptoms which include muscle pain and tenderness. The symptoms have been reported to respond to supplementation of TPN solutions with selenium.

Ketorolac7 Pharmacodynamics

Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits analgesic activity in animal models. The mechanism of action of ketorolac, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition. The biological activity of ketorolac tromethamine is associated with the S-form. Ketorolac tromethamine possesses no sedative or anxiolytic properties.

The peak analgesic effect of ketorolac tromethamine occurs within 2 to 3 hours and is not statistically significantly different over the recommended dosage range of ketorolac tromethamine. The greatest difference between large and small doses of ketorolac tromethamine is in the duration of analgesia.

Pharmacokinetics

Ketorolac tromethamine is a racemic mixture of [-]S and [+]R-enantiomeric forms, with the S-form having analgesic activity.

Linear Kinetics: In adults, following administration of single ORAL, IM or IV doses of ketorolac tromethamine in the recommended dosage ranges, the clearance of the racemate does not change. This implies that the pharmacokinetics of ketorolac tromethamine in adults, following single or multiple IM, IV or recommended oral doses of ketorolac tromethamine, are linear. At the higher recommended doses, there is a proportional increase in the concentrations of free and bound racemate.

Distribution: The mean apparent volume (Vβ) of ketorolac tromethamine following complete distribution was approximately 13 liters. This parameter was determined from single-dose data. The ketorolac tromethamine racemate has been shown to be

highly protein bound (99%). Nevertheless, plasma concentrations as high as 10 mcg/mL will only occupy approximately 5% of the albumin binding sites. Thus, the unbound fraction for each enantiomer will be constant over the therapeutic range. A decrease in serum albumin, however, will result in increased free drug concentrations.

Ketorolac tromethamine is excreted in human milk (see PRECAUTIONS: Nursing Mothers).

Metabolism: Ketorolac tromethamine is largely metabolized in the liver. The metabolic products are hydroxylated and conjugated forms of the parent drug. The products of metabolism, and some unchanged drug, are excreted in the urine.

Excretion: The principal route of elimination of ketorolac and its metabolites is renal. About 92% of a given dose is found in the urine, approximately 40% as metabolites and 60% as unchanged ketorolac. Approximately 6% of a dose is excreted in the feces. A single-dose study with 10 mg ketorolac tromethamine (n=9) demonstrated that the S-enantiomer is cleared approximately two times faster than the R-enantiomer and that the clearance was independent of the route of administration. This means that the ratio of S/R plasma concentrations decreases with time after each dose. There is little or no inversion of the R- to S- form in humans. The clearance of the racemate in normal subjects, elderly individuals and in hepatically and renally impaired patients is outlined in Table 2 (see CLINICAL PHARMACOLOGY: Kinetics in Special Populations). The half-life of the ketorolac tromethamine S-enantiomer was approximately 2.5 hours (SD ± 0.4) compared with 5 hours (SD ± 1.7) for the R-enantiomer. In other studies, the half-life for the racemate has been reported to lie within the range of 5 to 6 hours.

Accumulation: Ketorolac tromethamine administered as an IV bolus, every 6 hours for 5 days to healthy subjects (n = 13), showed no significant difference in Cmax on Day 1 and Day 5. Trough levels averaged 0.29 mcg/mL (SD ± 0.13) on Day 1 and 0.55 mcg/mL (SD ± 0.23) on Day 6. Steady state was approached after the fourth dose. Accumulation of ketorolac tromethamine has not been studied in special populations (geriatric, pediatric, renal failure or hepatic disease patients).

Kinetics in Special Populations

Geriatric Patients: Based on single-dose data only, the half-life of the ketorolac tromethamine racemate increased from 5 to 7 hours in the elderly (65 to 78 years) compared with young healthy volunteers (24 to 35 years) (see Table 2). There was little difference in the Cmax for the two groups (elderly, 2.52 mcg/mL ± 0.77; young, 2.99 mcg/mL ± 1.03) (see PRECAUTIONS - Geriatric Use).

Pediatric Patients: Limited information is available regarding the pharmacokinetics of dosing of ketorolac tromethamine in the pediatric population. Following a single intravenous bolus dose of 0.5 mg/kg in 10 children 4 to 8 years old, the half-life was 5.8 ± 1.6 hours, the average clearance was 0.042 ± 0.01 L/hr/kg, the volume of

distribution during the terminal phase (Vβ) was 0.34 ± 0.12 L/kg and the volume of distribution at steady state (Vss) was 0.26± 0.08 L/kg. The volume of distribution and clearance of ketorolac in pediatric patients was higher than those observed in adult subjects (see Table 1). There are no pharmacokinetic data available for administration of ketorolac tromethamine by the IM route in pediatric patients.

Renally Insufficiency: Based on single-dose data only, the mean half-life of ketorolac tromethamine in renally impaired patients is between 6 and 19 hours, and is dependent on the extent of the impairment. There is poor correlation between creatinine clearance and total ketorolac tromethamine clearance in the elderly and populations with renal impairment (r = 0.5). In patients with renal disease, the AUC∞ of each enantiomer increased by approximately 100% compared with healthy volunteers. The volume of distribution doubles for the S-enantiomer and increases by 1/5th for the R-enantiomer. The increase in volume of distribution of ketorolac tromethamine implies an increase in unbound fraction. The AUC∞-ratio of the ketorolac tromethamine enantiomers in healthy subjects and patients remained similar, indicating there was no selective excretion of either enantiomer in patients compared to healthy subjects (see WARNINGS - Renal Effects).

Hepatic Insufficiency: There was no significant difference in estimates of half-life, AUC∞ and Cmax in 7 patients with liver disease compared to healthy volunteers (see PRECAUTIONS: Hepatic Effect and Table 2).

Race: Pharmacokinetic differences due to race have not been identified.

Ketamine Hydrochloride8

Ketamine is a rapid-acting general anesthetic producing an anesthetic state characterized by profound analgesia, normal pharyngeal-laryngeal reflexes, normal or slightly enhanced skeletal muscle tone, cardiovascular and respiratory stimulation, and occasionally a transient and minimal respiratory depression.

When used for anesthesia, a patent airway is maintained partly by virtue of unimpaired pharyngeal and laryngeal reflexes. (See WARNINGS and PRECAUTIONS Sections.) The biotransformation of ketamine includes N-dealkylation (metabolite I), hydroxylation of the cyclohexone ring (metabolites III and IV), conjugation with glucuronic acid and dehydration of the hydroxylated metabolites to form the cyclohexene derivative (metabolite II).

Following intravenous administration, the ketamine concentration has an initial slope (alpha phase) lasting about 45 minutes with a half-life of 10 to 15 minutes. This first phase corresponds clinically to the anesthetic effect of the drug. The anesthetic action is terminated by a combination of redistribution from the CNS to slower equilibrating peripheral tissues and by hepatic biotransformation to metabolite I. This metabolite is about 1/3 as active as ketamine in reducing halothane requirements (MAC) of the rat. The later half-life of ketamine (beta phase) is 2.5 hours. The

anesthetic state produced by ketamine has been termed “dissociative anesthesia” in that it appears to selectively interrupt association pathways of the brain before producing somatesthetic sensory blockade. It may selectively depress the thalamoneocortical system before significantly obtunding the more ancient cerebral centers and pathways (reticular-activating and limbic systems).

Elevation of blood pressure begins shortly after injection, reaches a maximum within a few minutes and usually returns to preanesthetic values within 15 minutes after injection. In the majority of cases, the systolic and diastolic blood pressure peaks from 10% to 50% above preanesthetic levels shortly after induction of anesthesia, but the elevation can be higher or longer in individual cases (see CONTRAINDICATIONS Section).

Ketamine has a wide margin of safety; several instances of unintentional administration of overdoses of ketamine (up to ten times that usually required) have been followed by prolonged but complete recovery.

Ketamine has been studied in over 12,000 operative and diagnostic procedures, involving over 10,000 patients from 105 separate studies. During the course of these studies ketamine hydrochloride was administered as the sole agent, as induction for other general agents, or to supplement low-potency agents.

Specific areas of application have included the following:

1. debridement, painful dressings, and skin grafting in burn patients, as well as other superficial surgical procedures.2. neurodiagnostic procedures such as pneumonencephalograms, ventriculograms, myelograms, and lumbar punctures. See also PRECAUTION concerning increased intracranial pressure.

3. diagnostic and operative procedures of the eye, ear, nose, and mouth, including dental extractions.

4. diagnostic and operative procedures of the pharynx, larynx, or bronchial tree. NOTE: Muscle relaxants, with proper attention to respiration, may be required (see PRECAUTIONS section).

5. sigmoidoscopy and minor surgery of the anus and rectum, and circumcision.

6. extraperitoneal procedures used in gynecology such as dilatation and curettage.

7. orthopedic procedures such as closed reductions, manipulations, femoral pinning, amputations,

and biopsies.

8. as an anesthetic in poor-risk patients with depression of vital functions.

9. in procedures where the intramuscular route of administration is preferred.

10. in cardiac catheterization procedures.

In these studies, the anesthesia was rated either “excellent” or “good” by the anesthesiologist and the surgeon at 90% and 93%, respectively; rated “fair” at 6% and 4%, respectively; and rated “poor” at 4% and 3%, respectively. In a second method of evaluation, the anesthesia was rated “adequate” in at least 90% and “inadequate” in 10% or less of the procedures.

At subanesthetic dosages, Ketamine has been utilized for the treatment of refractory depression, migraines secondary to concussive events, and is under investigation as a rapid antidepressant tool. It has also been suggested for its role in the treatment of intractable chronic pain with an analgesic effect lasting beyond the duration of its infusion.

Indications and Usage Pro-IV Edge is indicated for mild inflammatory conditions that may benefit from micronutrient replacement

Pro-IV Elite and Pro-IV Commercial are indicated to release moderate to severe inflammatory conditions where we have a therapeutic need.

Pro-IV FiRe is indicated to improve symptomatic effects of concussion if given within 21 days of a precipitating concussive event.

Pro-IV Refractory Concussion is indicated to improve symptoms consistent with concussion for events identified as having taken place in excess of 21 days.

Contraindications Methylcobalamin1 Methylcobalamin is contraindicated in patients with methylcobalamin hypersensitivity or hypersensitivity to any of the medication components. Methylcobalamin is also contraindicated in patients with cobalt hypersensitivity because methylcobalamin contains cobalt. In the case of suspected cobalt hypersensitivity, an intradermal test dose should be administered because anaphylactic shock and death have followed parenteral administration of methylcobalamin.

Methylcobalamin should not be used in patients with early hereditary optic nerve atrophy (Leber's disease). Optic nerve atrophy can worsen in patients whose methylcobalamin levels are already elevated. Hydroxocobalamin is the preferred agent in this patient population (see separate monograph in Less Common Drugs).

B-Complex (Thiamine, Riboflavin, Niacinamide)3

Sensitivity to the ingredients listed.

Magnesium Sulfate5

Parenteral administration of the drug is contraindicated in patients with heart block or myocardial damage.

Ketorolac7 Ketorolac Tromethamine is contraindicated in patients with previously demonstrated hypersensitivity to ketorolac tromethamine.

Ketorolac tromethamine is contraindicated in patients with active peptic ulcer disease, in patients with recent gastrointestinal bleeding or perforation and in patients with a history of peptic ulcer disease or gastrointestinal bleeding.

Ketorolac tromethamine should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS – Anaphylactoid Reactions, and PRECAUTIONS – Preexisting Asthma).

Ketorolac tromethamine is contraindicated as prophylactic analgesic before any major surgery.

Ketorolac tromethamine is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

Ketorolac tromethamine is contraindicated in patients with advanced renal impairment or in patients at risk for renal failure due to volume depletion (see WARNINGS for correction of volume depletion).

Ketorolac tromethamine is contraindicated in labor and delivery because, through its prostaglandin synthesis inhibitory effect, it may adversely affect fetal circulation and inhibit uterine musculature, thus increasing the risk of uterine hemorrhage.

The use of ketorolac tromethamine is contraindicated in nursing mothers because of the potential adverse effects of prostaglandin-inhibiting drugs on neonates.

Ketorolac tromethamine inhibits platelet function and is, therefore, contraindicated in patients with suspected or confirmed cerebrovascular bleeding, hemorrhagic diathesis, incomplete hemostasis and those at high risk of bleeding (see WARNINGS and PRECAUTIONS).

Ketorolac tromethamine is contraindicated in patients currently receiving asprin or NSAIDs because of the cumulative risks of inducing serious NSAID-related adverse events.

The concomitant use of ketorolac tromethamine and probenecid is contraindicated.

The concomitant use of ketorolac tromethamine and pentoxifylline is contraindicated.

Ketorolac tromethamine injection is contraindicated for neuraxial (epidural or intrathecal) Administration due to its alcohol content.

Ketamine8

Ketamine is contraindicated in those in whom a significant elevation of blood pressure would constitute a serious hazard and in those who have shown hypersensitivity to the drug.

Warnings (also see Boxed Warning) Methylcobalamin Most formulations of methylcobalamin injection contain benzyl alcohol as a preservative. Benzyl alcohol may cause allergic reactions. Methylcobalamin injections should be used cautiously in those patients with benzyl alcohol hypersensitivity. Methylcobalamin, vitamin B12 preparations containing benzyl alcohol should be avoided in premature neonates because benzyl alcohol has been associated with 'gasping syndrome,' a potentially fatal condition characterized by metabolic acidosis and CNS, respiratory, circulatory, and renal dysfunction.

Ascorbic Acid2

Diabetics, patients prone to recurrent renal calculi, those undergoing stool occult blood tests and those on sodium restricted diets or anticoagulant therapy should not take excessive doses of ascorbic acid over an extended period of time.

B Complex (Thiamine, Riboflavin, Niacinamide)3

Anaphylactogenesis may occur with parenteral thiamine. Use with caution. An intradermal test dose is recommended prior to administration in patients suspected of being sensitive to the drug.

Folic Acid

Magnesium Sulfate5

FETAL HARM: Continuous administration of magnesium sulfate beyond 5 to 7 days to pregnant women can lead to hypocalcemia and bone abnormalities in the developing fetus. These bone abnormalities include skeletal demineralization and osteopenia. In addition, cases of neonatal fracture have been reported. The shortest duration of treatment that can lead to fetal harm is not known. Magnesium sulfate should be used during pregnancy only if clearly needed. If magnesium sulfate is given for treatment of preterm labor, the woman should be informed that the efficacy and safety of such use have not been established and that use of magnesium sulfate beyond 5 to 7 days may cause fetal abnormalities.

ALUMINUM TOXICITY: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

Parenteral use in the presence of renal insufficiency may lead to magnesium intoxication. Intravenous use in the eclampsia should be reserved for immediate control of life-threatening convulsions.

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Copper and Manganes e are eliminated via the bile. In patients with s evere liver dysfunction and/or biliary tract obstruction, decreasing or omitting copper and manganese supplements entirely may be necessary. This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

When used in conjunction with the Pro-IV Suite, clinicians are advised to use judgment on whether to omit the utilization of this product.

Ketorolac7 The total combined duration of use of oral ketorolac tromethamine and IV or IM dosing of ketorolac tromethamine is not to exceed 5 days in adults. Ketorolac tromethamine is not indicated for use in pediatric patients.

The most serious risks associated with ketorolac tromethamine are:

Gastrointestinal Effects- Risk of Ulceration, Bleeding, and Perforation

Ketorolac tromethamine is contraindicated in patients with previously documented peptic ulcers and/or GI bleeding. Ketorolac tromethamine can cause serious gastrointestinal (GI) adverse events including bleeding, ulceration and perforation, of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with ketorolac tromethamine.

Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Minor upper gastrointestinal problems, such as dyspepsia, are common and may also occur at any time during NSAID therapy. The incidence and severity of gastrointestinal complications increases with increasing dose of, and

duration of treatment with, ketorolac tromethamine. Do not use ketorolac tromethamine for more than five days.

However, even short-term therapy is not without risk. In addition to past history of ulcer disease, other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids, or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.

To minimize the potential risk for an adverse GI event, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of ketorolac tromethamine until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. NSAIDs should be given with care to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn’s disease) as their condition may be exacerbated.

Hemorrhage

Because prostaglandins play an important role in hemostasis and NSAIDs affect platelet aggregation as well, use of ketorolac tromethamine in patients who have coagulation disorders should be undertaken very cautiously, and those patients should be carefully monitored. Patients on therapeutic doses of anticoagulants (e.g., heparin or dicumarol derivatives) have an increased risk of bleeding complications if given ketorolac tromethamine concurrently; therefore, physicians should administer such concomitant therapy only extremely cautiously. The concurrent use of ketorolac tromethamine and therapy that affects hemostasis, including prophylactic low-dose heparin (2500 to 5000 units q12h), warfarin and dextrans have not been studied extensively, but may also be associated with an increased risk of bleeding. Until data from such studies are available, physicians should carefully weigh the benefits against the risks and use such concomitant therapy in these patients only extremely cautiously. Patients receiving therapy that affects hemostasis should be monitored closely.

In postmarketing experience, postoperative hematomas and other signs of wound bleeding have been reported in association with the peri-operative use of IV or IM dosing of ketorolac tromethamine. Therefore, peri-operative use of ketorolac tromethamine should be avoided and postoperative use be undertaken with caution when hemostasis is critical (see PRECAUTIONS).

Renal Effects

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

Ketorolac tromethamine and its metabolites are eliminated primarily by the kidneys, which, in patients with reduced creatinine clearance, will result in diminished clearance of the drug (see CLINICAL PHARMACOLOGY). Therefore, ketorolac tromethamine should be used with caution in patients with impaired renal function (see DOSAGE AND ADMINISTRATION) and such patients should be followed closely. With the use of ketorolac tromethamine, there have been reports of acute renal failure, interstitial nephritis and nephrotic syndrome.

Impaired Renal Function

Ketorolac tromethamine is contraindicated in patients with serum creatinine concentrations indicating advanced renal impairment (see CONTRAINDICATIONS). Ketorolac tromethamine should be used with caution in patients with impaired renal function or a history of kidney disease because it is a potent inhibitor of prostaglandin synthesis. Because patients with underlying renal insufficiency are at increased risk of developing acute renal decompensation or failure, the risks and benefits should be assessed prior to giving ketorolac tromethamine to these patients.

Anaphylactoid Reactions

As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to ketorolac tromethamine. Ketorolac tromethamine should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS - Preexisting Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs.

Cardiovascular Effects

Cardiovascular Thrombotic Events: Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients

treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see Gastrointestinal Effects– Risk of Ulceration, Bleeding, and Perforation). Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS).

Hypertension

NSAIDs, including ketorolac tromethamine, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including ketorolac tromethamine, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and Throughout the course of therapy.

Congestive Heart Failure and Edema

Fluid retention, edema, retention of NaCl, oliguria, elevations of serum urea nitrogen and creatinine have been reported in clinical trials with ketorolac tromethamine. Therefore, ketorolac tromethamine should be used only very cautiously in patients with cardiac decompensation, hypertension or similar conditions.

Skin Reactions

NSAIDs, including ketorolac tromethamine, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

Pregnancy

In late pregnancy, as with other NSAIDs, ketorolac tromethamine should be avoided because it may cause premature closure of the ductus arteriosus.

Ketamine Hydrochloride8

Cardiac function should be continually monitored during the procedure in patients found to have hypertension or cardiac decompensation. Postoperative confusional states may occur during the recovery period. (See SPECIAL NOTE.) Respiratory depression may occur with overdosage or too rapid a rate of administration of ketamine, in which case supportive ventilation should be employed. Mechanical support of respiration is preferred to administration of analeptics.

Precautions Methylcobalamin1 Vitamin B12 deficiency can suppress the symptoms of polycythemia vera. Treatment with methylcobalamin or hydroxocobalamin may unmask this condition.

Folic Acid, vitamin B9 is not a substitute for methylcobalamin, vitamin B12 deficiency, although it may improve vitamin B12 megaloblastic anemia. However, exclusive use of folic acid in treating vitamin B12 deficient megaloblastic anemia could result in progressive and irreversible neurologic damage. Before receiving folic acid or methylcobalamin, patients should be assessed for deficiency and appropriate therapy started concurrently. The intranasal formulations are not approved to treat acute B12 deficiency; all hematologic parameters should be normal before beginning the methylcobalamin intranasal formulations. Concurrent iron-deficiency anemia and folic acid deficiency may result in a blunted or impeded response to methylcobalamin therapy.

Certain conditions may blunt or impede therapeutic response to methylcobalamin therapy. These include serious infection, uremia or renal failure, drugs with bone marrow suppression properties (e.g., chloramphenicol), or concurrent undiagnosed folic acid or iron deficiency anemia. The mechanism appears to be interference with erythropoiesis. Patients with vitamin B12 deficiency and concurrent renal or hepatic disease may require increased doses or more frequent administration of methylcobalamin.

Clinical reports have not identified differences in responses between elderly and younger patients. Generally, dose selection for elderly patients should be done with caution. Elderly patients tend to have a greater frequency of decreased hepatic, renal, or cardiac function, and also have concomitant disease or receiving other drug therapy. Start with doses at the lower end of the dosing range.

Ascorbic Acid2

Avoid rapid infusion

General Precautions

Too-rapid intravenous injection is to be avoided.

Laboratory Tes ts

Diabetics taking more than 500 mg of ascorbic acid daily, may obtain false reading of the urinary glucose test. No exogenous ascorbic acid should be ingested for 48 to 72 hours before amine dependent stool occult blood tests are conducted because possible false negative results may occur.

Drug Interactions

Limited evidence suggests that ascorbic acid may influence the intensity and duration of action of bishydroxycoumarin.

Us age in Pregnancy

Pregnancy Category C

Animal reproduction studies have not been conducted with Ascorbic Acid Injection. It is also not known whether Ascorbic Acid Injection can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Ascorbic Acid Injection should be given to a pregnant woman only if clearly needed.

Nurs ing Mothers

Caution should be exercised when Ascorbic Acid Injection is administered to a nursing woman.

B Complex (Thiamine, Riboflavin, Niacinamide)3

The usual precautions for parenteral administration should be observed. Do not inject if precipitation occurs. Inject slowly by the intravenous route. High concentrations should be diluted using Normal Saline Injection when given intravenously.

Folic Acid4

Folic acid in doses above 0.1 mg daily may obscure pernicious anemia in that hematologic remission can occur while neurological manifestations remain progressive.

Magnesium Sulfate5

General

Administer with caution if flushing and sweating occurs. When barbiturates, narcotics or other hypnotics (or systemic anesthetics) are to be given in conjunction with magnesium, their dosage should be adjusted with caution because of additive CNS depressant effects of magnesium.

Because magnesium is removed from the body solely by the kidneys, the drug should be used with caution in patients with renal impairment. Urine output should be maintained at a level of 100 mL or more during the four hours preceding each dose. Monitoring serum magnesium levels and the patient’s clinical status is essential to avoid the consequences of overdosage in toxemia. Clinical indications of a safe dosage regimen include the presence of the patellar reflex (knee jerk) and absence of

respiratory depression (approximately 16 breaths or more/minute). When repeated doses of the drug are given parenterally, knee jerk reflexes should be tested before each dose and if they are absent, no additional magnesium should be given until they return. Serum magnesium levels usually sufficient to control convulsions range from 3 to 6 mg/100 mL (2.5 to 5 mEq/liter). The strength of the deep tendon reflexes begins to diminish when magnesium levels exceed 4 mEq/liter. Reflexes may be absent at 10 mEq magnesium/liter, where respiratory paralysis is a potential hazard. An injectable calcium salt should be immediately available to counteract the potential hazards of magnesium intoxication in eclampsia.

50% Magnesium Sulfate Injection, USP must be diluted to a concentration of 20% or less prior to intravenous infusion. Rate of administration should be slow and cautious, to avoid producing hypermagnesemia. The 50% solution also should be diluted to 20% or less for intramuscular injection in infants and children.

Laboratory Tests

Magnesium sulfate injection should not be given unless hypomagnesemia has been confirmed and the serum concentration of magnesium is monitored. The normal serum level is 1.5 to 2.5 mEq/L.

Pregnancy Category D (See WARNINGS and PRECAUTIONS)

See WARNINGS and PRECAUTIONS. 

Magnesium sulfate can cause fetal abnormalities when administered beyond 5 to 7 days to pregnant women. There are retrospective epidemiological studies and case reports documenting fetal abnormalities such as hypocalcemia, skeletal demineralization, osteopenia and other skeletal abnormalities with continuous maternal administration of magnesium sulfate for more than 5 to 7 days.1-10 Magnesium sulfate injection should be used during pregnancy only if clearly needed. If this drug is used during pregnancy, the woman should be apprised of the potential harm to the fetus.

Nonteratogenic Effects

When administered by continuous intravenous infusion (especially for more than 24 hours preceding delivery) to control convulsions in a toxemic woman, the newborn may show signs of magnesium toxicity, including neuromuscular or respiratory depression (See OVERDOSAGE).

Labor and Delivery

Continuous administration of magnesium sulfate is an unapproved treatment for preterm labor. The safety and efficacy of such use have not been established. The administration of magnesium sulfate outside of its approved indication in pregnant

women should be by trained obstetrical personnel in a hospital setting with appropriate obstetrical care facilities.

Nursing Mothers

Since magnesium is distributed into milk during parenteral magnesium sulfate administration, the drug should be used with caution in nursing women.

Geriatrics

Geriatric patients often require reduced dosage because of impaired renal function. In patients with severe impairment, dosage should not exceed 20 grams in 48 hours. Serum magnesium should be monitored in such patients.

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Frequent determinations of serum levels of the various trace elements are suggested as a guideline for adjusting the dosage or completely omitting the solution. ZINC is eliminated via the intestine and kidneys. The possibility of retention should be considered in patients with malfunctioning excretory routes.

COPPER and MANGANESE are eliminated via the bile, therefore the possibility of retention of these elements should be considered in patients with biliary obstruction. Ancillary routes of MANGANESE excretion, however, include pancreatic juice, or reabsorption into the lumen of duodenum, jejunum, or ileum.

In assessing the contribution of CHROMIUM supplements to maintenance of normal glucose homeostasis, consideration should be given to the possibility that the patient may be diabetic, in which case oral or intravenous antidiabetic medication may be indicated.

As SELENIUM is eliminated in urine and feces, SELENIUM supplements may be adjusted, reduced or omitted in renal dysfunction and/or gastrointestinal malfunction. In patients receiving blood transfusions, contribution from such transfusions should also be considered. Frequent selenium plasma level determinations are suggested as a guideline. In animals, SELENIUM has been reported to enhance the action of Vitamin E and decrease the toxicity of mercury, cadmium, and arsenic.

Pregnancy

Teratogenic Effects

Pregnancy Category C: SELENIUM at high dose levels (15-30 mcg/egg) has been reported to have adverse embryological effects among chickens. There are however no adequate and well-controlled studies in pregnant women. MULTITRACE - 5 CONCENTRATE should be used during pregnancy only if potential benefit justifies the potential risk to the fetus. Presence of SELENIUM in placenta and umbilical cord blood has been reported in humans.

Ketorolac7

General

Ketorolac tromethamine cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. The pharmacological activity of ketorolac tromethamine in reducing inflammation may diminish the utility of this diagnostic sign in detecting complications of presumed noninfectious, painful conditions.

Hepatic Effects

Ketorolac tromethamine should be used with caution in patients with impaired hepatic function or a history of liver disease. Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including ketorolac tromethamine. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.

A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with ketorolac tromethamine. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), ketorolac tromethamine should be discontinued.

Hematological Effects

Anemia is sometimes seen in patients receiving NSAIDs, including ketorolac tromethamine. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including ketorolac tromethamine, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving ketorolac tromethamine who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.

Preexisting Asthma

Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, ketorolac tromethamine should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.

Information for Patients

Ketorolac tromethamine is a potent NSAID and may cause serious side effects such as gastrointestinal bleeding or kidney failure, which may result in hospitalization and even fatal outcome. Physicians, when prescribing ketorolac tromethamine, should inform their patients or their guardians of the potential risks of ketorolac tromethamine treatment (see Boxed WARNING, WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS sections), instruct patients to seek medical advice if they develop treatment-related adverse events, and advise patients not to give oral ketorolac tromethamine to other family members and to discard any unused drug. Remember that the total combined duration of use of oral ketorolac tromethamine and IV or IM dosing of ketorolac tromethamine is not to exceed 5 days in adults. Ketorolac tromethamine is not indicated for use in pediatric patients. Patients should be informed of the following information before initiating therapy with an NSAID and periodically

during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.

1. Ketorolac tromethamine, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects).

2. Ketorolac tromethamine, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects: Risk of Ulceration, Bleeding, and Perforation).

3. Ketorolac tromethamine, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.

4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.

5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.

6. Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS).

7. In late pregnancy, as with other NSAIDs, ketorolac tromethamine should be avoided because it will cause premature closure of the ductus arteriosus.

Laboratory Tests

Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs, should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash etc.) or if abnormal liver tests persist or worsen, ketorolac tromethamine should be discontinued.

Carcinogenesis, Mutagenesis and Impairment of Fertility

An 18-month study in mice with oral doses of ketorolac tromethamine at 2 mg/kg/day (0.9 times the human systemic exposure at the recommended IM or IV dose of 30 mg qid, based on area-under-the-plasma-concentration curve [AUC]), and a 24-month study in rats at 5 mg/kg/day (0.5 times the human AUC) showed no evidence of tumorigenicity.

Ketorolac tromethamine was not mutagenic in the Ames test, unscheduled DNA synthesis and repair, and in forward mutation assays. Ketorolac tromethamine did not cause chromosome breakage in the in vivo mouse micronucleus assay. At 1590 mcg/mL and at higher concentrations, ketorolac tromethamine increased the incidence of chromosomal aberrations in Chinese hamster ovarian cells.

Impairment of fertility did not occur in male or female rats at oral doses of 9 mg/kg (0.9 times the human AUC) and 16 mg/kg (1.6 times the human AUC) of ketorolac tromethamine, respectively.

Pregnancy: Teratogenic Effects: Pregnancy Category C

Reproduction studies have been performed during organogenesis using daily oral doses of ketorolac tromethamine at 3.6 mg/kg (0.37 times the human AUC) in rabbits and at 10 mg/kg (1.0 times the human AUC) in rats. Results of these studies did not reveal evidence of teratogenicity to the fetus. However, animal reproduction studies are not always predictive of human response.

Nonteratogenic Effects: Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided. Oral doses of ketorolac tromethamine at 1.5 mg/kg (0.14 times the human AUC), administered after gestation Day 17, caused dystocia and higher pup mortality in rats.

There are no adequate and well-controlled studies of ketorolac tromethamine in pregnant women. Ketorolac tromethamine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery: The use of ketorolac tromethamine is contraindicated in labor and delivery because, through its prostaglandin synthesis inhibitory effect, it may adversely affect fetal circulation and inhibit uterine contractions, thus increasing the risk of uterine hemorrhage (see CONTRAINDICATIONS).

Effects on Fertility: The use of ketorolac tromethamine, as with any drug known to inhibit cyclooxygenase/prostaglandin synthesis, may impair fertility and is not recommended in women attempting to conceive. In women who have difficulty conceiving or are undergoing investigation of infertility, withdrawal of ketorolac tromethamine should be considered.

Nursing Mothers: After a single administration of 10 mg of oral ketorolac tromethamine to humans, the maximum milk concentration observed was 7.3 ng/mL, and the maximum milk-to-plasma ratio was 0.037. After 1 day of dosing (qid), the maximum milk concentration was 7.9 ng/mL, and the maximum milk-to-plasma ratio was 0.025. Because of the possible adverse effects of prostaglandin-inhibiting drugs on neonates, use in nursing mothers is contraindicated.

Pediatric Use: Ketorolac tromethamine is not indicated for use in pediatric patients. The safety and effectiveness of ketorolac tromethamine in pediatric patients below the age of 17 have not been established.

Geriatric Use (≥65 years of age): Because ketorolac tromethamine may be cleared more slowly by the elderly (see CLINICAL PHARMACOLOGY) who are also more sensitive to the dose-related adverse effects of NSAIDs (see WARNINGS:

Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation), extreme caution, reduced dosages (see DOSAGE AND ADMINISTRATION), and careful clinical monitoring must be used when treating the elderly with ketorolac tromethamine.

Ketamine Hydrochloride8

Ketamine should be used by or under the direction of physicians experienced in administering general anesthetics and in maintenance of an airway and in the control of respiration.

Resuscitative equipment should be ready for use.

Psychomimetic or dysphoria may occur with higher subanesthetic doses.

Drug Interactions This list may not describe all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine. Methylcobalamin1

Several drugs, including para-aminosalicylic acid, have been reported to reduce the absorption of methylcobalamin, vitamin B12. Monitor for the desired therapeutic response to vitamin B12.

The heavy consumption of ethanol for greater than 2 weeks has been reported to reduce the absorption of methylcobalamin, vitamin B12. Patients should be aware that heavy, chronic ethanol use may counteract the therapeutic effects of vitamin B12; such patients with regular and chronic ethanol consumption be monitored for the desired therapeutic response to vitamin B12.

Several drugs, including colchicine, have been reported to reduce the absorption of methylcobalamin, vitamin B12. Colchicine has been shown to induce reversible malabsorption of vitamin B12, apparently by altering the function of ileal mucosa. Although further study of these interactions is necessary, patients receiving these agents concurrently should be monitored for the desired therapeutic response to vitamin B12.

In a study of 10 healthy male volunteers, omeprazole, in doses of 20 mg—40 mg per day, caused a significant decrease in the oral absorption of methylcobalamin, vitamin B12. Theoretically this interaction is possible with other proton pump inhibitors (PPIs), although specific clinical data are lacking. Patients receiving long-term therapy with omeprazole or other proton pump inhibitors (PPIs) should be monitored for signs of B12deficiency.

Chloramphenicol can antagonize the hematopoietic response to methylcobalamin, vitamin B12 through interference with erythrocyte maturation. Chloramphenicol is

known to cause bone marrow suppression, especially when serum concentrations exceed 25 mcg/ml. Chloramphenicol should be discontinued if anemia attributable to chloramphenicol is noted during periodic blood studies, which should be done approximately every 2 days during chloramphenicol receipt. Aplastic anemia and hypoplastic anemia are known to occur after chloramphenicol administration. Peripherally, pancytopenia is most often observed, but only 1—2 of the major cell types (erythrocytes, leukocytes, platelets) may be depressed in some cases.

Metformin may result in suboptimal oral vitamin B12 absorption by competitively blocking the calcium-dependent binding of the intrinsic factor-vitamin B12 complex to its receptor. The interaction very rarely results in a pernicious anemia that appears reversible with discontinuation of metformin or with Methylcobalamin, vitamin B12 supplementation. Certain individuals may be predisposed to this interaction. Regular measurement of hematologic parameters is recommended in all patients on chronic metformin treatment; abnormalities should be investigated.

Medications known to cause bone marrow suppression (e.g., myelosuppressive antineoplastic agents) may result in a blunted or impeded response to methylcobalamin, vitamin B12 therapy. Antineoplastics that are antimetabolites for the vitamin may induce inadequate utilization of vitamin B12. However, cancer patients usually benefit from vitamin B12 supplementation. The use of methotrexate may additionally invalidate diagnostic assays for folic acid and vitamin B12; however, this is a diagnostic laboratory test interference and not a drug interaction.

Magnesium Sulfate5

CNS Depressants — When barbiturates, narcotics or other hypnotics (or systemic anesthetics), or other CNS depressants are to be given in conjunction with magnesium, their dosage should be adjusted with caution because of additive CNS depressant effects of magnesium. CNS depression and peripheral transmission defects produced by magnesium may be antagonized by calcium.

Neuromuscular Blocking Agents — Excessive neuromuscular block has occurred in patients receiving parenteral magnesium sulfate and a neuromuscular blocking agent; these drugs should be administered concomitantly with caution.

Cardiac Glycosides — Magnesium sulfate should be administered with extreme caution in digitalized patients, because serious changes in cardiac conduction which can result in heart block may occur if administration of calcium is required to treat magnesium toxicity.

Ketorolac7

Drug Interactions

Ketorolac is highly bound to human plasma protein (mean 99.2%). There is no evidence in animal or human studies that ketorolac tromethamine induces or inhibits hepatic enzymes capable of metabolizing itself or other drugs.

Warfarin, Digoxin, Salicylate, and Heparin: The in vitro binding of warfarin to plasma proteins is only slightly reduced by ketorolac tromethamine (99.5% control vs 99.3%) when ketorolac plasma concentrations reach 5 to 10 mcg/mL. Ketorolac does not alter digoxin protein binding. In vitro studies indicate that, at therapeutic concentrations of salicylate (300 mcg/mL), the binding of ketorolac was reduced from approximately 99.2% to 97.5%, representing a potential twofold increase in unbound ketorolac plasma levels. Therapeutic concentrations of digoxin, warfarin, ibuprofen, naproxen, piroxicam, acetaminophen, phenytoin and tolbutamide did not alter ketorolac tromethamine protein binding.

In a study involving 12 adult volunteers, oral ketorolac tromethamine was coadministered with a single dose of 25 mg warfarin, causing no significant changes in pharmacokinetics or pharmacodynamics of warfarin. In another study, ketorolac tromethamine dosed IV or IM was given with two doses of 5000 U of heparin to 11 healthy volunteers, resulting in a mean template bleeding time of 6.4 minutes (3.2 to 11.4 min) compared to a mean of 6 minutes (3.4 to 7.5 min) for heparin alone and 5.1 minutes (3.5 to 8.5 min) for placebo. Although these results do not indicate a significant interaction between ketorolac tromethamine and warfarin or heparin, the administration of ketorolac tromethamine to patients taking anticoagulants should be done extremely cautiously, and patients should be closely monitored (see WARNINGS and PRECAUTIONS: Hematologic Effect).

The effects of warfarin and NSAIDs, in general, on GI bleeding are synergistic, such that the users of both drugs together have a risk of serious GI bleeding higher than the users of either drug alone.

Aspirin: When ketorolac tromethamine is administered with aspirin, its protein binding is reduced, although the clearance of free ketorolac tromethamine is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of ketorolac tromethamine and aspirin is not generally recommended because of the potential of increased adverse effects.

Diuretics: Clinical studies, as well as postmarketing observations, have shown that ketorolac tromethamine can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS: Renal Effects), as well as to assure diuretic efficacy.

Probenecid: Concomitant administration of oral ketorolac tromethamine and probenecid resulted in decreased clearance and volume of distribution of ketorolac and significant increases in ketorolac plasma levels (total AUC increased approximately threefold from 5.4 to 17.8 mcg/h/mL) and terminal half-life increased approximately twofold from 6.6 to 15.1 hours. Therefore, concomitant use of ketorolac tromethamine and probenecid is contraindicated.

Lithium: NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.

Methotrexate: NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.

ACE Inhibitors/Angiotensin II Receptor Antagonists: Concomitant use of ACE inhibitors and/or angiotensin II receptor antagonists may increase the risk of renal impairment, particularly in volume-depleted patients. Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors and/or angiotensin II receptor antagonists. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors and/or angiotensin II receptor antagonists.

Antiepileptic Drugs: Sporadic cases of seizures have been reported during concomitant use of ketorolac tromethamine and antiepileptic drugs (phenytoin, carbamazepine).

Psychoactive Drugs: Hallucinations have been reported when ketorolac tromethamine was used in patients taking psychoactive drugs (fluoxetine, thiothixene, alprazolam).

Pentoxifylline: When ketorolac tromethamine is administered concurrently with pentoxifylline, there is an increased tendency to bleeding.

Nondepolarizing Muscle Relaxants: In postmarketing experience there have been reports of a possible interaction between ketorolac tromethamine IV/IM and nondepolarizing muscle relaxants that resulted in apnea. The concurrent use of ketorolac tromethamine with muscle relaxants has not been formally studied.

Selective Serotonin Reuptake Inhibitors (SSRIs): There is an increased risk of gastrointestinal bleeding when selective serotonin reuptake inhibitors (SSRIs) are combined with NSAIDs. Caution should be used when NSAIDs are administered concomitantly with SSRIs.

Ketamine Hydrochloride8

Adverse effects may be exacerbated in patients if barbiturates and/or narcotics are used concurrently with ketamine.

Adverse Reactions Methylcobalamin1

In most cases, methylcobalamin is nontoxic, even in large doses. Adverse reactions reported following methylcobalamin administration include headache, infection, nausea/vomiting, paresthesias, and rhinitis. Adverse reactions following intramuscular (IM) injection have included anxiety, mild transient diarrhea, ataxia, nervousness, pruritus, transitory exanthema, and a feeling of swelling of the entire body. Some patients have also experienced a hypersensitivity reaction following intramuscular injection that has resulted in anaphylactic shock and death. In cases of suspected cobalt hypersensitivity, an intradermal test dose should be administered.

During the initial treatment period with methylcobalamin, pulmonary edema and congestive heart failure have reportedly occurred early in treatment with parenteral methylcobalamin. This is believed to result from the increased blood volume induced by methylcobalamin. Peripheral vascular thrombosis has also occurred. In post-marketing experience, angioedema and angioedema-like reactions were reported with parenteral methylcobalamin.

Hypokalemia and thrombocytosis could occur upon conversion of severe megaloblastic anemia to normal erythropoiesis with methylcobalamin therapy. Therefore, monitoring of the platelet count and serum potassium concentrations are recommended during therapy. Polycythemia vera has also been reported with parenteral methylcobalamin. Diarrhea and headache are infrequent. Ascorbic Acid2

Too-rapid intravenous administration of the solution may cause temporary faintness or dizziness.

B Complex (Thiamine, Riboflavin, Niacinamide)3

Mild transient diarrhea, polycythemia vera, peripheral vascular thrombosis, itching transitory xanthema, feeling of swelling of entire body, anaphylactic shock and death. Sensitivity to the ingredients listed may occur (see WARNINGS). Use should be discontinued upon observance of any untoward reaction.

Folic Acid4 Allergic sensitization has been reported following both oral and parenteral administration of folic acid.

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The amounts of ZINC, COPPER, MANGANESE, CHROMIUM and SELENIUM in the solution are very small and toxicity symptoms due to these trace elements at suggested dosage levels are considered unlikely to occur.

Ketamine Hydrochloride8

Cardiovascular

Blood pressure and pulse rate are frequently elevated following administration of ketamine alone. However, hypotension and bradycardia have been observed. Arrhythmia has also occurred.

Respiration

Although respiration is frequently stimulated, severe depression of respiration or apnea may occur following rapid intravenous administration of high doses of ketamine. Laryngospasms and other forms of airway obstruction have occurred during ketamine anesthesia.

Eye

Diplopia and nystagmus have been noted following ketamine administration. It also may cause a slight elevation in intraocular pressure measurement.

Genitourinary

Severe irritative and inflammatory urinary tract and bladder symptoms including cystitis have been reported in individuals with history of chronic ketamine use or abuse.

Psychological: (See SPECIAL NOTE.)

Neurological

In some patients, enhanced skeletal muscle tone may be manifested by tonic and clonic movements sometimes resembling seizures at anesthetic doses

Gastrointestinal

Anorexia, nausea and vomiting have been observed; however, this is not usually severe and allows the great majority of patients to take liquids by mouth shortly after regaining consciousness from anesthesia. These are not anticipated to be significant for subanesthetic doses.

General: Anaphylaxis

Local pain and exanthema at the injection site have infrequently been reported. Transient erythema and/or morbilliform rash have also been reported.

Overdosage Overdose treatment with all Pro-IV products are symptomatic.

Magnesium Sulfate5

Magnesium intoxication is manifested by a sharp drop in blood pressure and respiratory paralysis. Disappearance of the patellar reflex is a useful clinical sign to detect the onset of magnesium intoxication. In the event of overdosage, artificial

ventilation must be provided until a calcium salt can be injected intravenously to antagonize the effects of magnesium.

For Treatment of Overdose

Artificial respiration is often required. Intravenous calcium, 10 to 20 mL of a 5% solution (diluted if desirable with isotonic sodium chloride for injection) is used to counteract effects of hypermagnesemia. Subcutaneous physostigmine, 0.5 to 1 mg may be helpful.

Hypermagnesemia in the newborn may require resuscitation and assisted ventilation via endotracheal intubation or intermittent positive pressure ventilation as well as intravenous calcium.

Multitrace 56

Symptoms of ZINC overdosage resulting from oral ingestion of Zinc Sulfate in large amounts have resulted in death. Symptoms included nausea, vomiting, dehydration, electrolyte imbalances, dizziness, abdominal pain, lethargy and incoordination. Single intravenous doses of 1 to 2 mg zinc/kg bodyweight have been given to adult leukemic patients without toxic manifestations. Normal plasma levels for Zinc vary from approximately 88 to 112 mcg/100 mL. Plasma levels sufficient to produce symptoms of toxic manifestations are not known. Calcium supplements may confer a protective effect against Zinc toxicity.

Symptoms of COPPER toxicity reported in literature include prostration, behavior change, diarrhea, progressive marasmus, hypotonia, photophobia and peripheral edema. D-penicillamine has been reported effective as an antidote.

MANGANESE toxicity has not been reported in patients receiving TPN. Neither have reports of manganese toxicity from excessive intake in foods and/or beverages been published.

Symptoms of CHROMIUM toxicity include nausea, vomiting, ulcers of gastrointestinal tract, renal and hepatic damage, and abnormalities of the central nervous system culminating in convulsions and coma. Trivalent Chromium administered intravenously to TPN patients has been shown to be nontoxic when given at dosage levels up to 250 mcg/day for two consecutive weeks.

Chronic toxicity in humans resulting from exposure to SELENIUM in industrial environments, intake of foods grown in seleniferous soils, use of selenium contaminated water, and application of cosmetics containing selenium has been reported in literature. Toxicity symptoms include hair loss, weakened nails, dermatitis, dental defects, gastrointestinal disorders, nervousness, mental depression, metallic taste, vomiting, and garlic odor of breath and sweat. Acute poisoning due to ingestion of large amounts of selenium compounds has resulted in death with histopathological changes including fulminating peripheral vascular

collapse, internal vascular congestion, diffusely hemorrhagic, congested and edematous lungs, brick-red color gastric mucosa. The death was preceded by coma. No effective antidote to selenium poisoning in humans is known. Animal studies have shown casein and linseed oil in feeds, reduced glutathione, arsenic, magnesium sulfate, and bromobenzene to afford limited protection.

Dosage and Administration Pro-IV Commercial, Pro-IV Elite, Pro-IV FiRe, Pro-IV Refractory Concussion are administered under the guidance of a qualified practitioner via intravenous route over 30 to 60 minutes as tolerated by the patient.

PRESSURE MAY DEVELOP WITHIN THE ASCORBIC ACID VIAL UPON STORAGE. Exercise care when withdrawing and/or relieve pressure by first inserting sterile empty syringe into vial thus allowing pressure to equilibrate.2

Drug products should be mixed according to Aseptic technique.

Protect all mixed products from light during administration.

Drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever the solution and the container permit. Consider administration with a filtered line.

The Pro-IV Suite of products is not intended for individual vial administration. The finished product will contain benzyl alcohol and ethanol.

Formulations may add Multitrace 5 where available.

Pro-IV Edge

API Concentration

Utilization

Per Infusion Dose

Vitamin B12 1mg/ml 1 ml 1mg

Ascorbic Acid 500mg/ml 2 ml 1500mg

B Complex (including Thiamine, Riboflavin, Niacinamide)

100mg/ml 30mg/ml 100mg/ml

1 ml 100mg/30mg/100mg

Folic Acid 1mg/ml 0.8 ml 800mcg

Magnesium (as Sulfate) 50% 3 ml 1500mg

Pro-IV Commercial

*Contains 10% (w/v) alcohol

Pro-IV Elite

*Contains 10% (w/v) alcohol

Pro-IV FiRe

*Not for direct administration, must be diluted due to alcohol content.

API Concentration Utilization Per Infusion Dose

Vitamin B12 1mg/ml 1 ml 1mg

Ascorbic Acid 500mg/ml 2 ml 1500mg

Thiamine 100mg/ml 1 ml 100mg

Folic Acid 1mg/ml 0.8 ml 800mcg

Magnesium (as Sulfate) 50% 3 ml 1500mg

Ketorolac Tromethamine* 30mg/ml 0.5 ml 15mg

API Concentration

Utilization

Per Infusion Dose

Vitamin B12 1mg/ml 1 ml 1mg

Ascorbic Acid 500mg/ml 2 ml 1500mg

B Complex (including Thiamine, Riboflavin, Niacinamide)

100mg/ml 30mg/ml 100mg/ml

1 ml 100mg/30mg/100mg

Folic Acid 1mg/ml 0.8 ml 800mcg

Magnesium (as Sulfate) 50% 3 ml 1500mg

Ketorolac Tromethamine* 30mg/ml 0.5 ml 15mg

API Concentration

Utilization

Per Infusion Dose

Vitamin B12 1mg/ml 1 ml 1mg

Ascorbic Acid 500mg/ml 2 ml 1500mg

B Complex (including Thiamine, Riboflavin, Niacinamide)

100mg/ml 30mg/ml 100mg/ml

1 ml 100mg/30mg/100mg

Folic Acid 1mg/ml 0.8 ml 800mcg

Magnesium (as Sulfate) 50% 3 ml 1500mg

Acetaminophen* 100mg/ml* 10 ml* 1000mg*

Pro-IV Refractory Concussion

How Supplied The Pro-IV Suite is supplied in a kit containing individual vials for mixing at the site of administration. Each kit contains USP Type I glass vials in Amber or Clear depending on light sensitivity. The individual vials are listed below for combination with the various Pro-IV Products

API Concentration

Utilization Per Infusion Dose

Vitamin B12 1mg/ml 1 ml 1mg

Ascorbic Acid 500mg/ml 2 ml 1500mg

B Complex (including Thiamine, Riboflavin, Niacinamide)

100mg/ml 30mg/ml 100mg/ml

1 ml 100mg/30mg/100mg

Folic Acid 1mg/ml 0.8 ml 800mcg

Magnesium (as Sulfate) 50% 3 ml 1500mg

Ketamine Hydrochloride 50mg/ml 0.1mg/kg to 0.4mg/kg as tolerated

variable

Vial Vial Type Vial Size Temperature Recommendation

Methylcobalamin USP Type I - Amber

Single Dose 5 ml

Room temperature with excursions permitted 15° to 30°C

Ascorbic Acid USP Type I - Amber

Single Dose 5 ml

2° to 8 °C with excursions permitted 0° to 15°C Do not Freeze

B Complex (including Thiamine, Riboflavin, Niacinamide)

USP Type I - Amber

Single Dose 5 ml

2° to 8 °C with excursions permitted 0° to 15°C Do not Freeze

Folic Acid USP Type I - Clear

Single Dose 5 ml

Room temperature with excursions permitted 15° to 30°C

Magnesium (as Sulfate) USP Type I - Clear

Single Dose 5 ml

Room temperature with excursions permitted 15° to 30°C

Multitrace 5 USP Type I - Clear

Single Dose 5ml

Room temperature with excursions permitted 15° to 30°C

Ketorolac Tromethamine USP Type I - Amber

Single Dose 5 ml

Room temperature with excursions permitted 15° to 30°C

Ketamine Hydrochloride USP Type I - Amber

Single Dose 5 ml

Room temperature with excursions permitted 15° to 30°C

Acetaminophen* USP Type I - Clear

Single Dose 5ml

Room temperature with excursions permitted 15° to 30°C

*Proposed

Administer mixed product at controlled room temperature, 15° to 30°C (59° to 86° F). Protect from light. Retain in carton until time of use.

Refrigeration of the B-Complex (Thiamine, Riboflavin, Niacinamide) product may cause darkening of the solution due to the riboflavin content. The color does not affect the safety or efficacy of the product.

References:

1. Methylcobalamin (Vitamin B12) Injection [package insert]. EmpowerRx Pharmacy, Houston, TX; https://www.empowerpharmacy.com/drugs/methylcobalamin-vitamin-b12-injection.html. Accessed Jul 15, 2017.

2. Ascorbic Acid – ascorbic acid injection, solution [package insert]. Mylan Institutional LLC, Rockford, IL. Revised October 2012.

3. Vitamin B-Complex 100 Injection [package insert]. Mylan Institutional LLC, Rockford, IL. Revised October 2012.

4. Folic Acid Injection, USP [package insert]. Fresenius Kabi USA, LLC Lake Surich, IL. November 2016.

5. Magnesium Sulfate – magnesium sulfate heptahydrate injection, solution [package insert]. Hospira, Inc. Lake Forest, IL. Revised 3/2016.

6. Multitrace-5-trace elements 5 injection, solution, concentrate [package insert]. American Regent, Inc. Shirley, NY. Revised 11/2005

7. Ketorolac Tromethamine Injection USP [package insert]. Bedford Laboratories™. Bedford, OH. January 2009.

8. Ketamine Hydrochloride Injection, USP [package insert]. Hospira, Inc. Lake Forest, IL. Revised January 2013.

Channel Partners

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(1) Economic Empowerment (2) Educational

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