# Presentation: 056435

## Slide 1

## Overview

- Immunosuppressive drugs
- Cardiovascular disease & hyperlipidemia
- Hypertension
- Diabetes
- Vaccines

## Immunosuppressive Drugs

- Corticosteroids
- Antiproliferative agents
- Azathioprine
- Mycophenolate mofetil (MMF)
- Mycophenolic acid (MPA)

- Calcineurin inhibitors
- Cyclosporine
- Tacrolimus
- mTOR inhibitors
- Sirolimus
- Everolimus

**Notes:**
In the interest of time we will only be covering mycophenolate/mycophenolic acid, the calcineurin inhibitors and sirolimus

## Mycophenolate Mofetil (Cellcept®)

- Prodrug converted to active moiety mycophenolic acid (MPA)
- Typical Dose: 1000mg BID
- Monitoring: CBC, MPA levels +/-

**Notes:**

Does not require extra monitoring when switching between formulations

## Mycophenolic Acid (Myfortic®)

- Enteric coated product that provides active moiety
- Typical Dose: 720mg BID
- Monitoring: CBC, MPA levels +/-

## Adverse Effects of MMF & MPA

-  Gastritis, anorexia, cramping, diarrhea
-  Neutropenia, thrombocytopenia, anemia
-  Trend toward  incidence of infections
- CMV, HSV
- Progressive multifocal leukoencephalopathy (PML) - rare

**Notes:**
PML is a rare disorder that affects the central nervous system.  When it occurs, it is usually in patients with immune systems suppressed by disease or medicines.  It happens when the polyomavirus, also known as the JC virus, is activated.  The JC virus is found in most adults but does not usually cause symptoms.  Scientists do not know exactly how the JC virus is activated.  Once activated, the JC virus attacks the cells that make myelin, the protective coating around nerve cells.  Signs and symptoms of PML can include localized neurologic signs and symptoms including vision changes, loss of coordination, clumsiness, memory loss, difficulty speaking or understanding what others say, and weakness in the legs.  Many patients who develop PML die.  Patients who survive may have permanent disability due to irreversible nerve damage. More information on PML can be found at the National Institutes of Health website.

## Practical Tips for MMF & MPA

- Take with food
- Do not crush, cut or chew tablets (MPA)
- Transplant center may reduce dose, split into TID dosing, or convert to MPA
- Equimolar dosing
- 500mg MMF = 360mg MPA
- Do not take with iron

## Calcineurin Inhibitors

- Tacrolimus (Prograf®, FK506)
- Usual Starting Dose
- 0.05mg/kg q 12 hours
- Cyclosporine (Sandimmune®, Neoral®, Gengraf®)
- Usual Starting Dose
- 2.5mg/kg q 12 hours
- Dose adjustment
- By the transplant center based on drug level

## Adverse Effects of Calcineurin Inhibitors

- Cyclosporine > Tacrolimus
- Hypertension and hyperlipidemia
- Gingival hyperplasia, hirsutism
- Tacrolimus > Cyclosporine
- Hyperglycemia, neurotoxicity, and GI side effects
-  Alopecia
- Tacrolimus ~ Cyclosporine
- Nephrotoxicity (Serum Cr)
- Hyperkalemia
- Hypomagnesemia

## Calcineurin Inhibitor Monitoring

- Drug levels (12-hr trough drug level)
- BUN, creatinine, electrolytes, Mg
- Blood sugar, lipid profile, blood pressure
- CNS toxicity (tremor, headache, seizures)

## mTOR Inhibitor: Sirolimus (Rapamune®)

- Typical dose
- 6-15mg loading dose, then 2-5mg/day maintenance dose (once daily)
- Monitoring
- 24-hr trough level (goal 5-15ng/mL)
- Check levels 5-7 days after dose adjustments
- Lipid profile, CBC
- Dose adjustment
- By the transplant center based on drug level

## Adverse Effects of Sirolimus

- Hyperlipidemia (cholesterol and TGs)
- Hypertension
- Thrombocytopenia, leukopenia, anemia
- Constipation, diarrhea, nausea
- Impaired wound healing

## Cyclosporine, Tacrolimus, and Sirolimus Interactions

- Decreased immunosuppressive drug levels by induction of CYP3A4
- Antibiotics
- Rifampin
- Nafcillin
- Anti-convulsants
- Phenobarbital, phenytoin, and carbamazepine
- Herbs
- St. John’s Wort

## Cyclosporine, Tacrolimus, and Sirolimus Interactions 

- Increased immunosuppressive drug levels by inhibition of CYP3A4
- Antihypertensives: verapamil, diltiazem
- Azole Antifungals: e.g., fluconazole
- Antibacterial: erythromycin, clarithromycin
- Antiretroviral: ritonavir, nelfinavir
- Anti-arrhythmic: amiodarone
- Other: grapefruit/ grapefruit juice

## Complications of Immunosuppression

- Cardiovascular disease (CVD)
- Hypertension
- Dyslipidemia
- Diabetes
- Renal failure

- Infection
- Anemia
- Osteoporosis
- Malignancy
- Gout

## CVD in Transplant Recipients

- Prevalence:
- Kidney transplant recipient
- 5 yr risk of CV event with hyperlipidemia: 12%
- 5 yr CV mortality with hyperlipidemia: 5%
- 5 yr mortality (all cause): 8 -15%
- Heart or liver transplant recipient
- 5 yr mortality (all cause): 25%

**Notes:**
5 yr risk of CV event with hyperlipidemia: ALERT study 12% (cf USRDS 11% at 3 yrs)

## CVD in Transplant Recipients

- Many patients die of CVD with an otherwise functioning transplant
- e.g., 40% of kidney transplant patients die with a functioning kidney

**Notes:**
5 yr risk of CV event with hyperlipidemia: ALERT study 12% (cf USRDS 11% at 3 yrs)

## Risk Factors for CVD are Highly Prevalent in Transplant Recipients

- Prevalence in kidney transplant patients:
- Hypertension 80%
- Hypercholesterolemia 80%
- Diabetes Mellitus 55%
- Obesity 30%
- Smoking 20%

## Reasons for Hyperlipidemia in Transplant Recipients

- Reflects incidence in general population
- DM, obesity, lifestyle
- Diabetes and atherosclerosis contributes to end organ failure necessitating transplant
- Increased incidence of DM after transplantation
- Weight gain after organ transplant
- Use of prednisone and tacrolimus
- Direct effect of immunosuppressive agents

## Immunosuppressive Drugs Contribute to Hyperlipidemia

- Increased LDL-C
- Cyclosporine > prednisone
- Lower HDL-C
- Cyclosporine > prednisone
- Increased triglycerides
- Sirolimus > prednisone

## Hyperlipidemia in Transplant Recipients

- Why treat?
- Statins are effective in reducing CV mortality
- Transplant recipients are at high risk for CV events
- What is the data in transplant recipients?
- Excluded from large hyperlipidemia trials
- Recent randomized prospective studies in transplant pts are just beginning to demonstrate reductions in CV events

## Management of Hyperlipidemia: NCEP (ATPIII) Guidelines

- Therapeutic lifestyle changes (TLC)
- Diet, weight loss, physical activity
- Drug therapy
- HMG CoA reductase inhibitors
- Bile acid sequestrants
- Fibric acid derivatives
- Omega 3 fatty acids

## Management of Hyperlipidemia

- HMG-CoA reductase inhibitors (statins)–preferred for LDL-C
- Low dose pravastatin or simvastatin are generally well tolerated in transplant patients
- Increased risk of myopathy & rhabdomyolysis when combined with cyclosporine or tacrolimus
- Bile acid sequestrants e.g. cholestyramine
- Reduces LDL-C but may increase triglycerides
- May interfere with immunosuppressive drug absorption

## Management of Hyperlipidemia

- Fibric acid derivatives e.g. gemfibrozil
- More effective for hypertriglyceridemia
- Avoid combining with a statin in patients on cyclosporine or tacrolimus
- Omega 3 fatty acids
- Useful for hypertriglyceridemia
- Decreased risk of rhabdomyolysis when combined with CSA or tacrolimus

## Hyperlipidemia Summary

- Immunosuppressive medications contribute to hyperlipidemia
- Transplant recipients should be screened yearly and 2-3 months after changes in therapy that affect lipid levels
- NCEP guidelines should be followed as a guide to therapy; transplant recipients should be considered high risk
- LDL-C < 100 mg/dl is optimal

**Notes:**
No randomized studies on cholesterol lowering in organ transplant recipients except ALERT study – transplantation or CKD  is an exclusion criteria for hyperlipidemia trials

## Hyperlipidemia Summary

- HMG-Co reductase inhibitors (statins) should be used as first line therapy to lower LDL-C after lifestyle changes
- Monitor for myopathy and rhabdomyolysis

**Notes:**
No randomized studies on cholesterol lowering in organ transplant recipients except ALERT study – transplantation or CKD  is an exclusion criteria for hyperlipidemia trials

## Risk Factors for Developing HTN in Transplant Recipient

- Obesity
- Ethnicity/Race
- Genetics
- Immunosuppressive medications
- Cyclosporine > tacrolimus, steroids
- Preexisting hypertension
- Development of renal failure

## Hypertension in Organ Transplant Recipients

- Effective antihypertensive treatment
- Reduces target organ damage
- Decreases cardiovascular events
- Promotes long-term allograft and patient survival

## Management of Hypertension

- JNC-7 Guidelines
- Life style modifications
- Diet – including salt reduction
- Weight management
- Increased physical activity
- Moderation of alcohol consumption
- Medications

- www.nhlbi.nih.gov/guidelines/hypertension

## Calcium Channel Blockers (CCBs)

- Dihydropyridine:
- amlodipine, felodipine, nifedipine
- Non-dihydropyridine:
- verapamil, diltiazem

## CCB Adverse Effects

- Gingival hyperplasia
- Peripheral edema
- Decreased heart rate (verapamil & diltiazem)
- Increases immunosuppressant drug levels (verapamil & diltiazem)

## Beta Blockers

- Cardioselective preferred - metoprolol, atenolol
- Beneficial in patients with heart failure or post MI
- Adverse effects
- Bradycardia
- Significant sinus bradycardia or heart block when combined with non-dihydropyridine CCB
- May increase bronchospasm

## ACE Inhibitors (ACEI)/ Angiotension II Receptor Blockers (ARBs)

- Long acting ACEI preferred
- Especially beneficial in:
- Patients with heart failure or post MI
- Patients with kidney disease and proteinuria
- ARBs can be used for ACEI-induced cough

## ACEI/ARBs Adverse Effects

- May decrease renal function, especially    if renal artery stenosis present
- May contribute to anemia
- May cause hyperkalemia, esp. with tacrolimus, cyclosporine
- ACEI may lead to cough

## Alpha-1 Blockers

- Long acting agents preferred
- e.g. doxazosin, terazosin
- Often used as add-on therapy
- Beneficial in patients with BPH
- Adverse effects:
- First dose hypotension: begin with low dose at bed time
- Increased risk for orthostatic hypotension

## Diuretics

- Low dose thiazide diuretics preferred
- e.g. HCTZ (12.5-25mg)
- Beneficial in patients with edema or resistant hypertension
- May be ineffective with severe renal disease
- Adverse effects:
- May cause volume depletion and elevate creatinine, BUN
- May cause hypokalemia

## Hypertension Summary

- Common in transplant patients
- Follow JNC7 guidelines for the mgmt. of HTN, beginning with lifestyle changes
- Many will require combination drug therapy
- Monitor for side effects and drug interactions
- Contact transplant center or hypertension specialist for difficult cases

## Diabetes Mellitus

- Increasing in the general population
- Diagnostic criteria redefined
- Increased obesity
- More common after transplant
- Immunosuppressive drug therapy
- Incidence of new onset diabetes
- Renal transplant 4-25%
- Liver transplant 2.5-25%
- In Hepatitis C patients 40-60%

## Working Definitions

- Diabetes mellitus
- FPG ≥ 126mg/dL OR
- Random plasma glucose level ≥ 200mg/dL and symptoms of diabetes
- Impaired fasting glucose (IFG)
- FPG ≥ 100mg/dL and < 126mg/dL

## Risk Factors

- African American, Hispanic, Native American
- Family history
- Pre-transplant glucose intolerance
- Obesity or presence of other components of metabolic syndrome
- Age > 40 years
- HCV infection, CMV infection
- Immunosuppressant medications
- Prednisone, tacrolimus > cyclosporine

## Consequences of Diabetes Mellitus

- Infection
- Microvascular complications
- Neuropathy, nephropathy, retinopathy
- Macrovascular complications
- CVD

## Treatment Goals

- In general, should follow established guidelines
-  Blood glucose goals
- A1c < 7% (not always accurate after blood transfusions, hemolysis, or anemia)
- FPG 70-130mg/dL
- Postprandial <180mg/dL
- Blood pressure <130/80 mmHg
- LDL <100mg/dL

- .

- Diabetes  Care 2007: 30:S4-S41; www.oqp.med.va.gov/cpg/cpg.htm

## Treatment Strategies

- Non-pharmacologic
- Counseling on weight control, diet, and exercise
- Pharmacologic
- Oral or insulin monotherapy
- Combination therapy
- Altering immunosuppressive regimens                (in consultation with the transplant center)

**Notes:**
Treatment options include adjustment of immunosuppression
May be effective, but insulin necessary in up to 40% of patients

## Sulfonylureas (Glipizide, Glyburide)

- Pros
- Does not require injection
- Cons
- Less effective in patients on high dose prednisone
- Risk for hypoglycemia lower with glipizide than glyburide

## Biguanides (Metformin)

- Pros
- Beneficial in obese patients with insulin resistance
- Cons
- Increased risk of lactic acidosis with renal impairment
- Use with extreme caution in transplant patients, as renal function can change rapidly

**Notes:**
Cr > 1.4 in females
Cr > 1.5 in males

## Insulin  

- Pros
- Allows for tight glucose control
- Easy to titrate
- NPH insulin’s onset and duration follows blood glucose rise caused by steroids
- Cons
- Patients have to learn to self inject
- Risk of severe hypoglycemia
- Often requires multiple injections
- Requires intensive blood glucose monitoring

## Immunosuppressive Alterations by Transplant Center

- Possible options
- Taper or discontinue steroids
- Decrease calcineurin inhibitor dose
- Change tacrolimus to cyclosporine

## Diabetes Summary

- Diabetes is common in the transplant population
- Goals for the diabetic transplant patient should follow standard guidelines
- Treating diabetes is important for preventing complications & promoting survival
- Insulin and glipizide are safe first-line agents for post-transplant patients

## Vaccines in Solid Organ Recipients: General Principles

- Transplant recipients are more susceptible to infections, including those that can be prevented by vaccination
- Optimal time to vaccinate is before transplantation
- After transplantation
- Killed vaccines are less effective
- Live viral vaccines are contraindicated

## Vaccines in Solid Organ Recipients: General Principles

- Seasonal, periodic or booster doses of common killed vaccines should be administered after transplant
- Vaccines required for specific risk factors or for travel should be given after consultation with transplant center or ID specialist

## Inactivated (Killed) Vaccines

- Inactivated Influenza vaccine
- Yearly during influenza season
- Pneumococcal vaccine
- 2 doses with the second dose after 5 yr
- Tetanus/Diptheria
- Td every 10 years as booster
- Tdap should be given once instead of Td if pt hasn’t previously received it AND is <65 yrs
- Hepatitis A and B
- If not previously immunized

## Live Vaccines Contraindicated 

- MMR
- Nasal influenza
- Oral Polio
- Oral typhoid
- Rotavirus
- Varicella
- Zoster
- Household contacts who receive a live vaccine present a risk to the transplant patient

## Long Term Health of the Transplant Recipient

**Long Term Health of the Transplant Recipient**

- Optimize length and quality of life for Veterans
- Transplant Center focuses on long term immunosuppression and monitoring transplant function
- Primary Care Team focuses on preventive healthcare and management of common problems

## When to Contact the Transplant Center

- Dysfunction of the transplanted organ
- Immunosuppressive drug-related issues
- Life threatening infections
- Malignancy
- Major organ failure

**VANTS Calls**
**September 4, 2008****October 28, 2008****1-800-767-1750****Access code: 86360#**