Calcineurin inhibitors: Uses, common brands, and safety info

Our immune system is made of organs, tissues, cells, and proteins that fight infectious organisms and cancer cells. Unfortunately, the immune system can behave in ways that harm the body rather than protect it. Autoimmune diseases arise when abnormal immune responses cause inflammation throughout the body. Immune cells also attack transplanted organs, because the immune system recognizes the organ is from another person. 

Calcineurin inhibitors are a class of drugs that modify the activity of immune cells to help patients with organ transplants or inflammatory conditions. Here we will discuss all the drugs in this class, including their uses, side effects, how they work, and how to use them safely.

Other calcineurin inhibitors:

One June 24, 2021, Santen Pharmaceutical Co. announced its product Verkazia (cyclosporine ophthalmic emulsion) 0.1% eye drops received approval from the U.S. Food and Drug Administration (FDA) for the treatment of vernal keratoconjunctivitis (VKC) in children and adults. Product details can be accessed on the FDA website.

What are calcineurin inhibitors?

Calcineurin inhibitors (CNIs) are prescription drugs that alter the immune system. They belong to a more general class of drugs called immunosuppressants. They are prescribed for medical conditions that cause the immune system to damage the body rather than protect it. For example, after organ transplantation, a person’s immune system may attack the transplanted organ because it recognizes it as ‘foreign’ to the recipient’s body. This harmful process is called ‘allograft rejection.’ Calcineurin inhibitors are prescribed after organ transplant surgery to minimize damage from the immune system. They are usually required for the remainder of the recipient’s lifetime. Patients taking calcineurin inhibitors require ongoing supervision from a healthcare provider who is experienced in managing immunosuppressive therapy. Calcineurin inhibitors are used in combination with other immunosuppressants such as corticosteroids. They are also used for other inflammatory diseases such as rheumatoid arthritis and lupus nephritis.

How do calcineurin inhibitors work?

Calcineurin inhibitors block the activity of calcineurin. This protein is located inside T cells, which are white blood cells that fight infections. When calcineurin is blocked, T cells cannot produce the molecule interleukin-2 (IL-2). Without IL-2, T cells become less responsive to antigens (foreign molecules). This explains why calcineurin inhibitors make patients more susceptible to infections. So why might it be helpful to have less responsive T cells? Patients with an autoimmune disease like rheumatoid arthritis, lupus, or psoriasis have T cells that behave abnormally. The overactive T cells cause widespread inflammation, resulting in tissue damage in areas like the joints or skin. Patients who receive a transplanted organ or tissue (graft) from another person need calcineurin inhibitors to suppress T cells from mounting an attack on the donated organ.

What are calcineurin inhibitors used for?

Not all calcineurin inhibitors have the same uses. Most are only FDA approved for a few conditions. Below is a list of medical conditions that may be treated with an appropriate calcineurin inhibitor:

• Allogeneic post-transplant organ rejection

• Prevention of organ rejection following liver, heart, or kidney transplant

• Chronic atopic dermatitis

• Chronic dry eye syndrome (DES)

• Vernal keratoconjunctivitis

• Lupus nephritis

• Plaque psoriasis

• Rheumatoid arthritis

Calcineurin inhibitors are often used “off-label” for the following conditions:

• Seborrheic dermatitis

• Chronic hand dermatitis

• Contact dermatitis

• Vitiligo

• Localized scleroderma

• Lichen sclerosis

• Cutaneous lupus erythematosus

Who can take calcineurin inhibitors?

Infants, children, and adolescents

Calcineurin inhibitors are often prescribed for pediatric patients. However, their use may be considered “off-label” depending on the specific drug and the patient’s age. The FDA has not approved certain calcineurin inhibitors for all ages. 

Topical calcineurin inhibitors (TCIs) carry a theoretical risk of skin malignancy and lymphoma. Neither tacrolimus ointment (Protopic) nor pimecrolimus cream (Elidel) are approved for use in children less than 2 years old. The higher strength of tacrolimus ointment (0.1%) is not approved for patients younger than 16 years old. Several calcineurin inhibitors are not approved for all ages due to a lack of safety data. Restasis (cyclosporine 0.05% eye drops) is not approved in patients younger than 16 years old and Cequa (cyclosporine 0.09% eye drops) is not approved for patients younger than 18 years old. Verkazia (cyclosporine 0.1% eye drops) is not approved for patients younger than four years old. Lupkynis, the newest oral calcineurin inhibitor, is currently not approved for pediatric use.

Adults

Calcineurin inhibitors are safe and effective for use in adults. The most important side effect to watch out for is an infection. Tell your doctor immediately if you have any signs or symptoms of infection such as fever, stiff neck, swollen lymph nodes in the neck, armpits, or groin, burning or pain with urination, sore throat, rapid breathing, or rapid pulse. Patients taking oral calcineurin inhibitors must have their drug levels and kidney function monitored by a doctor, and patients with hypertension must have their blood pressure checked regularly.

During pregnancy or breastfeeding

Calcineurin inhibitors may be used in women who are pregnant or breastfeeding if the potential benefits to the mother justify the risks to the fetus. For example, the risk of graft rejection is more significant than the risk of drug-related harm to the fetus in solid organ transplant recipients. However, for certain conditions such as plaque psoriasis, the benefits of oral calcineurin inhibitors might not justify the risks.

Cyclosporine use is associated with premature births and low birth weight, and oral tacrolimus is associated with premature delivery, low birth weight, high potassium, and kidney dysfunction in the fetus. Lupkynis should not be used in women who are pregnant or breastfeeding due to lack of safety data. Lupkynis treatment should not be restarted until seven days after breastfeeding. Topical calcineurin inhibitors and cyclosporine eye drops do not pose any risk to the fetus and are safe to use during pregnancy and breastfeeding. For more information on the risks of calcineurin inhibitor use during pregnancy visit Transplant Pregnancy Registry.

Seniors

Calcineurin inhibitors are safe to use in the elderly. All patients taking calcineurin inhibitors require supervision from a doctor experienced in managing immunosuppressive therapy, and this is especially true for seniors. Older patients are more susceptible to the adverse effects of calcineurin such as nephrotoxicity (kidney damage), cardiovascular disease, infection, and malignancy. The reason for higher susceptibility is twofold. Kidney, heart, and immune system function deteriorate as adults age. Secondly, elderly patients clear calcineurin inhibitors from the body more slowly than younger adults, so seniors might need to take lower doses to avoid toxic drug effects.

Are calcineurin inhibitors safe?

Calcineurin inhibitors can cause significant side effects and therefore require careful monitoring by a physician experienced in managing immunosuppressive therapy. The following risks should be discussed with a clinician before starting therapy with a calcineurin inhibitor:

• Patients taking oral calcineurin inhibitors are at an increased risk for developing serious infections and malignancies that may lead to hospitalization or death.

• Patients receiving oral calcineurin inhibitors should have their drug levels tested regularly by a doctor. Different cyclosporine-containing products have different bioavailability and are not interchangeable. All forms of tacrolimus are not equivalent and may not have the same dose or schedule. Toxicity can result from high drug levels and organ rejection may result from low drug levels.

• Calcineurin inhibitors cause immunosuppression which can make vaccines less effective. During treatment with oral calcineurin inhibitors, patients should not receive vaccines containing live viruses. Live vaccines include measles, mumps, rubella (MMR), rotavirus, typhoid, yellow fever, varicella (chickenpox), zoster (shingles), and nasal influenza (flu) vaccine.

Recalls

June 3, 2021—Sun Pharmaceuticals Industries recalled Cequa (cyclosporine ophthalmic solution) 0.009% (national drug code 47335-0506-96) due to low drug concentration and elevated levels of particulate matter in affected lots.

July 7, 2020—Mylan Pharmaceutical recalled tacrolimus 5 mg (national drug code 0378-2047-01), due to presence of commingled tacrolimus 1 mg capsules.

March 18, 2020—Novartis recalled Sandimmune (cyclosporine capsules) 100 mg soft gelatin capsules and Neoral (cyclosporine capsules) MODIFIED 100 mg soft gelatin capsules due to failure to meet child-resistant packaging requirements set by the Poison Prevention Packaging Act.

Restrictions

• Patients should not take a calcineurin inhibitor product if they have a hypersensitivity to the active ingredient or any component of the product. In addition, patients should not use cyclosporine if they have a hypersensitivity to polyoxyethylated castor oil and should not take tacrolimus if they have a hypersensitivity to polyxyl 60 hydrogenated castor oil.

• Patients with an active infection should not use calcineurin inhibitors. Patients taking a calcineurin inhibitor should report signs of infection promptly.

• Patients with cancer or malignancy should not use calcineurin inhibitors. Patients taking oral calcineurin inhibitors are at an increased risk for developing serious infections and malignancies that may lead to hospitalization or death. Patients taking cyclosporine have a greater risk of skin cancer if they have used methotrexate, PUVA, UBV, coal tar, radiation therapy, or other immunosuppressive therapy in the past. These treatments should not be used with cyclosporine. Patients taking topical calcineurin inhibitors have had rare cases of malignancy (e.g., skin lymphoma). Topical calcineurin inhibitors should only be applied to areas affected by the skin condition being treated. Continuous use in any age group should be avoided.

• Patients with poor renal function or high blood pressure should use extreme caution when taking cyclosporine or Lupkynis. Patients taking these drugs must have kidney function monitored by a doctor. Cyclosporine and Lupkynis can cause high blood pressure and nephrotoxicity (kidney damage) when used at recommended doses.

• Patients with liver impairment must have their liver function monitored by a doctor while taking cyclosporine. Some patients taking cyclosporine have reported liver damage, including liver failure. Patients with liver impairment may require lower doses of other oral calcineurin inhibitors such as Lupkynis and tacrolimus. 

• Patients with severe gout should not take cyclosporine. Cyclosporine can elevate uric acid levels significantly and may lead to an accelerated form of gout.

• Patients may need to avoid certain calcineurin inhibitors if they interact with their other medications. For example, cyclophosphamide, ketoconazole, itraconazole and clarithromycin should not be taken with Lupkynis. Simvastatin, dronedarone, and cisapride may not be safe to take with cyclosporine. This is not a complete list of drugs that have strong interactions with calcineurin inhibitors. Always inform your doctor or pharmacist of your current medications to avoid serious drug interactions.

Are calcineurin inhibitors controlled substances?

No, calcineurin inhibitors are not controlled substances.

Common calcineurin inhibitors side effects

Calcineurin inhibitors cause different side effects when they are taken orally, topically (on the skin) or administered to the eyes. The following are common side effects categorized by route of administration:

Oral administration (tablets, capsules, liquid):

• Diarrhea

• Nausea

• Vomiting

• Stomach upset

• Headache

• cough

• Nephrotoxicity (kidney damage)

• Hepatotoxicity (liver damage)

• Infections

• Increased risk of lymphomas

• Increased risk of cutaneous squamous cell carcinoma

• High blood pressure

• High cholesterol

• High potassium

• Elevated uric acid levels

• Low magnesium

• Tremors (shaking)

• Alopecia (hair loss)

• Acne

Additional side effects of cyclosporine include hirsutism (excessive hair growth) and gingival hyperplasia. Tacrolimus can also cause diabetes mellitus, and skin photosensitivity (sensitivity to sun). Lupkynis can cause urinary tract infection, anemia, and fatigue.

Topical administration (cream and ointment):

• Burning, redness, itching at the application site

• Fever

• Headache

• Nausea

• Cough

• Nasal congestion

• Sinusitis (inflamed sinuses)

• Upper respiratory tract infection

• Sore throat

• Acne

• Worsening of asthma symptoms

• Folliculitis (inflamed hair follicles)

• Skin infections

Ophthalmic administration (eye drops)

• Blurred vision

• Burning, stinging, or itching of the eyes

• Discharge from the eyes

• Headache

• Lacrimation (excessive tears)

This is not an exhaustive list of side effects for all calcineurin inhibitors. Additional side effects may occur for individual drugs in this class. If you are experiencing worrisome or intolerable side effects, consult a doctor or pharmacist for further information and advice.

How much do calcineurin inhibitors cost?

Generic versions are available for Prograf, Sandimmune, Gengraf, Neoral, Protopic, and Elidel. These are sold at a much lower cost than their brand-name counterparts. For example, Sandimmune can cost more than $100 for 30 capsules of 100 mg strength. The generic capsules cost around $35 with a SingleCare coupon. Most brand-name calcineurin inhibitors cost hundreds of dollars without insurance. Fortunately, generic versions can be more affordable with SingleCare.

Medicare Part D plans will cover oral, ophthalmic, and topical calcineurin inhibitors if the drug is being prescribed for one of its FDA approved uses. Two exceptions are tacrolimus and cyclosporine, which are covered for “off-label” use. Health plans may require the prescriber to verify you have tried other treatments first.

Medicare Part B will also cover oral calcineurin inhibitors used for transplant surgery short-term after you leave the hospital following a transplant. Part D plans are required to cover nearly all immunosuppressant drugs and will cover transplant drugs that Part B doesn’t cover. Starting December 2020, patients requiring kidney transplantation will be eligible for Medicare coverage of their immunosuppressive drugs lifelong, even if they would not otherwise be eligible for Medicare.

Even if an insurance plan covers your medication, it may be less expensive to use a SingleCare savings coupon.

Resources:

• Astagraf XL prescribing information

• Cequa prescribing information

• Cyclosporine drug summary

• Calcineurin inhibitors

• Drug-induced hyperuricaemia and gout

• Elidel prescribing information

• Envarsus XR prescribing information

• Expanded Medicare coverage of immunosuppressive drugs for kidney transplant recipients

• Gengraf prescribing information

• Lower calcineurin inhibitor doses in older compared to younger kidney transplant recipients yield similar troughs

• Lupkynis prescribing information

• Neoral prescribing information

• Prescription drugs (outpatient)

• Prograf prescribing information

• Protopic prescribing information

• Restasis prescribing information

• Sandimmune prescribing information

• Verkazia new drug application