Titel.: Risk Management Plan Hydrokortison Orifarm 10 mg and 20 mg tablets Valid from: 10.2017 Dok. no./version: : RMP189-DK1.6 Prepared by: LAH Replaces doc. no./version: 1.5

VI.2 Elements for a public summary Hydrocortisone (i.e. cortisol) is a natural hormone that belongs to a class of medicines called corticosteroids. Corticosteroids mimic the effects of hormones that the body produces naturally in the adrenal glands that are located on top of each kidney. These hormones are essential for life. When prescribed in doses that exceed body's usual levels, corticosteroids suppress inflammation. This can reduce the signs and symptoms of inflammatory conditions. Corticosteroids also suppress immune system, which can e.g. help control conditions in which the immune system mistakenly attacks its own tissues.

VI.2.1 Overview of disease epidemiology

Congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) is an inherited disorder of the adrenal glands. The condition is often diagnosed at birth. People with congenital adrenal hyperplasia lack an enzyme that adrenal gland needs, to make the hormones cortisol and aldosterone. The most common enzymatic defect is cytochrome P450 21-hydroxylase (CYP21) deficiency accounting for approximately 95% of cases. The person with CAH will either not produce adrenal hormones or will produce them in the wrong amounts (e.g. too little cortisol, too much androgens). There is no cure, but CAH can be managed with hormonal treatment e.g. hydrocortisone. Congenital adrenal hyperplasia can affect both boys and girls. About 1 in 10,000 to 18,000 children are born with congenital adrenal hyperplasia.

Adrenal insufficiency Adrenal insufficiency is a hormonal-disorder that occurs when the adrenal glands do not produce enough of certain hormones. Adrenal insufficiency can be primary or secondary. Primary adrenal insufficiency, also called Addison's disease, occurs when the adrenal glands are damaged and cannot produce enough of the hormone cortisol and often the hormone aldosterone. Addison's disease affects one to four of every 100,000 people, in all age groups and both sexes. Addison's disease can be life-threatening. Secondary adrenal insufficiency occurs when the pituitary gland-a bean-sized organ in the brain- fails to produce enough adrenocorticotropin (ACTH), a hormone that stimulates the adrenal glands to produce cortisol. If ACTH output is too low, cortisol production drops. Eventually, the adrenal glands can shrink due to lack of ACTH stimulation. Secondary adrenal insufficiency is much more common than Addison's disease

Allergic/hypersensitivity reactions Allergies occur when immune system reacts to a foreign substance such as pollen, bee venom or pet dander. Those are called allergens. In allergy immune system makes antibodies that identify a particular allergen as something harmful. When an allergic person comes into contact with the certain allergen, the immune system's reaction can inflame skin, sinuses, airways or digestive system. The severity of allergies varies from person to person and can range from minor irritation to anaphylaxis - a potentially life-threatening emergency.

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Titel.: Risk Management Plan Hydrokortison Orifarm 10 mg and 20 mg tablets Valid from: 10.2017 Dok. no./version: : RMP189-DK1.6 Prepared by: LAH Replaces doc. no./version: 1.5

Angioneurotic edema (angioedema) is caused by triggers that stimulate mast cells to release histamine and other chemicals into the bloodstream causing swelling that affects deeper layers in skin, often around eyes and lips. Allergic reactions are common trigger of acute angioedema. However, sometimes it is not possible to pinpoint the cause of angioedema, especially when the condition becomes chronic or recurs. There are 2 major types of angioedema: the rare hereditary angioedema (HAE) and the more common non-hereditary angioedema (non-HAE).

The rare hereditary form occurs in about 1 in 50,000 individuals (range: 1 in 10,000–1 in 150,000 worldwide) and typically first appears during childhood or adolescence, worsens during puberty, and persists throughout the patient’s lifetime. About half of patients have their first attack before age 10. Untreated patients may have attacks every 7 to 14 days on average, while patients whose disease is well controlled with long-term prophylactic therapy may be symptom-free for a decade or more. The severity of attacks also varies considerably, even within affected families.

The more common non-HAE form occurs in about 7 in 100 individuals and becomes chronic in approximately 50% of affected patients. Non-HAE is typically a benign, self-limiting disease, but in some cases it can become lifelong and troublesome. Angioedema lasting more than 6 weeks is defined as chronic angioedema. Non-HAE angioedema occurs in patients of all ages.

Serum sickness describes a delayed immune system response e.g. to certain kinds of medications. Serum sickness is similar to an allergy, in that the body mistakenly identifies a protein from the antiserum or medication as harmful and activates the immune system to fight against it. The most common cause of serum sickness is the antibiotic agent penicillin. Serum sickness will usually develop within 7 - 10 days after initial exposure, but sometimes it can take as long as 3 weeks. Symptoms include fever, general ill feeling, hives, itching, joint pain, rash and swollen lymph nodes. Serum sickness may occur in individuals of an age in response to the introduction of heterologous protein.

Asthma (severe asthma) is a condition in which airways narrow and swell and produce extra mucus. This can make breathing difficult and trigger coughing, wheezing and shortness of breath. Development of asthma is probably due to a combination of environmental and genetic (inherited) factors. Exposure to various substances that trigger allergies (allergens) and irritants can trigger signs and symptoms of asthma. Asthma is a worldwide disease, with an estimated 300 million affected individuals and is estimated to cause 346.000 deaths worldwide per year. The global prevalence is estimated to be 1-16% of the population in different countries but there are insufficient data to determine the likely causes of the described variations within and between populations. Asthma is the most prevalent chronic disease in children, adolescents, and young adults living in western societies. In Denmark, according to the prescription data, the prevalence of asthma is >400,000, with an estimated 30,000 new diagnoses per year.The factors influencing the risk of developing asthma include host and environmental factors but the mechanisms influencing the development and expression of the disease are complex

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Titel.: Risk Management Plan Hydrokortison Orifarm 10 mg and 20 mg tablets Valid from: 10.2017 Dok. no./version: : RMP189-DK1.6 Prepared by: LAH Replaces doc. no./version: 1.5 and interactive..

VI.2.2 Summary of treatment benefits

Hydrocortisone is well established drug for the treatment of congenital adrenal hyperplasia and adrenal insufficiency in children and adolescent. The efficacy of hydrocortisone has been demonstrated by clinical practice rather than clinical studies meeting today’s standards for a randomised controlled trial

Corticosteroids, such as hydrocortisone, are also frequently used drugs that mediate immunosuppressive and anti-inflammatory effects. They relieve the inflammation, pain and discomfort of many different diseases and conditions. They lessen swelling, redness, itching, and allergic reactions. Therefore they are often used as part of the treatment for a number of different diseases, such as severe allergies or asthma. High doses of corticosteroids are usually required in patients with severe diseases involving major organs. In intensive or emergency therapy, parenteral (given e.g. intravenously or injected in muscle) administration may be required.

VI.2.3 Unknowns relating to treatment benefits

None.

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Titel.: Risk Management Plan Hydrokortison Orifarm 10 mg and 20 mg tablets Valid from: 10.2017 Dok. no./version: : RMP189-DK1.6 Prepared by: LAH Replaces doc. no./version: 1.5

VI.2.4 Summary of safety concerns

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Titel.: Risk Management Plan Hydrokortison Orifarm 10 mg and 20 mg tablets Valid from: 10.2017 Dok. no./version: : RMP189-DK1.6 Prepared by: LAH Replaces doc. no./version: 1.5

Risk What is known Preventability Increased likelihood to get People who receive Any current infections and infections and masking of corticosteroids, such as medical history of infections symptoms of infection hydrocortisone, for a long should be taken into account period of time are prone to before therapy is initiated. infections as their immune system can become weak. Hydrocortisone should not be This is the case especially if given to patients who have high doses are administered. microbial infection in their body system without Infections may become more appropriate antimicrobial drug severe than they usually therapy. would be and the symptoms that would usually be used to Live vaccines should not be identify such infections can given during high-dose be hidden. hydrocortisone therapy. Special attention should be paid for signs and symptoms of infection during hydrocortisone therapy and doctor should be contacted if symptoms appear.

Close contact with people who have acute infections should be avoided.

Symptoms of too little cortisol Long-term use of Dose should be adjusted in body corticosteroids may cause individually using the smallest suppression of body’s own effective dose. corticosteroid production. Long-term corticosteroid The severity and duration of therapy should not be stopped this conditions vary by the abruptly. The dose should be patient and depend on the decreased gradually. If the dose, dosing interval, time of patient’s own corticosteroid day of administration, and production is suppressed, length of therapy. she/he should receive additional corticosteroids in If the dose of hydrocortisone case of stressful situations, is reduced too rapidly serious such as illness or injury. problems may occur.

Eye disorders such as The occurrence of secondary Special caution should be infections fungal and viral eye administered when treating infections may increase in patients with ocular infections.

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Risk What is known Preventability patients receiving Medical history of increased corticosteroids and there is a eye pressure, cataract or risk of corneal perforation, in glaucoma should be taken into patients with ocular herpes account and discussed with simplex infection. doctor. Long term corticosteroid use may cause cataract, bulging of the eyes, or increased eye pressure, which may lead to glaucoma and a potential subsequent injury to the optic nerve.

Bones become weak and brittle Osteoporosis is a common, Medical history of (osteoporosis) yet rarely recognized, adverse osteoporosis should be taken effect of prolonged high-dose into account and discussed corticosteroid treatment. with doctor. Vitamin D and calcium supplements, healthy diet, weight-bearing exercise and certain medications may help to prevent bone loss or strengthen already weak bones. Development or worsening of Corticosteroids, including Medical history of diabetes, diabetes hydrocortisone, may increase glucose intolerance or blood glucose concentration, increased blood sugar should exacerbate diabetes and be taken into account and predispose patients receiving discussed with doctor. long-term corticosteroid The dose of insulin or other treatment to diabetes. antidiabetic drugs may need to be adjusted. Psychiatric adverse reactions Psychiatric disorders, such as Medical history of mental (depression, mania, psychosis) euphoria, insomnia, mood problems should be taken into alterations, personality account and discussed with changes, deep depression, or doctor. definite psychotic symptoms, Most psychiatric reactions may occur in connection with recover after either dose the use of corticosteroids. reduction or treatment During the corticosteroid withdrawal, although specific medication, the condition treatment may be needed. may become exacerbated in Patients and/or their carers emotionally unstable patients should contact doctor, if psychiatric symptoms develop,

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Titel.: Risk Management Plan Hydrokortison Orifarm 10 mg and 20 mg tablets Valid from: 10.2017 Dok. no./version: : RMP189-DK1.6 Prepared by: LAH Replaces doc. no./version: 1.5

Risk What is known Preventability or those with a psychotic especially if depressed mood tendency. or suicidal thoughts are Potentially serious psychiatric suspected. adverse effects may occur Patients and/or their carers during therapy. Typically, should be aware of the symptoms appear after a potential psychiatric effects couple of days or weeks from which may occur at reduction starting the treatment. of the corticosteroid dose or Psychiatric effects have been immediately after cessation of reported on cessation of the their use. use of corticosteroids. The frequency of such effects is unknown. Peptic ulcers and bleeding from Peptic ulcers are sores that Medical history of stomach or intestine develop on the inside lining diseases/conditions affecting of esophagus, stomach and alimentary canal and the upper portion of small concomitant medications intestine. The most common should be taken into account symptom of a peptic ulcer is and discussed with doctor. abdominal pain. Doctor should be contacted Bleeding can occur as slow immediately in case of blood loss that leads to symptoms of stomach pain and anemia or as severe blood bleeding from the anus, black loss that may require acute or bloodstained stools and/or hospitalization. vomiting blood. There is no consensus on whether peptic ulcers developing during the treatment are caused by corticosteroids. However corticosteroid therapy may mask the symptoms of peptic ulcers, allowing perforation or bleeding to develop without any notable pain. Deficiency symptoms when the When a person has been Withdrawal of hydrocortisone treatment is discontinued treated with hydrocortisone should be done gradually. for some time the body with react with symptoms when the treatment is discontinued. This can be avoided if the treatment us discontinued step wise.

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Titel.: Risk Management Plan Hydrokortison Orifarm 10 mg and 20 mg tablets Valid from: 10.2017 Dok. no./version: : RMP189-DK1.6 Prepared by: LAH Replaces doc. no./version: 1.5

Risk What is known Preventability

Use in elderly patients Treatment of elderly patients, particularly if long term, should be planned bearing in mind the more serious consequences of the common side effects of corticosteroids in old age, especially osteoporosis, diabetes, hypertension, susceptibility to infection and thinning of the skin. Use in pregnancy and lactation Hydrocortisone may cause Hydrocortisone should only be adverse events in the fetus used in pregnancy and during during pregnancy and in the lactation if the benefit for the breastfed infant mother clearly outweighs the risk for the child. Use of hydrocortisone Hydrocortisone may interact The doctor should monitor the concomitantly with with the effect of patient when the 2 medicines anticoagulants anticoagulants are used concomitantly.

VI.2.5 Summary of additional risk minimisation measures by safety concern

All medicines have a Summary of Product Characteristics (SmPC) which provides physicians, pharmacists and other health care professionals with details on how to use the medicine, the risks and recommendations for minimising them. An abbreviated version of this in lay language is provided in the form of the package leaflet (PL). The measures in these documents are known as routine risk minimisation measures. The Summary of Product Characteristics and the Package leaflet for Hydrokortison Alternova can be found on the homepage of the Danish Health and Medicines Agency after the product has been approved.

VI.2.6 Planned post authorisation development plan (if applicable)

Not Applicable.

VI.2.7 Summary of changes to the risk management plan over time

Not Applicable.

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