Acthar

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Infections [see Warnings and Precautions (5.1) ] Cushing's Syndrome and Adrenal Insufficiency Upon Withdrawal [see Warnings and Precautions (5.2) ] Elevated Blood Pressure, Salt and Water Retention, and Hypokalemia [see Warnings and Precautions (5.3) ] Masking Symptoms of Other Diseases [see Warnings and Precautions (5.5) ] Gastrointestinal Perforation and Bleeding [see Warnings and Precautions (5.6) ] Behavioral and Mood Disturbances [see Warnings and Precautions (5.7) ] Ophthalmic Effects [see Warnings and Precautions (5.9) ] Immunogenicity Potential [see Warnings and Precautions (5.10) ] Negative Effects on Growth and Physical Development [see Warnings and Precautions (5.12) ] Decrease in Bone Density [see Warnings and Precautions (5.13) ] Commonly reported postmarketing adverse reactions for Acthar Gel include injection site reaction, asthenic conditions (including fatigue, malaise, asthenia and lethargy), fluid retention (including peripheral swelling), insomnia, headache, and blood glucose increased. ( 6.2 ) The most common adverse reactions (5% or greater in the recommended twice daily dosing group) for the treatment of infantile spasms are increased risk of infections, convulsions, hypertension, irritability, and pyrexia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mallinckrodt at 1-800-844-2830 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Infants and Children Under 2 Years of Age While the types of adverse reactions seen in infants and children under age 2 treated for infantile spasms are similar to those seen in older patients, their frequency and severity may be different due to the very young age of the infant, the underlying disorder, the duration of therapy and the dosage regimen. Below is a summary of adverse reactions specifically tabulated from source data derived from retrospective chart reviews and clinical trials in children under 2 years of age treated for infantile spasms. The number of patients in controlled trials at the recommended dose was too few to provide meaningful incidence rates or to permit a meaningful comparison to the control groups. The most common adverse reactions (5% or greater in the recommended twice daily dosing group) for the treatment of infantile spasms are increased risk of infections, convulsions, hypertension, irritability, and pyrexia. TABLE: Incidence (%) of Adverse Reactions Occurring in ≥2% of Infants and Children Under 2 Years of Age Treated with Acthar Gel Adverse Reactions Recommended 75 U/m 2 twice daily n=122, (%) 150 U/m 2 once daily n=37 (%) Cardiac disorders Cardiac Hypertrophy 3 0 Endocrine disorders Cushingoid 3 22 Gastrointestinal disorders Diarrhea 3 14 Vomiting 3 5 Constipation 0 5 General disorders and administration site conditions Irritability 7 19 Pyrexia 5 8 Infections and infestations Infection Specific infections that occurred at ≥ 2% were candidiasis, otitis media, pneumonia and upper respiratory tract infections. 20 46 Investigations Weight gain 1 3 Metabolism and nutrition disorders Increased appetite 0 5 Decreased appetite 3 3 Nervous system disorders Convulsion In the treatment of infantile spasms, other types of seizures/convulsions may occur because some patients with infantile spasms progress to other forms of seizures (for example, Lennox-Gastaut Syndrome). Additionally, the spasms sometimes mask other seizures and once the spasms resolve after treatment, the other seizures may become visible. 12 3 Respiratory, thoracic and mediastinal disorders Nasal Congestion 1 5 Skin and subcutaneous tissue disorders Acne 0 14 Rash 0 8 Vascular disorders Hypertension 11 19 These adverse reactions may also be seen in adults and children over 2 years of age when treated for other purposes and with different doses and regimens. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of Acthar Gel. Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Allergic Reactions Allergic responses have presented as dizziness, nausea, and anaphylaxis (anaphylactic shock, hypotension, respiratory compromise, urticaria, edema). Cardiovascular Necrotizing angitis (adults only), congestive heart failure, atrial fibrillation, and palpitations. Dermatologic Skin thinning (adults only), facial erythema, and increased sweating (adults only). Endocrine Decreased carbohydrate tolerance (infants only), hirsutism, and menstrual irregularities. Gastrointestinal Pancreatitis (adults only), abdominal distention, and ulcerative esophagitis. General Disorders and Administration Site Conditions Injection site reaction and asthenic conditions (including fatigue, malaise, asthenia, and lethargy). Infections and Infestations Abscess. Investigations Blood glucose increased. Metabolic Hypokalemic alkalosis (infants only) and fluid retention (including peripheral swelling). Musculoskeletal Muscle weakness and vertebral compression fractures (infants only). Neurological Headache (adults only), vertigo (adults only), subdural hematoma, intracranial hemorrhage (adults only), and reversible brain shrinkage (usually secondary to hypertension) (infants only). Psychiatric Disorders Insomnia. 6.3 Possible Additional Steroidogenic Effects Based on steroidogenic effects of Acthar Gel certain adverse events may be expected due to the pharmacological effects of corticosteroids. The adverse events that may occur but have not been reported for Acthar Gel are: Dermatologic Impaired wound healing, petechiae and ecchymoses, and suppression of skin test reactions. Metabolic Negative nitrogen balance due to protein catabolism and alteration in glucose tolerance. Musculoskeletal Loss of muscle mass and aseptic necrosis of femoral and humeral heads. Neurological Increased intracranial pressure with papilledema, (pseudo-tumor cerebri) usually after treatment, and subdural effusion. Ophthalmic Exophthalmos.

4 CONTRAINDICATIONS Acthar Gel is contraindicated: for intravenous administration. in infants under 2 years of age who have suspected congenital infections. with concomitant administration of live or live attenuated vaccines in patients receiving immunosuppressive doses of Acthar Gel. in patients with scleroderma, osteoporosis, systemic fungal infections, ocular herpes simplex, recent surgery, history of or the presence of a peptic ulcer, congestive heart failure, uncontrolled hypertension, primary adrenocortical insufficiency, adrenocortical hyperfunction, or sensitivity to proteins of porcine origin. Acthar Gel is contraindicated: for intravenous administration ( 4 ) in infants under 2 years of age who have suspected congenital infections ( 4 ) with concomitant administration of live or live attenuated vaccines in patients receiving immunosuppressive doses of Acthar Gel ( 4 ) in patients with scleroderma, osteoporosis, systemic fungal infections, ocular herpes simplex, recent surgery, history of or the presence of a peptic ulcer, congestive heart failure, uncontrolled hypertension, primary adrenocortical insufficiency, adrenocortical hyperfunction, or sensitivity to proteins of porcine origin ( 4 )

11 DESCRIPTION Acthar Gel is a naturally sourced complex mixture of adrenocorticotropic hormone analogs and other pituitary peptides. The Acthar Gel manufacturing process converts the initial porcine pituitary extract with low ACTH content into a mixture having modified porcine ACTH and other related peptide analogs solubilized in gelatin. A major component in the formulated complex mixture is N-25 deamidated porcine ACTH (1-39). Acthar Gel is supplied as a sterile preparation in 16% gelatin to provide a prolonged release after intramuscular or subcutaneous injection. Acthar Gel also contains 0.5% phenol, not more than 0.1% cysteine (added), sodium hydroxide and/or acetic acid to adjust pH and water for injection.

2 DOSAGE AND ADMINISTRATION In the treatment of infantile spasms, the recommended dose is 150 U/m 2 divided into twice daily intramuscular injections of 75 U/m 2 . After 2 weeks of treatment, dosing should be gradually tapered and discontinued over a 2-week period. ( 2.1 ) In the treatment of acute exacerbations of multiple sclerosis, daily intramuscular or subcutaneous doses of 80-120 units for 2-3 weeks may be administered. It may be necessary to taper the dose. ( 2.2 ) In the treatment of other disorders and diseases, dosing will need to be individualized depending on the disease under treatment and the medical condition of the patient. It may be necessary to taper the dose. ( 2.3 ) 2.1 Specific Recommended Dosage Regimen for Infantile Spasms in Infants and Children Under 2 Years of Age In the treatment of infantile spasms, Acthar Gel must be administered intramuscularly. The recommended regimen is a daily dose of 150 U/m 2 (divided into twice daily intramuscular injections of 75 U/m 2 ) administered over a 2-week period. Dosing with Acthar Gel should then be gradually tapered over a 2-week period to avoid adrenal insufficiency. The following is one suggested tapering schedule: 30 U/m 2 in the morning for 3 days; 15 U/m 2 in the morning for 3 days; 10 U/m 2 in the morning for 3 days; and 10 U/m 2 every other morning for 6-days. Acthar Gel is typically dosed based on body surface area (BSA). For calculation of body surface area, use the following formula Image 2.2 Recommended Dosage Regimen for the Treatment of Acute Exacerbations in Adults with Multiple Sclerosis The recommended dose is daily intramuscular or subcutaneous doses of 80-120 units for 2-3 weeks for acute exacerbations. Dosage should be individualized according to the medical condition of each patient. Frequency and dose of the drug should be determined by considering the severity of the disease and the initial response of the patient. Although drug dependence does not occur, sudden withdrawal of Acthar Gel after prolonged use may lead to adrenal insufficiency or recurrent symptoms which make it difficult to stop the treatment. It may be necessary to taper the dose and increase the injection interval to gradually discontinue the medication. 2.3 Recommended Dosage Regimen for Other Indications for Adults and Children Over 2 Years of Age Dosage should be individualized according to the disease under treatment and the general medical condition of each patient. Frequency and dose of the drug should be determined by considering severity of the disease and the initial response of the patient. The usual dose of Acthar Gel is 40-80 units given intramuscularly or subcutaneously every 24-72 hours. Although drug dependence does not occur, sudden withdrawal of Acthar Gel after prolonged use may lead to adrenal insufficiency or recurrent symptoms which make it difficult to stop the treatment. It may be necessary to taper the dose and increase the injection interval to gradually discontinue the medication. 2.4 Preparation Acthar Gel should be warmed to room temperature before using. Caution should be taken not to over-pressurize the vial prior to withdrawing the product.

1 INDICATIONS AND USAGE Acthar Gel is indicated as monotherapy for the treatment of infantile spasms in infants and children under 2 years of age. ( 1.1 ) Acthar Gel is indicated for the treatment of exacerbations of multiple sclerosis in adults. ( 1.2 ) Acthar Gel may be used for the following disorders and diseases: rheumatic ( 1.3 ); collagen ( 1.4 ); dermatologic ( 1.5 ); allergic states ( 1.6 ); ophthalmic ( 1.7 ); respiratory ( 1.8 ); and edematous state ( 1.9 ). 1.1 Infantile Spasms Acthar Gel is indicated as monotherapy for the treatment of infantile spasms in infants and children under 2 years of age. 1.2 Multiple Sclerosis Acthar Gel is indicated for the treatment of acute exacerbations of multiple sclerosis in adults. Controlled clinical trials have shown Acthar Gel to be effective in speeding the resolution of acute exacerbations of multiple sclerosis. However, there is no evidence that it affects the ultimate outcome or natural history of the disease. 1.3 Rheumatic Disorders As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in: Psoriatic arthritis; Rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy); Ankylosing spondylitis. 1.4 Collagen Diseases During an exacerbation or as maintenance therapy in selected cases of: systemic lupus erythematosus, systemic dermatomyositis (polymyositis). 1.5 Dermatologic Diseases Severe erythema multiforme, Stevens-Johnson syndrome. 1.6 Allergic States Serum sickness. 1.7 Ophthalmic Diseases Severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as: keratitis; iritis, iridocyclitis, diffuse posterior uveitis and choroiditis, optic neuritis, chorioretinitis; anterior segment inflammation. 1.8 Respiratory Diseases Symptomatic sarcoidosis. 1.9 Edematous State To induce a diuresis or a remission of proteinuria in the nephrotic syndrome without uremia of the idiopathic type or that due to lupus erythematosus.

7 DRUG INTERACTIONS Formal drug-drug interaction studies have not been performed. Acthar Gel may accentuate the electrolyte loss associated with diuretic therapy. Acthar Gel may accentuate the electrolyte loss associated with diuretic therapy. ( 7 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of Acthar Gel in the treatment of infantile spasms is unknown. Acthar Gel and endogenous ACTH stimulate the adrenal cortex to secrete cortisol, corticosterone, aldosterone, and a number of weakly androgenic substances. Prolonged administration of large doses of Acthar Gel induces hyperplasia and hypertrophy of the adrenal cortex and continuous high output of cortisol, corticosterone and weak androgens. The release of endogenous ACTH is under the influence of the nervous system via the regulatory hormone released from the hypothalamus and by a negative corticosteroid feedback mechanism. Elevated plasma cortisol suppresses ACTH release. Acthar Gel is also reported to bind to melanocortin receptors. The trophic effects of endogenous ACTH and Acthar Gel on the adrenal cortex are not well understood beyond the fact that they appear to be mediated by cyclic AMP. 12.3 Pharmacokinetics ACTH rapidly disappears from the circulation following its intravenous administration; in people, the plasma half-life is about 15 minutes. The pharmacokinetics of Acthar Gel have not been adequately characterized. The maximal effects of a trophic hormone on a target organ are achieved when optimal amounts of hormone are acting continuously. Thus, a fixed dose of Acthar Gel will demonstrate a linear increase in adrenocortical secretion with increasing duration for the infusion.

12.1 Mechanism of Action The mechanism of action of Acthar Gel in the treatment of infantile spasms is unknown. Acthar Gel and endogenous ACTH stimulate the adrenal cortex to secrete cortisol, corticosterone, aldosterone, and a number of weakly androgenic substances. Prolonged administration of large doses of Acthar Gel induces hyperplasia and hypertrophy of the adrenal cortex and continuous high output of cortisol, corticosterone and weak androgens. The release of endogenous ACTH is under the influence of the nervous system via the regulatory hormone released from the hypothalamus and by a negative corticosteroid feedback mechanism. Elevated plasma cortisol suppresses ACTH release. Acthar Gel is also reported to bind to melanocortin receptors. The trophic effects of endogenous ACTH and Acthar Gel on the adrenal cortex are not well understood beyond the fact that they appear to be mediated by cyclic AMP.

12.3 Pharmacokinetics ACTH rapidly disappears from the circulation following its intravenous administration; in people, the plasma half-life is about 15 minutes. The pharmacokinetics of Acthar Gel have not been adequately characterized. The maximal effects of a trophic hormone on a target organ are achieved when optimal amounts of hormone are acting continuously. Thus, a fixed dose of Acthar Gel will demonstrate a linear increase in adrenocortical secretion with increasing duration for the infusion.

20231011

20

3 DOSAGE FORMS AND STRENGTHS 5 mL multi-dose vial containing 80 USP Units per mL. 5 mL multi-dose vial containing 80 USP units per mL. ( 3 )

Acthar Repository Corticotropin CORTICOTROPIN CORTICOTROPIN GELATIN, UNSPECIFIED PHENOL CYSTEINE SODIUM HYDROXIDE ACETIC ACID WATER

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Adequate studies of the carcinogenic potential of Acthar Gel have not been conducted. Mutagenesis The genotoxic potential of Acthar Gel has not been adequately evaluated. Impairment of Fertility The potential effects of Acthar Gel on fertility have not been adequately assessed in animals.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Adequate studies of the carcinogenic potential of Acthar Gel have not been conducted. Mutagenesis The genotoxic potential of Acthar Gel has not been adequately evaluated. Impairment of Fertility The potential effects of Acthar Gel on fertility have not been adequately assessed in animals.

NDA008372

Acthar

Repository Corticotropin

63004-8710

HUMAN PRESCRIPTION DRUG

INTRAMUSCULAR,SUBCUTANEOUS

PRINCIPAL DISPLAY PANEL - 5 mL Vial Carton NDC 63004-8710-1 Acthar ® Gel (repository corticotropin injection) 400 USP units/5 mL (80 USP units/mL) For intramuscular or subcutaneous use. 5 mL multiple-dose vial Dispense the enclosed Medication Guide to each Infantile Spasm patient. Rx only PRINCIPAL DISPLAY PANEL - 5 mL Vial Carton

Warnings and Precautions, Immunogenicity Potential ( 5.10 ) 10/2021 Warnings and Precautions, Use in Pregnancy (5.14) - removal 10/2021

Mallinckrodt, the "M" brand mark, the Mallinckrodt Pharmaceuticals logo and other brands are trademarks of a Mallinckrodt company. © 2023 Mallinckrodt. For a list of patents, see https://www.mallinckrodt.com/patents/ Manufactured for: Mallinckrodt ARD LLC Bridgewater, NJ 08807 PL065 Rev.06/2023

17 PATIENT COUNSELING INFORMATION Advise caretakers of patients with infantile spasms to read the FDA-approved patient labeling (Medication Guide). Patients should be instructed to take Acthar Gel only as prescribed. They should not stop treatment suddenly unless instructed by their healthcare provider to do so. Patients, their caregivers and families should be advised as to the importance of the need for careful monitoring while on and during titration from Acthar Gel treatment and the importance of not missing scheduled doctor's appointments. Infections Advise patients, their caregivers, and families to contact their healthcare provider if the patient develops an infection or fever. Inform patients and caregivers that a fever may not necessarily be present during infection and to try to limit contact with other people with infections to minimize the risk of infection while taking Acthar Gel [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ] . Cushing's Syndrome and Adrenal Insufficiency Upon Withdrawal Advise patients to contact their healthcare provider if they develop signs or symptoms of Cushing's Syndrome, such as fat increases in the face (moon face) or trunk area, cutaneous striae, easy bruisability, weight gain, muscle weakness, hyperglycemia, and hypertension [see Warnings and Precautions (5.2) ] . Inform patients that adrenal insufficiency can occur upon withdrawal of Acthar Gel. Advise patients to contact their healthcare provider if they develop weakness, hyperpigmentation, weight loss, hypotension, or abdominal pain. Advise caregivers of patients with infantile spasms that symptoms of adrenal insufficiency may be difficult to identify and that additional symptoms may include anorexia, fatigue, or lethargy [see Warnings and Precautions (5.2) ] . Elevated Blood Pressure, Salt and Water Retention, and Hypokalemia Advise patients, their caregivers and families to contact their healthcare provider if the patient experiences an increase in blood pressure or water retention [see Warnings and Precautions (5.3) and Adverse Reactions (6.1) ] . Vaccinations Advise patients and caregivers of patients to not to be vaccinated with live or live attenuated vaccines during treatment with Acthar Gel. Additionally, other immunization procedures in patients or in family members who will be in contact with the patient should be undertaken with caution while the patient is taking Acthar Gel [see Warnings and Precautions (5.4) ] . Masking Symptoms of Other Diseases Inform patients, their caregivers, and families that Acthar Gel may mask symptoms of other diseases/disorders without altering the course of the other disease/disorder. Monitor the patient carefully during and for a period following discontinuation of therapy and inform their healthcare provider if signs of infection, abnormal cardiac function, hypertension, hyperglycemia, change in body weight, or fecal blood loss occur [see Warnings and Precautions (5.5) ] . Gastrointestinal Perforation and Bleeding Advise patients, their caregivers and families to contact their healthcare provider if the patient or the caregiver notices blood or a change in color of the patient's stool [see Warnings and Precautions (5.6) ] . Behavioral and Mood Disturbances Inform patients, their caregivers and families that signs of irritability, sleep disturbances, mood swings, personality changes, or severe depression may occur. These effects are reversible once Acthar Gel therapy is stopped [see Warnings and Precautions (5.7) and Adverse Reactions (6.1) ] . Negative Effects on Growth and Physical Development Advise patients, their caregivers and families that changes in appetite, most often leading to weight gain, are seen with Acthar Gel therapy, becoming more frequent as the dose or treatment period increases. These effects are reversible once Acthar Gel therapy is stopped [see Warnings and Precautions (5.12) and Adverse Reactions (6.1) ] . Decrease in Bone Density Advise patients, their caregivers and families that prolonged use of Acthar Gel may inhibit skeletal growth in children and adolescents and may cause osteoporosis and decreased bone density at any age. If prolonged use is necessary, Acthar Gel should be given intermittently along with careful observation [see Warnings and Precautions (5.13) and Adverse Reactions (6.1) ] . Infantile Spasms Additional Information Inform caregivers that, in the treatment of infantile spasms, other types of seizures may occur because some patients with infantile spasms progress to other forms of seizures (for example, Lennox-Gastaut Syndrome). Additionally, the spasms sometimes mask other seizures and once the spasms resolve after treatment with Acthar Gel, the other seizures may become visible. Advise parents and caregivers to inform the patient's healthcare provider of any new onset of seizures so that appropriate management can then be instituted [see Adverse Reactions (6.1) ] . Pregnancy Advise pregnant women of the potential risk to a fetus [see Use in Specific Populations ( 8.1) ].

MEDICATION GUIDE Acthar® Gel (AK-thar jel) (repository corticotropin injection) This Medication Guide provides information only about the use of Acthar Gel for the treatment of Infantile Spasms. If your doctor prescribes Acthar Gel for you or your child for any other reason, talk to your doctor for information about how this medicine is used to treat your medical condition. Read this Medication Guide before your child receives Acthar Gel and each time you refill your child's prescription. There may be new information. This Medication Guide does not take the place of talking with your doctor about your child's medical condition or treatment. What is the most important information I should know about Acthar Gel? Acthar Gel can cause serious side effects including: 1. Increased risk of infections. Acthar Gel is a medicine that can affect your child's immune system. When your child is taking Acthar Gel, it can lower the ability of your child's immune system to fight infections. Acthar Gel may: make your child more likely to get new infections worsen an infection that your child already has cause an inactive infection to become active, such as tuberculosis (TB) Before starting Acthar Gel, tell your doctor if your child has: an infection or signs of an infection, such as: fever cough vomiting diarrhea other signs of flu or illness a family member with an infection or signs of an infection While taking Acthar Gel, your child should: stay away from people who are sick or who have infections tell your doctor right away if your child has any sign of infection such as: fever (but your child may not have a fever with an infection) cough vomiting diarrhea or other signs of illness or flu and any open cuts or sores on his or her body 2. Effects on the adrenal gland after stopping Acthar Gel. When your child stops taking Acthar Gel, his or her body may not produce enough of a hormone called cortisol on its own (adrenal insufficiency). Your child may need to take steroid medicine to protect the body until the adrenal gland recovers and is working well again, especially to protect the body if they have surgery or trauma. Do not stop giving your child injections of Acthar Gel without talking to your doctor first. Your doctor will tell you when and how to slowly stop giving the injections to avoid serious side effects. While slowly stopping your child's injections of Acthar Gel or after you stop giving the injections, call your doctor right away if your child has any of the following: appears weak loses weight or has a decrease in appetite appears tired or lacking energy appears pale has stomach pain appears sick or is with a fever 3. Effects on the adrenal gland while taking Acthar Gel. When your child is taking Acthar Gel, his or her adrenal gland may produce too much cortisol. This can cause symptoms of Cushing's syndrome. Cushing's syndrome is more common in children who take Acthar Gel for a long time. Symptoms of Cushing's syndrome include: increased upper body fat around the neck, but not the arms and legs weight gain rounded or "moon" face thin skin, easy bruising, and stretch marks on thighs, belly and trunk slowed growth rates in children weak bones (osteoporosis) While receiving treatment with Acthar Gel other side effects can happen that are like side effects that happen due to treatment with steroid medicines. The risk of getting side effects may increase the longer your child is treated with Acthar Gel. Side effects may include: increased blood pressure. Your doctor may check your child's blood pressure during treatment. If your child's blood pressure increases, your doctor may talk with you about possible treatment choices. too much water in the body (water retention), increased amount of body salts, and low potassium in the blood. Acthar Gel may cause your child to have an increased amount of body salts and water that stays in the body, and may lower the amount of potassium in your child's blood. Follow your doctor's instructions about if you need to decrease your child's salt intake or if you need to feed your child foods high in potassium. 4. Your child should not receive certain vaccines during treatment with Acthar Gel. Your child may receive killed or inactivated vaccines while receiving Acthar Gel. Before your child receives any vaccines, talk to your doctor about which vaccines are safe for your child. Certain vaccines could cause your child to have serious side effects, or the vaccine may not be effective. 5. Hiding (masking) symptoms of other conditions or diseases. It may be more difficult for your doctor to diagnose other conditions or diseases in your child during treatment with Acthar Gel. During treatment and after treatment ends, tell your doctor if your child has: any signs or symptoms of infection. See number 1 of this section in the Medication Guide. changes in body weight bloody or black tarry stool vomiting stomach pain excessive tiredness increased thirst fast heart rate difficulty breathing 6. Stomach and intestinal problems. Acthar Gel may cause bleeding of the stomach or intestine. Your child has an increased risk for bleeding from the stomach or having a stomach ulcer. Tell your doctor if your child has any pain in the stomach area (abdominal pain), vomits blood, or has bloody or black stools. 7. Changes in mood and behavior. During treatment with Acthar Gel your child may be irritable, have rapid changes in his or her mood, be depressed, have other changes in his or her behavior, or have trouble sleeping. Tell your doctor if your child has any of the side effects or symptoms listed above. What is Acthar Gel? Acthar Gel is a prescription medicine that is used to treat infantile spasms in infants and children under 2 years of age. What should I tell my doctor before my child takes Acthar Gel? Before your child takes Acthar Gel, read the section above "What is the most important information I should know about Acthar Gel?" and tell your doctor if your child has: an infection diabetes heart problems kidney problems stomach or intestinal problems thyroid problems liver problems neuromuscular problems convulsions or seizures had exposure to someone with Tuberculosis (TB) a previous allergic reaction such as hives, itching or trouble breathing, to Acthar Gel or pork products had recent surgery had a recent vaccination or is scheduled to receive a vaccination a family member who is receiving vaccinations Tell your doctor about all the medicines your child takes, including prescription and non- prescription medicines, vitamins and herbal supplements. Do not start giving a new medicine to your child without first speaking to your doctor. How should I give Acthar Gel to my child? Acthar Gel is given as an injection into the muscle. Do not inject it under the skin, into a vein, or give it to your child by mouth. Inject Acthar Gel exactly as your doctor tells you. Your doctor will tell you where to give the injection, how much to give, how often and when to give it to your child. Do not use Acthar Gel until your doctor has taught you how to give the injection to your child. To give Acthar Gel: Take the bottle from the refrigerator. Do not open the bottle or pry the cap (rubber stopper) off. Warm the contents by rolling the bottle between your hands for a few minutes. Wash your hands. Prepare the skin where you are going to give the injection by wiping it with a new sterile alcohol wipe. Before giving the injection, look at the site prepared for the injection and make sure that it no longer looks wet. A wet site can cause burning. Wipe the top of the vial rubber stopper with a new sterile alcohol wipe. Use a new sterile needle and syringe to draw up the amount of Acthar Gel the doctor has told you to use. Give the injection the way the doctor has instructed you. Return the bottle to the refrigerator as soon as possible. Keep all of your child's follow-up appointments with your doctor It is important for you to tell your doctor if your child's spasms continue or change in any way during treatment or after treatment has stopped so that they can monitor your child's progress. Infantile Spasms sometimes hides (masks) other seizures your child or infant may have. Once treated with Acthar Gel, the Infantile Spasms symptoms may disappear. This may allow the other seizures to become visible for the first time. Tell your child's doctor right away if you see a change in your child's seizures/spasms. What are the possible side effects of Acthar Gel? Acthar Gel can cause serious side effects. See " What is the most important information I should know about Acthar Gel. " Acthar Gel may make certain other medical conditions worse, such as diabetes (may increase blood sugar). Eye problems. Your child can get cataracts, increased pressure in the eye (glaucoma), and possible damage to the optic nerve if treated with Acthar Gel for a long time. Allergic reactions to Acthar Gel. Your child may have an allergic reaction to Acthar Gel. Allergic reactions may not happen until your child has received several injections of Acthar Gel. Tell your doctor right away if your child has any of the following signs of an allergic reaction: skin rash swelling of the face, tongue, lips, or throat trouble breathing Changes in growth and physical development. Acthar Gel may affect your child's growth and physical development and may weaken his or her bones. This is more likely to happen with long term use of Acthar Gel. Enlarged heart. Acthar Gel may cause an increase in the size of your child's heart. This is more likely to happen with long term use of Acthar Gel but usually goes away after Acthar Gel is stopped. The most common side effects of Acthar Gel for patients with infantile spasms include: Infections muscle contractions that you cannot control (convulsions) increased blood pressure irritability and changes in behavior fever These are not all the possible side effects of Acthar Gel. Tell your doctor if your child has any side effect that bothers them or does not go away. For more information, ask your child's doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store Acthar Gel? Store vials of Acthar Gel in the refrigerator between 36°F to 46°F (2°C to 8°C). Throw away any vials after the expiration date printed on the label. Keep Acthar Gel and all other medicines out of the reach of children General information About Acthar Gel Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Acthar Gel for a condition for which it has not been prescribed. Do not give Acthar Gel to other people, even if they have the same symptoms. It may harm them. This Medication Guide summarizes the most important information about Acthar Gel. If you would like more information, talk with your child's doctor. You can ask your child's doctor or pharmacist for information about Acthar Gel that is written for healthcare professionals. For more information, go to www.acthar.com or call 1-800-844-2830. What are the ingredients in Acthar Gel? Active ingredient: Corticotropin Inactive ingredients: gelatin, phenol, cysteine, sodium hydroxide and/or acetic acid to adjust pH, and water for injection Manufactured for: Mallinckrodt ARD LLC Bridgewater, NJ 08807 PL122 Rev 06/2023 This Medication Guide has been approved by the U.S. Food and Drug Administration. Mallinckrodt, the "M" brand mark, the Mallinckrodt Pharmaceuticals logo and other brands are trademarks of a Mallinckrodt company. © 2023 Mallinckrodt. For a list of patents, see https://www.mallinckrodt.com/patents/ Mallinckrodt ™ Pharmaceuticals

14 CLINICAL STUDIES The effectiveness of Acthar Gel as a treatment for infantile spasms was demonstrated in a single blinded (video EEG interpreter blinded) clinical trial in which patients were randomized to receive either a 2-week course of treatment with Acthar Gel (75 U/m 2 intramuscular twice daily) or prednisone (1 mg/kg by mouth twice daily). The primary outcome was a comparison of the number of patients in each group who were treatment responders, defined as a patient having complete suppression of both clinical spasms and hypsarrhythmia on a full sleep cycle video EEG performed 2 weeks following treatment initiation, rated by an investigator blinded to treatment. Thirteen of 15 patients (86.7%) responded to Acthar Gel as compared to 4 of 14 patients (28.6%) given prednisone (p<0.002). The 2-week treatment was followed by a 2-week period of taper. Nonresponders to the prednisone treatment were eligible to receive Acthar Gel treatment. Seven of 8 patients (87.5%) responded to Acthar Gel after not responding to prednisone. Similarly, the 2 nonresponder patients from the Acthar Gel treatment were eligible to receive treatment with prednisone. One of the 2 patients (50%) responded to the prednisone treatment after not responding to Acthar Gel. A supportive single-blind, randomized clinical trial comparing high-dose, long-duration treatment (150 U/m 2 once daily for 3 weeks, n=30) of Acthar Gel with low-dose, short-duration treatment (20 U once daily for 2 weeks, n=29) for the treatment of infantile spasms was also evaluated in infants and children less than 2 years of age. Nonresponders (defined as in the previously described study) in the low-dose group received a dose escalation at 2 weeks to 30 U once daily. Nominal statistical superiority of the high dose treatment, as compared to the low dose treatment, was observed for cessation of spasms but not for the resolution of hypsarrhythmia.

8.4 Pediatric Use Acthar Gel is indicated as monotherapy for the treatment of infantile spasms in infants and children less than 2 years of age. Both serious and other adverse reactions can occur in this population [see Warnings and Precautions (5) and Adverse Reactions (6.1) ] . The efficacy of Acthar Gel for the treatment of infantile spasms in infants and children less than 2 years of age was evaluated in a randomized, single blinded (video EEG interpreter blinded) clinical trial and an additional active control supportive trial [see Clinical Studies (14) ] . A responding patient was defined as having both complete cessation of spasms and elimination of hypsarrhythmia. Safety in the pediatric population for infantile spasms was evaluated by retrospective chart reviews and data from non-sponsor conducted clinical trials [see Adverse Reactions (6.1) ] . While the types of adverse reactions seen in infants and children under 2 years of age treated for infantile spasms are similar to those seen in older patients, their frequency and severity may be different due to the very young age of the infant, the underlying disorder, the duration of therapy and the dosage regimen. Effects on growth are of particular concern [see Warnings and Precautions (5.12) ] . Serious adverse reactions observed in adults may also occur in children [see Warnings and Precautions (5) ] .

8.1 Pregnancy Risk Summary Based on Acthar Gel's pharmacological effect of stimulating an endogenous steroid response [see Clinical Pharmacology ( 12.1) ] , Acthar Gel may cause fetal harm when administered to a pregnant woman. The published literature on systemic corticosteroid use during pregnancy, which may be relevant, suggests potential concerns. Intrauterine growth restriction, decreased birth weight, and preterm birth have been reported with maternal use of corticosteroids; however, the underlying maternal condition may also contribute to these risks. Hypoadrenalism has also been reported in infants after high-dose and/or long-term use of corticosteroids during pregnancy (see Clinical Considerations ) . The potential adverse developmental effects of Acthar Gel have not been adequately assessed in animals. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal-Neonatal Adverse Reactions Hypoadrenalism has been reported in infants born to mothers treated with systemic corticosteroids during pregnancy. Infants born to mothers treated with Acthar Gel should be carefully observed for signs of hypoadrenalism, such as poor feeding, irritability, weakness, and vomiting, and managed accordingly [see Warnings and Precautions (5.2) ] .

8 USE IN SPECIFIC POPULATIONS Pediatric Use: Prolonged use of Acthar Gel in children may inhibit skeletal growth. If use is necessary, it should be given intermittently with careful observation. ( 5.12 , 5.13 , and 8.4 ) Pregnancy: May cause fetal harm. ( 8.1 ) 8.1 Pregnancy Risk Summary Based on Acthar Gel's pharmacological effect of stimulating an endogenous steroid response [see Clinical Pharmacology ( 12.1) ] , Acthar Gel may cause fetal harm when administered to a pregnant woman. The published literature on systemic corticosteroid use during pregnancy, which may be relevant, suggests potential concerns. Intrauterine growth restriction, decreased birth weight, and preterm birth have been reported with maternal use of corticosteroids; however, the underlying maternal condition may also contribute to these risks. Hypoadrenalism has also been reported in infants after high-dose and/or long-term use of corticosteroids during pregnancy (see Clinical Considerations ) . The potential adverse developmental effects of Acthar Gel have not been adequately assessed in animals. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal-Neonatal Adverse Reactions Hypoadrenalism has been reported in infants born to mothers treated with systemic corticosteroids during pregnancy. Infants born to mothers treated with Acthar Gel should be carefully observed for signs of hypoadrenalism, such as poor feeding, irritability, weakness, and vomiting, and managed accordingly [see Warnings and Precautions (5.2) ] . 8.2 Lactation Risk Summary There are no available data on the presence of corticotropin in either human or animal milk, the effects on the breastfed infant, or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Acthar Gel and any potential adverse effects on the breastfed infant from Acthar Gel or from the underlying maternal condition. 8.4 Pediatric Use Acthar Gel is indicated as monotherapy for the treatment of infantile spasms in infants and children less than 2 years of age. Both serious and other adverse reactions can occur in this population [see Warnings and Precautions (5) and Adverse Reactions (6.1) ] . The efficacy of Acthar Gel for the treatment of infantile spasms in infants and children less than 2 years of age was evaluated in a randomized, single blinded (video EEG interpreter blinded) clinical trial and an additional active control supportive trial [see Clinical Studies (14) ] . A responding patient was defined as having both complete cessation of spasms and elimination of hypsarrhythmia. Safety in the pediatric population for infantile spasms was evaluated by retrospective chart reviews and data from non-sponsor conducted clinical trials [see Adverse Reactions (6.1) ] . While the types of adverse reactions seen in infants and children under 2 years of age treated for infantile spasms are similar to those seen in older patients, their frequency and severity may be different due to the very young age of the infant, the underlying disorder, the duration of therapy and the dosage regimen. Effects on growth are of particular concern [see Warnings and Precautions (5.12) ] . Serious adverse reactions observed in adults may also occur in children [see Warnings and Precautions (5) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING Acthar Gel (repository corticotropin injection) is supplied as 5 mL multi-dose vial (NDC 63004-8710-1) containing 80 USP Units per mL. Acthar Gel (repository corticotropin injection) should be warmed to room temperature before using. Do not over pressurize the vial prior to withdrawing the product. Store Acthar Gel (repository corticotropin injection) under refrigeration between 2°C to 8°C (36°F to 46°F). Product is stable for the period indicated on the label when stored under the conditions described.

Store Acthar Gel (repository corticotropin injection) under refrigeration between 2°C to 8°C (36°F to 46°F). Product is stable for the period indicated on the label when stored under the conditions described.