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.

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/m2 (divided into twice daily intramuscular injections of 75 U/m2) 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/m2 in the morning for 3 days; 15 U/m2 in the morning for 3 days; 10 U/m2 in the morning for 3 days; and 10 U/m2 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

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.

5.1 Infections

Acthar Gel may increase the risks related to infections with any pathogen, including viral, bacterial, fungal, protozoan or helminthic infections. Patients with latent tuberculosis or tuberculin reactivity should be observed closely, and if therapy is prolonged, chemoprophylaxis should be instituted.

5.2 Cushing's Syndrome and Adrenal Insufficiency Upon Withdrawal

Treatment with Acthar Gel can cause hypothalamic-pituitary-adrenal (HPA) axis suppression and Cushing's syndrome. These conditions should be monitored especially with chronic use.

Suppression of the HPA may occur following prolonged therapy with the potential for adrenal insufficiency after withdrawal of the medication. Patients should be monitored for signs of insufficiency such as weakness, hyperpigmentation, weight loss, hypotension and abdominal pain.

The symptoms of adrenal insufficiency in infants treated for infantile spasms can be difficult to identify. The symptoms are non-specific and may include anorexia, fatigue, lethargy, weakness, excessive weight loss, hypotension and abdominal pain. It is critical that parents and caregivers be made aware of the possibility of adrenal insufficiency when discontinuing Acthar Gel and should be instructed to observe for, and be able to recognize, these symptoms [see Patient Counseling Information (17)].

The recovery of the adrenal gland may take from days to months so patients should be protected from the stress (e.g., trauma or surgery) by the use of corticosteroids during the period of stress.

The adrenal insufficiency may be minimized in adults and infants by tapering of the dose when discontinuing treatment.

Signs or symptoms of Cushing's syndrome may occur during therapy but generally resolve after therapy is stopped. Patients should be monitored for these signs and symptoms such as deposition of adipose tissue in characteristics sites (e.g., moon face, truncal obesity), cutaneous striae, easy bruisability, decreased bone mineralization, weight gain, muscle weakness, hyperglycemia, and hypertension.

5.3 Elevated Blood Pressure, Salt and Water Retention, and Hypokalemia

Acthar Gel can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium and calcium. Dietary salt restriction and potassium supplementation may be necessary. Caution should be used in the treatment of patients with hypertension, congestive heart failure, or renal insufficiency.

5.4 Vaccination

Administration of live or live attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of Acthar Gel. Killed or inactivated vaccines may be administered; however, the response to such vaccines can not be predicted. Other immunization procedures should be undertaken with caution in patients who are receiving Acthar Gel, especially when high doses are administered, because of the possible hazards of neurological complications and lack of antibody response.

5.5 Masking Symptoms of Other Diseases

Acthar Gel often acts by masking symptoms of other diseases/disorders without altering the course of the other disease/disorder. Patients should be monitored carefully during and for a period following discontinuation of therapy for signs of infection, abnormal cardiac function, hypertension, hyperglycemia, change in body weight and fecal blood loss.

5.6 Gastrointestinal Perforation and Bleeding

Acthar Gel can cause GI bleeding and gastric ulcer. There is also an increased risk for perforation in patients with certain gastrointestinal disorders. Signs of gastrointestinal perforation, such as peritoneal irritation, may be masked by the therapy. Use caution where there is the possibility of impending perforation, abscess or other pyogenic infections, diverticulitis, fresh intestinal anastomoses, and active or latent peptic ulcer.

5.7 Behavioral and Mood Disturbances

Use of Acthar Gel may be associated with central nervous system effects ranging from euphoria, insomnia, irritability (especially in infants), mood swings, personality changes, and severe depression, to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated. These effects are reversible once Acthar Gel therapy is stopped.

5.8 Comorbid Diseases

Patients with a comorbid disease may have that disease worsened. Caution should be used when prescribing Acthar Gel in patients with diabetes and myasthenia gravis.

5.9 Ophthalmic Effects

Prolonged use of Acthar Gel may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves and may enhance the establishment of secondary ocular infections due to fungi and viruses.

5.10 Immunogenicity Potential

Acthar Gel is immunogenic. Limited available data suggest that a patient may develop antibodies to Acthar Gel after chronic administration and loss of endogenous ACTH and Acthar Gel activity. Prolonged administration of Acthar Gel may increase the risk of hypersensitivity reactions. Cases of anaphylaxis have been reported in the postmarketing setting. Use in patients with sensitivity to porcine protein is contraindicated, and the possibility of sensitivity should be considered during the course of treatment should symptoms arise.

5.11 Use in Patients with Hypothyroidism or Liver Cirrhosis

There is an enhanced effect in patients with hypothyroidism and in those with cirrhosis of the liver.

5.12 Negative Effects on Growth and Physical Development

Long-term use of Acthar Gel may have negative effects on growth and physical development in pediatric patients. Changes in appetite are seen with Acthar Gel therapy, with the effects becoming more frequent as the dose or treatment period increases. These effects are reversible once Acthar Gel therapy is stopped. Growth and physical development of pediatric patients on prolonged therapy should be carefully monitored.

5.13 Decrease in Bone Density

Decrease in bone formation and an increase in bone resorption both through an effect on calcium regulation (i.e., decreasing absorption and increasing excretion) and inhibition of osteoblast function may occur. These, together with a decrease in the protein matrix of the bone (secondary to an increase in protein catabolism) and reduced sex hormone production, may lead to inhibition of bone growth in children and adolescents and to the development of osteoporosis at any age. Special consideration should be given to patients at increased risk of osteoporosis (i.e., postmenopausal women) before initiating therapy, and bone density should be monitored in patients on long term therapy.

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.

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.

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:

8.1 Pregnancy

8.2 Lactation

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)].

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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

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)].