H.P. Acthar Gel

Your doctor may tell you to follow a low sodium or high potassium diet. Your doctor may also tell you to take a potassium supplement during your treatment. Ask your doctor for more information.

Corticotropin repository injection may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• increased or decreased appetite
• weight gain
• irritability
• changes in mood or personality
• abnormally happy or excited mood
• difficulty falling asleep or staying asleep

Some side effects can be serious. If you experience any of these symptoms during or after your treatment, call your doctor immediately or get emergency medical treatment:

• sore throat, fever, cough, vomiting, diarrhea, or other signs of infection
• open cuts or sores
• puffiness or fullness of the face
• increased fat around the neck, but not the arms or legs
• thin skin
• stretch marks on the skin of the abdomen, thighs, and breasts
• easy bruising
• muscle weakness
• stomach pain
• vomit that is bloody or looks like coffee grounds
• bright red blood in stools
• black or tarry stools
• depression
• difficulty recognizing reality
• vision problems
• excessive tiredness
• increased thirst
• fast heartbeat
• rash
• swelling of the face, tongue, lips, or throat
• difficulty breathing
• new or different seizures

Corticotropin repository injection may slow growth and development in children. Your child's doctor will watch his or her growth carefully. Talk to your doctor about the risks of giving this medication to your child.

Using corticotropin repository injection may increase the risk that you will develop osteoporosis. Your doctor may order tests to check your bone density during your treatment. Talk to your doctor about the risks of using this medication and about things you can do to decrease the chance that you will develop osteoporosis.

Corticotropin repository injection may cause other side effects. Call your doctor if you have any unusual problems while using this medication.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it in the refrigerator.

Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for more information if you do not have access to a take-back program.

It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. http://www.upandaway.org

• H.P. Acthar Gel^®

Specific Drugs

Absorption

Bioavailability

Corticotropin is rapidly inactivated by proteolytic enzymes in the GI tract and is administered parenterally.c l p

Absorbed over 8–16 hours following IM administration; peak concentrations of 17-hydroxycorticosteroid (17-OHCS) occur during this period.c m z Peak 11-hydroxycorticosteroid concentrations following sub-Q administration of 80 units of repository corticotropin injection in healthy individuals is evident in 3–12 hours; baseline concentrations attained in 10–25 hours (mean: 16 hours).aa

Onset

Diagnosis of adrenocortical insufficiency: Plasma corticosteroid concentrations generally close to maximum stimulation 1 hour after administration.l

Duration

Following IM administration of repository corticotropin injection, duration of action is 18 hours secondary to delayed uptake from tissues; duration dependent upon dose.a c m p y z

Distribution

Extent

Distributed to liver and kidneys; highest concentrations found in kidneys.l bb

Rapidly removed from plasma by many tissues.a c m n

Does not cross placenta.c m

Elimination

Metabolism

Rapidly metabolized in the blood.z Exact metabolic fate unknown.c Circulating corticotropin may also be enzymatically cleaved by plasmin-plasminogen system and/or by aminopeptidases in the muscle and skin.c m n

Elimination Route

Not substantially eliminated in the urine.l

Half-life

>3 hours following IM or sub-Q administration of repository corticotropin injection.l

15–20 minutes following IV administration of corticotropin for injection (no longer commercially available in the US). a l

Please refer to Adverse Reactions in Infants and Children Under 2 Years of Age (Section 6.1.1) for consideration when treating patients with Infantile Spasms. The adverse reactions presented in Section 6.2 are primarily provided for consideration in use in adults and in children over 2 years of age, but these adverse reactions should also be considered when treating infants and children under 2 years of age.

H.P. Acthar Gel causes the release of endogenous cortisol from the adrenal gland. Therefore all the adverse effects known to occur with elevated cortisol may occur with H.P. Acthar Gel administration as well. Common adverse reactions include fluid retention, alteration in glucose tolerance, elevation in blood pressure, behavioral and mood changes, increased appetite and weight gain.

Clinical Studies 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.

.1 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.

 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.

Postmarketing Experience

The following adverse reactions associated with the use of H.P. Acthar Gel have been identified from postmarketing experience with H.P. Acthar Gel. Only adverse events that are not listed above as adverse events reported from retrospective chart reviews and non-sponsor conducted clinical trials and those not discussed elsewhere in labeling, are listed in this section. Because the adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to use with H.P. Acthar Gel. Events are categorized by system organ class. Unless otherwise noted these adverse events have been reported in infants, children and adults.

.1 Allergic Reactions

Allergic responses have presented as dizziness, nausea and shock (adults only).

.2 Cardiovascular

Necrotizing angitis (adults only) and congestive heart failure.

.3 Dermatologic

Skin thinning (adults only), facial erythema and increased sweating (adults only).

.4 Endocrine

Decreased carbohydrate tolerance (infants only) and hirsutism.

.5 Gastrointestinal

Pancreatitis (adults only), abdominal distention and ulcerative esophagitis.

.6 Metabolic

Hypokalemic alkalosis (infants only).

.7 Musculoskeletal

Muscle weakness and vertebral compression fractures (infants only).

.8 Neurological

Headache (adults only), vertigo (adults only), subdural hematoma, intracranial hemorrhage (adults only), and reversible brain shrinkage (usually secondary to hypertension) (infants only).

Possible Additional Steroidogenic Effects

Based on steroidogenic effects of H.P. 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 H.P. Acthar Gel are:

.1 Dermatologic

Impaired wound healing, abscess, petechiae and ecchymoses, and suppression of skin test reactions.

.2 Endocrine

Menstrual irregularities.

.3 Metabolic

Negative nitrogen balance due to protein catabolism.

.4 Musculoskeletal

Loss of muscle mass and aseptic necrosis of femoral and humeral heads.

.5 Neurological

Increased intracranial pressure with papilledema, (pseudo-tumor cerebri) usually after treatment, and subdural effusion.

.6 Ophthalmic

Exophthalmos.

Formal drug-drug interaction studies have not been performed.

H.P. Acthar Gel may accentuate the electrolyte loss associated with diuretic therapy.

While chronic exposure to H.P. Acthar Gel at high doses can be associated with a variety of potential serious adverse effects, it is not expected that a single high dose, or even several large doses, has the potential for serious adverse effects compared to a standard dose. There have been no reports of death or acute overdose symptoms from H.P. Acthar Gel in clinical studies or in the published literature.

The intramuscular route of administration makes it unlikely that an inadvertent acute overdose will occur. The typical daily dose of H.P. Acthar Gel to treat an infant that has a BSA of 0.4 m2 would be 60 U/day. Using the 1-cc syringe supplied with H.P. Acthar Gel, the maximum amount that can be injected is 80 U/injection, which is a well-tolerated single dose.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Adequate and well-controlled studies have not been done in animals. Human use has not been associated with an increase in malignant disease. [see Warnings and Precautions (5.14) and Use in Specific Populations (8.1)]