H.P. Acthar (Page 4 of 6)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of H.P. Acthar Gel in the treatment of infantile spasms is unknown.

H.P. 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 H.P. 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.

H.P. Acthar Gel is also reported to bind to melanocortin receptors.

The trophic effects of endogenous ACTH and H.P. Acthar Gel on the adrenal cortex are not well understood beyond the fact that they appear to be mediated by cyclic AMP.

ACTH rapidly disappears from the circulation following its intravenous administration; in people, the plasma half-life is about 15 minutes. The pharmacokinetics of H.P. 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 H.P. Acthar Gel will demonstrate a linear increase in adrenocortical secretion with increasing duration for the infusion.

13 NONCLINICAL TOXICOLOGY

13.1 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) ].

14 CLINICAL STUDIES

The effectiveness of H.P. 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 H.P. Acthar Gel (75 U/m2 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 H.P. 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 H.P. Acthar Gel treatment. Seven of 8 patients (87.5%) responded to H.P. Acthar Gel after not responding to prednisone. Similarly, the 2 nonresponder patients from the H.P. 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 H.P. Acthar Gel.

A supportive single-blind, randomized clinical trial comparing high-dose, long-duration treatment (150 U/m2 once daily for 3 weeks, n=30) of H.P. 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.

16 HOW SUPPLIED / STORAGE AND HANDLING

H.P. Acthar Gel (repository corticotropin injection) is supplied as 5 mL multi-dose vial (63004-8710-1) containing 80 USP Units per mL. H.P. 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 H.P. Acthar Gel (repository corticotropin injection) under refrigeration between 2° to 8°C (36° to 46°F). Product is stable for the period indicated on the label when stored under the conditions described.

17 PATIENT COUNSELING INFORMATION

Caretakers of patients with infantile spasms should be informed of the availability of a Medication Guide, and they should be instructed to read the Medication Guide prior to administering H.P. Acthar Gel. Patients should be instructed to take H.P. Acthar Gel only as prescribed. They should not stop treatment suddenly unless instructed by their physician 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 H.P. Acthar Gel treatment and the importance of not missing scheduled doctor’s appointments.

Patients, their caregivers and families should be advised that if the patient develops an infection or fever they should contact their physician. They should be educated that a fever may not necessarily be present during infection. The patient should also try to limit contact with other people with infections to minimize the risk of infection while taking H.P. Acthar Gel [see Warnings and Precautions (5.1) and Adverse Reactions (6.1.1) ].

Patients, their caregivers and families should be advised that if the patient experiences an increase in blood pressure they should contact their physician [see Warnings and Precautions (5.3) and Adverse Reactions (6.1.1) ].

Patients, their caregivers and families should be advised that if the patient or the caregiver notices blood or a change in color of the patient’s stool they should contact their physician. [see Warnings and Precautions (5.6) ]

Caregivers and families of infants and children treated with H.P. Acthar Gel should be informed that the patient may show signs of irritability and sleep disturbances. These effects are reversible once H.P. Acthar Gel therapy is stopped [see Warnings and Precautions (5.7) and Adverse Reactions (6.1.1) ].

Patients, their caregivers and families should be advised that changes in appetite, most often leading to weight gain, are seen with H.P. Acthar Gel therapy, becoming more frequent as the dose or treatment period increases. These effects are reversible once H.P. Acthar Gel therapy is stopped [see Warnings and Precautions (5.12) and Adverse Reactions (6.1.1) ].

Patients, their caregivers and families should be advised that the patient may be monitored for signs of adrenal insufficiency such as weakness, fatigue, lethargy, anorexia, weight loss, hypotension, abdominal pain or hyperpigmentation (adults only) after treatment has stopped. Since the recovery of the adrenal gland varies from days to months, patients may need to be protected from the stress of trauma or surgery by the use of corticosteroids during the period of stress [see Warnings and Precautions (5.2) ].

Patients should be advised not to be vaccinated with live or live attenuated vaccines during treatment with H.P. 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 H.P. Acthar Gel [see Warnings and Precautions (5.4) ].

Patients, their caregivers and families should be advised that prolonged use of H.P. Acthar Gel in children may result in Cushing’s syndrome and associated adverse reactions, may inhibit skeletal growth, and may cause osteoporosis and decreased bone density. If prolonged use is necessary, H.P. Acthar Gel should be given intermittently along with careful observation [see Warnings and Precautions (5.2), (5.12), and (5.13) and Adverse Reactions (6.1.1) ].

Patients, their caregivers and families should be informed that H.P. Acthar Gel may mask symptoms of other diseases/disorders without altering the course of the other disease/disorder. The patient will need to 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 [see Warnings and Precautions (5.5) ].

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 H.P. Acthar Gel, the other seizures may become visible. Parents and caregivers should inform their physician of any new onset of seizures so that appropriate management can then be instituted [see Adverse Reactions (6.1.1) ].

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