Limitations of use:

INCRELEX is not a substitute to GH for approved GH indications.

INCRELEX is not indicated for use in patients with secondary forms of IGF-1 deficiency, such as GH deficiency, malnutrition, hypothyroidism, or chronic treatment with pharmacologic doses of anti-inflammatory corticosteroids.

2.1 Recommended Dosage

• Treatment with INCRELEX should be supervised by a physician who is experienced in the diagnosis and management of pediatric patients with short stature associated with severe primary IGF-1 deficiency or with growth hormone gene deletion and who have developed neutralizing antibodies to growth hormone.
• The dosage of INCRELEX should be individualized for each patient. The recommended starting dose of INCRELEX is 0.04 mg/kg to 0.08 mg/kg of body weight twice daily by subcutaneous injection. If well-tolerated for at least one week, the dose may be increased by 0.04 mg/kg of body weight per dose, to the maximum dose of 0.12 mg/kg of body weight given twice daily [see Warnings and Precautions (5.1 and 5.7)].
• Preprandial glucose monitoring is recommended at treatment initiation and until a well-tolerated dose is established. If frequent symptoms of hypoglycemia or severe hypoglycemia occur, preprandial glucose monitoring should continue, and glucose monitoring should also occur at the time of event if possible. If hypoglycemia occurs with recommended doses despite adequate food intake, the dose should be reduced. INCRELEX should be administered shortly before or after (± 20 minutes) a meal or snack. If the patient is unable to eat shortly before or after a dose for any reason, that dose of INCRELEX should be withheld.
• If one or more doses of INCRELEX is missed, do not increase the subsequent doses to make up for omitted doses.

2.2 Administration Instructions

INCRELEX is administered by subcutaneous injection only. Do not administer intravenously.

INCRELEX injection sites should be rotated to a different site (upper arm, thigh, buttock or abdomen) with each injection to help prevent lipohypertrophy.

INCRELEX should be administered using sterile disposable syringes and needles. The syringes should be of small enough volume so that the prescribed dose can be withdrawn from the vial with accuracy.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if the solution is cloudy or contains particulate matter.

If using syringes that measure dose in units, doses in mg/kg must be converted to units using the following formula: Weight (kg) × Dose (mg/kg) × 1 mL/10 mg × 100 units/1 mL = units/injection.

5.1 Hypoglycemia

Severe hypolgycemia leading to hypolycemic seizures has been observed with INCRELEX treatment [see Adverse Reactions (6.1)]. Because INCRELEX has insulin-like hypoglycemic effects it should be administered shortly before or after (± 20 minutes) a meal or snack. Glucose monitoring and INCRELEX dose titration are recommended until a well-tolerated dose is established [see Dosage and Administration (2.1)] and subsequently as medically indicated. Special attention should be paid to small children because their oral intake may not be consistent. Patients should avoid engaging in any high-risk activities (e.g., driving, exercise, etc.) within 2 to 3 hours after dosing, particularly during the initiation of INCRELEX treatment until tolerability and a stable dose have been established [see Adverse Reactions (6.1)]. INCRELEX should not be administered when the meal or snack is omitted.

The dose of INCRELEX should never be increased to make up for one or more omitted doses.

5.2 Hypersensitivity and Allergic Reactions, including Anaphylaxis

Allergic reactions to INCRELEX have been reported post-marketing. They range from localized (injection site) reactions to systemic reactions, including anaphylaxis requiring hospitalization. Parents and patients should be informed that such reactions are possible and that if a systemic allergic reaction occurs, treatment should be interrupted and prompt medical attention should be sought. [see Contraindications (4) and Adverse Reactions (6.3)]

5.3 Intracranial Hypertension

Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea and/or vomiting have occurred in patients treated with INCRELEX. IH-associated signs and symptoms resolved after interruption of dosing. Funduscopic examination is recommended at the initiation and periodically during the course of INCRELEX therapy. [see Adverse Reactions (6.3)].

5.4 Lymphoid Tissue Hypertrophy

Lymphoid tissue (e.g., tonsillar and adenoidal) hypertrophy associated with complications, such as snoring, sleep apnea, and chronic middle-ear effusions have been reported with the use of INCRELEX. Patients should have periodic examinations to rule out such potential complications and receive appropriate treatment if necessary [see Adverse Reactions (6.3)].

5.5 Slipped Capital Femoral Epiphysis

Slipped capital femoral epiphysis can occur in patients who experience rapid growth. Any pediatric patient with the onset of a limp or complaints of hip or knee pain during INCRELEX therapy should be carefully evaluated.

5.6 Progression of Preexisting Scoliosis

Progression of scoliosis may occur in patients who experience rapid growth. Because INCRELEX increases growth rate, patients with a history of scoliosis who are treated with INCRELEX should be monitored for progression of scoliosis.

5.7 Malignant Neoplasia

There have been postmarketing reports of malignant neoplasms in pediatric patients who have received treatment with INCRELEX [see Adverse Reactions (6.3)]. The cases of malignant neoplasms represented a variety of different malignancies. It is unknown whether there is any relationship between INCRELEX therapy and new occurrence of neoplasia. The occurrence of neoplasia was mostly reported in patients with rare genetic conditions of short stature associated with an increased risk of cancer, or in patients with other cancer predisposing conditions. The tumors were observed also more frequently in patients who received INCRELEX at higher than recommended doses, or at doses that produced serum IGF-1 levels above the normal reference ranges for age and sex. Monitor all patients receiving INCRELEX carefully for development of neoplasms. Advise patients/caregivers to report development of new neoplasms. If malignant neoplasia develops, discontinue INCRELEX treatment [see Contraindications (4)].

5.8 Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preserved Solution

Serious and fatal adverse reactions including "gasping syndrome" can occur in neonates and infants treated with benzyl alcohol-preserved drugs, including INCRELEX. The "gasping syndrome" is characterized by central nervous system depression, metabolic acidosis, and gasping respirations.

Use of INCRELEX in infants is not recommended [see Use in Specific Populations 8.4)].

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.

In clinical studies of 71 subjects with Primary IGFD treated for a mean duration of 3.9 years and representing 274 subject-years, no subjects withdrew from any clinical study because of adverse reactions. Adverse reactions to INCRELEX treatment that occurred in 5% or more of these study participants are listed below by organ class.

 

Metabolism and Nutrition Disorders: hypoglycemia

 

General Disorders and Administrative Site Conditions: lipohypertrophy, bruising

 

Infections and Infestations: otitis media, serous otitis media

 

Respiratory, Thoracic and Mediastinal Disorders: snoring, tonsillar hypertrophy

 

Nervous System Disorders: headache, dizziness, convulsions

 

Gastrointestinal Disorders: vomiting

 

Ear and Labyrinth Disorders: hypoacusis, fluid in middle ear, ear pain, abnormal tympanometry

 

Investigations: cardiac murmur

 

Musculoskeletal and Connective Tissue Disorders: arthralgia, pain in extremity

 

Blood and Lymphatic System Disorders: thymus hypertrophy

 

Surgical and Medical Procedures: ear tube insertion

Hypoglycemia was reported by 30 subjects (42%) at least once during their course of therapy. Most cases of hypoglycemia were mild or moderate in severity. Five subjects had severe hypoglycemia (requiring assistance and treatment) on one or more occasions and 4 subjects experienced hypoglycemic seizures/loss of consciousness on one or more occasions. Of the 30 subjects reporting hypoglycemia, 14 (47%) had a history of hypoglycemia prior to treatment. The frequency of hypoglycemia was highest in the first month of treatment, and episodes were more frequent in younger children. Symptomatic hypoglycemia was generally avoided when a meal or snack was consumed either shortly (i.e., 20 minutes) before or after the administration of INCRELEX.

Tonsillar hypertrophy was noted in 11 (15%) subjects in the first 1 to 2 years of therapy with lesser tonsillar growth in subsequent years. Tonsillectomy or tonsillectomy/adenoidectomy was performed in 7 subjects; 3 of these had obstructive sleep apnea, which resolved after the procedure in all three cases.

Intracranial hypertension occurred in three subjects. In two subjects the events resolved without interruption of INCRELEX treatment. INCRELEX treatment was discontinued in the third subject and resumed later at a lower dose without recurrence.

Mild elevations in the serum AST and LDH were found in a significant proportion of patients before and during treatment. Rise in levels of these serum enzymes did not lead to treatment discontinuation. ALT elevations were occasionally noted during treatment.

Renal and splenic lengths (measured by ultrasound) increased rapidly on INCRELEX treatment during the first years of therapy. This lengthening slowed down subsequently; though in some patients, renal and/or splenic length reached or surpassed the 95th percentile. Renal function (as defined by serum creatinine and calculated creatinine clearance) was normal in all patients, irrespective of renal growth.

Elevations in cholesterol and triglycerides to above the upper limit of normal were observed before and during treatment.

Echocardiographic evidence of cardiomegaly/valvulopathy was observed in a few individuals without associated clinical symptoms. The relation of these cardiac changes to drug treatment cannot be assessed due to underlying disease and the lack of a control group.

Thickening of the soft tissues of the face was observed in several patients and should be monitored during INCRELEX treatment.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of INCRELEX. Because these 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.

Systemic hypersensitivity: anaphylaxis, generalized urticaria, angioedema, dyspnea

In the post-marketing setting, the frequency of cases indicative of anaphylaxis was estimated to be 0.3%. Symptoms included hives, angioedema, and dyspnea, and some patients required hospitalization. Upon re-administration, symptoms did not re-occur in all patients.

Local allergic reactions at the injection site: pruritus, urticaria

Skin and Subcutaneous Tissue Disorders: alopecia, hair texture abnormal

General Disorders and Administrative Site Conditions: injection site reactions (e.g. erythema, pain, hematoma, hemorrhage, induration, rash, swelling)

Musculoskeletal and Connective Tissue Disorders: osteonecrosis/avascular necrosis (occasionally associated with slipped capital femoral epiphysis)

Neoplasms Benign, Malignant and Unspecified (including cysts and polyps)

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

The safety and effectiveness of INCRELEX in patients aged 65 and over has not been established.

12.1 Mechanism of Action

Insulin-like growth factor-1 (IGF-1) is a key hormonal mediator on statural growth. Under normal circumstances, growth hormone (GH) binds to its receptor in the liver, and other tissues, and stimulates the synthesis/secretion of IGF-1. In target tissues, the Type 1 IGF-1 receptor, which is homologous to the insulin receptor, is activated by IGF-1, leading to intracellular signaling which stimulates multiple processes resulting in statural growth. The metabolic actions of IGF-1 are in part directed at stimulating the uptake of glucose, fatty acids, and amino acids so that metabolism supports growing tissues.

12.2 Pharmacodynamics

The following actions have been demonstrated for endogenous human IGF-1:

12.3 Pharmacokinetics

Race –The effect of race on pharmacokinetics of INCRELEX has not been studied.

Table 1. Summary of INCRELEX Single-Dose Pharmacokinetic Parameters in Children with Severe Primary IGFD (0.12 mg/kg, SC)

	Cmax (ng/mL)	Tmax (hr)	AUC0-8 (hr*ng/mL)	t1/2 (hr)	Vd/F (L/kg)	CL/F (L/hr/kg)
n	3	3	3	3	12*	12*
Cmax = maximum concentration; Tmax = time of maximum concentration; AUC0-8 = area under the curve; t1/2 = half-life; Vd/F = apparent volume of distribution; CL/F = apparent systemic clearance; SC = subcutaneous injection; CV% = coefficient of variation in %. Male/female data combined, ages 12 to 22 years. PK parameters based on baseline adjusted plasma concentrations.
* Data represents 3 subjects each at doses 0.015, 0.03, 0.06, and 0.12 mg/kg SC.
Mean	234	2	2932	5.8	0.257	0.0424
CV%	23	0	50	64	28	38

Figure 1. Mean Total IGF-1 Concentration after a Single Subcutaneous Dose of INCRELEX in Children with Severe Primary IGFD (0.06 mg/kg and 0.12 mg/kg, n=3 per group)

12.6 Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of INCRELEX or other growth hormones.

Anti-IGF-1 antibodies were present at one or more of the periodic assessments in 14 of 23 children with Primary IGFD treated for 2 years. However, no clinical consequences of these antibodies were observed (e.g., attenuation of growth).

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Effects of INCRELEX Treatment in Children with Severe Primary Insulin-like Growth Factor-1 Deficiency (Severe Primary IGFD)

Five clinical studies (four open-label and one double-blind, placebo-controlled), with subcutaneous doses of INCRELEX generally ranging from 0.06 to 0.12 mg/kg (60 to 120 micrograms/kg) administered twice daily, were conducted in 71 pediatric subjects with severe Primary IGFD. Patients were enrolled in the trials on the basis of extreme short stature, slow growth rates, low IGF-1 serum concentrations, and normal growth hormone secretion. Data from these 5 clinical studies were pooled for a global efficacy and safety analysis. Baseline characteristics for the patients evaluated in the primary and secondary efficacy analyses were (mean, SD): chronological age (years): 6.7 ± 3.8; height (cm): 84.8 ± 15.3 cm; height standard deviation score (SDS): -6.7 ± 1.8; height velocity (cm/yr): 2.8 ± 1.8; height velocity SDS: -3.3 ± 1.7; IGF-1 (ng/mL): 21.6 ± 20.6; IGF-1 SDS: -4.3 ± 1.6; and bone age (years): 4.2 ± 2.8. Sixty-one subjects had at least one year of treatment. Fifty-three (87%) had Laron Syndrome; 7 (11%) had GH gene deletion, and 1 (2%) had neutralizing antibodies to GH. Thirty-seven (61%) of the subjects were male; forty-eight (79%) were Caucasian. Fifty-six (92%) of the subjects were pre-pubertal at baseline.

Annual results for height velocity, height velocity SDS, and height SDS are shown in Table 2. Pre-treatment height velocity data were available for 58 subjects. The height velocities at a given year of treatment were compared by paired t-tests to the pre-treatment height velocities of the same subjects completing that treatment year.

Forty-nine subjects were included in an analysis of the effects of INCRELEX on bone age advancement. The mean ± SD change in chronological age was 4.9 ± 3.4 years and the mean ± SD change in bone age was 5.3 ± 3.4 years.

How Supplied

INCRELEX injection is supplied as a 40 mg/4 mL (10 mg/mL) sterile, clear, and colorless solution in multiple-dose glass vials (NDC-71863-216-04).

Storage and Handling