Increlex
(mecasermin)Dosage & Administration
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Increlex Prescribing Information
Severe Primary IGF-1 Deficiency (Primary IGFD)
INCRELEX is indicated for the treatment of growth failure in pediatric patients 2 years of age and older with:
- severe primary IGF-1 deficiency or
- growth hormone (GH) gene deletion who have developed neutralizing antibodies to GH.
Severe Primary IGF-1 deficiency (IGFD) is defined by:
- height standard deviation score ≤ –3.0 and
- basal IGF-1 standard deviation score ≤ –3.0 and
- normal or elevated growth hormone (GH).
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.
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.
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.
Injection: 40 mg/4 mL (10 mg/mL) clear and colorless solution in a multiple-dose glass vial.
Pregnancy
Risk Summary
There are no available data on INCRELEX use in pregnant women. Exposure to INCRELEX during pregnancy is unlikely because the drug is not indicated for use after epiphyseal closure. In animal reproduction studies, there were no observed embryo-fetal development abnormalities with intravenous administration of INCRELEX to pregnant rats and rabbits during fetal organogenesis given at exposures up to 11 and 3 times the maximum recommended human dose (MRHD) of 0.24 mg/kg/day based on body surface area (BSA), respectively (see Data).
The estimated background risk of birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data
Animal Data
Studies to assess embryo-fetal toxicity evaluated the effects of INCRELEX during organogenesis in Sprague Dawley rats given 1, 4, and 16 mg/kg/day and in New Zealand White rabbits given 0.125, 0.5, and 2 mg/kg/day, administered intravenously. There were no observed embryo-fetal developmental abnormalities in rats given up to 16 mg/kg/day (11 times the MRHD based on BSA comparison). In the rabbit study, the NOAEL for fetal toxicity was 0.5 mg/kg/day (approximately equivalent to the MRHD based on BSA) due to an increase in fetal death at 2 mg/kg. INCRELEX displayed no teratogenicity or maternal toxicity in rabbits given up to 2 mg/kg (3 times the MRHD based on BSA).
Lactation
Risk Summary
There is no information available on the presence of mecasermin in human or animal milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for INCRELEX and any potential adverse effects on the breast-fed child from INCRELEX or from the underlying maternal condition.
Pediatric Use
Toxicity (Gasping Syndrome) with Benzyl Alcohol
Serious adverse reactions including fatal reactions and the "gasping syndrome" occurred in premature neonates and infants in the intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 mg/kg/day to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 mmol/L to 1.378 mmol/L). INCRELEX contains 9 mg/mL benzyl alcohol as a preservative.
Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. Use of INCRELEX in infants is not recommended [see Warnings and Precautions (5.8)].
Safety and effectiveness in pediatric patients below the age of 2 years of age have not been established.
Geriatric Use
The safety and effectiveness of INCRELEX in patients aged 65 and over has not been established.
- Known Hypersensitivity
INCRELEX should not be used by patients who are allergic to mecasermin (rhIGF-1) or any of the inactive ingredients in INCRELEX, or who have experienced a severe hypersensitivity to INCRELEX [see Warnings and Precautions (5.2) and Adverse Reactions (6.3)].
- Closed Epiphyses
INCRELEX should not be used for growth promotion in patients with closed epiphyses.
- Malignant Neoplasia
INCRELEX is contraindicated in pediatric patients with malignant neoplasia or a history of malignancy [see Warnings and Precautions (5.7) and Adverse Reactions (6.3)].
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.
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)]
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)].
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)].
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.
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.
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)].
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)].