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These highlights do not include all the information needed to use MACRILEN safely and effectively. See full prescribing information for MACRILEN.MACRILEN (macimorelin) for oral solution Initial U.S. Approval: 2017 | Macrilen [Strongbridge U.S. Inc] | BioPortfolio

13:07 EST 27th January 2019 | BioPortfolio

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MACRILEN is indicated for the diagnosis of adult growth hormone deficiency (AGHD).

Limitations of Use

The safety and diagnostic performance of MACRILEN have not been established for subjects with a body mass index (BMI) > 40 kg/m.

The recommended dose is a single oral dose of 0.5 mg/kg of macimorelin. The dose is administered as a reconstituted solution [see Dosage and Administration (2.3)] in patients fasted for at least 8 hours.

Prepare and administer by a healthcare professional exactly as follows.

Prepare the MACRILEN solution:

Determine the volume of MACRILEN solution needed for the test:

Administer the MACRILEN solution and perform the test:

Clinical studies have established that a maximally stimulated serum GH level of less than 2.8 ng/mL (i.e., at the 30, 45, 60 and 90 minute timepoints) following MACRILEN administration confirms the presence of adult growth hormone deficiency.

For oral solution: 60 mg white to off-white granules in a pouch for reconstitution in 120 mL of water, resulting in a solution of 0.5 mg/mL of macimorelin.

None

MACRILEN causes an increase of about 11 msec in the corrected QT (QTc) interval [see Clinical Pharmacology (12.2)]. QT prolongation can lead to development of torsade de pointes-type ventricular tachycardia with the risk increasing as the degree of prolongation increases. The concomitant use of MACRILEN with drugs that are known to prolong the QT interval should be avoided [see Dosage and Administration (2.2) and Drug Interactions (7.1)].

Concomitant use of strong CYP3A4 inducers with MACRILEN can decrease macimorelin plasma levels significantly and thereby lead to a false positive result [see Drug Interactions (7.2)]. Strong CYP3A4 inducers should be discontinued and enough time should be given to allow washout of CYP3A4 inducers prior to test administration [see Dosage and Administration (2.2)].

Adult growth hormone (GH) deficiency caused by a hypothalamic lesion may not be detected early in the disease process. Macimorelin acts downstream from the hypothalamus and macimorelin stimulated release of stored GH reserves from the anterior pituitary could produce a false negative result early when the lesion involves the hypothalamus. Repeat testing may be warranted in this situation.

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 trial of another drug and may not reflect the rates observed in practice.

The data in Table 1 are derived from an open-label, randomized, cross-over study that compared the diagnostic performance of MACRILEN to the insulin tolerance test (ITT) for the diagnosis of adult growth hormone deficiency [see Clinical Studies (14)]. A total of 154 subjects with a high to low pre-test probability of having adult growth hormone deficiency received a single oral dose of 0.5 mg/kg MACRILEN. Out of 154 subjects, 58% were male, 42% female, and 86% of white origin. Median values were for age 41 years (range: 18 – 66 years) and body mass index was 27.5 kg/m (range: 16 – 40 kg/m). Common adverse reactions presented in Table 1 were adverse reactions that were not present at baseline and occurred during MACRILEN dosing in at least two individuals.

Table 1: Common Adverse Reactions Reported in at Least Two Individuals Dosed with MACRILEN in an Open-Label Study
Number of Subjects
(n = 154)
Proportion of Subjects
(%)
Dysgeusia 7 4.5
Dizziness 6 3.9
Headache 6 3.9
Fatigue 6 3.9
Nausea 5 3.2
Hunger 5 3.2
Diarrhea 3 1.9
Upper respiratory tract infection 3 1.9
Feeling hot 2 1.3
Hyperhidrosis 2 1.3
Nasopharyngitis 2 1.3
Sinus bradycardia 2 1.3

Co-administration of MACRILEN with drugs that prolong the QT interval (such as antipsychotic medications (e.g., chlorpromazine, haloperidol, thioridazine, ziprasidone), antibiotics (e.g., moxifloxacin), Class 1A (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) antiarrhythmic medications or any other medications known to prolong the QT interval) may lead to development of torsade de pointes-type ventricular tachycardia. Avoid concomitant use of MACRILEN with drugs that prolong the QT interval. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of MACRILEN is recommended [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)].

Co-administration of a strong CYP3A4 inducer with MACRILEN (e.g., carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John's wort, bosentan, efavirenz, etravirine, modafinil, armodafinil, rufinamide) may reduce the plasma macimorelin concentrations and may lead to false positive test results. Discontinue strong CYP3A4 inducers prior to MACRILEN use. Sufficient washout time of strong CYP3A4 inducers prior to administration of MACRILEN is recommended [see Dosage and Administration (2.2) and Warnings and Precautions (5.2)].

The following drugs may impact the accuracy of the MACRILEN diagnostic test. Avoid concomitant use of MACRILEN with the following [see Dosage and Administration (2.2)]:

Sufficient washout time of drugs affecting growth hormone release prior to administration of MACRILEN is recommended.

Risk summary

There are no available data with MACRILEN use in pregnant women to inform a drug associated risk for adverse developmental outcomes. Animal reproduction studies have not been conducted with MACRILEN. MACRILEN is indicated as a single dose which limits the risk of adverse developmental outcomes from exposure to MACRILEN.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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.

Risk Summary

There are no data on the presence of macimorelin in human or animal milk, the effects on the breastfed infant or the effects on milk production. The lack of clinical data during lactation precludes a clear determination of the risk of MACRILEN to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for MACRILEN and any potential adverse effecs on the breastfed infant from MACRILEN or the underlying maternal condition.

The safety and efficacy of MACRILEN in pediatric patients have not been established.

Growth hormone secretion normally decreases with age. Therefore, elderly subjects might require a lower cut-off point for diagnosis of adult growth hormone deficiency. Clinical studies of MACRILEN did not include a sufficient number of subjects aged 65 and over to determine whether elderly patients respond differently from younger subjects.

In the event of an overdose, symptomatic and supportive measures should be employed.

MACRILEN for oral solution is macimorelin acetate, a synthetic growth hormone secretagogue receptor agonist. Macimorelin acetate is described chemically as D-Tryptophanamide, 2-methylalanyl-N-[(1R)-1-(formylamino)-2-(1H-indol-3-yl)ethyl]-acetate.

The molecular formula for macimorelin acetate is CHNO with a molecular weight of 534.6 g/mol.

Figure 1: Chemical structure of macimorelin acetate

Each aluminum pouch of MACRILEN contains 60 mg of macimorelin, equivalent to 68 mg of macimorelin acetate, and the following inactive ingredients: lactose monohydrate, crospovidone, sodium stearyl fumarate, saccharin sodium and colloidal silicon dioxide.

Macimorelin stimulates GH release by activating growth hormone secretagogue receptors present in the pituitary and hypothalamus.

GH stimulation

Maximum GH levels are observed between 30 to 90 minutes after administration of MACRILEN.

Cardiac electrophysiology

The effects of macimorelin on ECG parameters were investigated in a dedicated Thorough QT study that investigated in a 3-way cross-over design with 60 healthy subjects the effects of a supra-therapeutic dose of macimorelin (2 mg/kg) (4 times the recommended dosage) in comparison with placebo and with moxifloxacin. This study showed a mean baseline- and placebo-adjusted change (upper single-sided 95% confidence interval) in QTcF of 9.6 msec (11.4 msec) at 4 h post-dose, which occurred after the mean maximum macimorelin plasma concentration (0.5 h). A similar increase in the QTcF interval was also observed in a single-ascending dose study, which included three dose levels (0.5 mg/kg, and 1 mg/kg and 2 mg/kg (2 times and 4 times the recommended dosage, respectively). All three doses levels studied showed a similar magnitude of QTcF prolongation in the Thorough QT study, suggesting an absence of dose dependent changes. The mechanism for the observed QTcF prolongation is unknown [see Warnings and Precautions (5.1)].

The mean plasma macimorelin concentrations are similar between patients with AGHD and healthy subjects for 1.5 hours following administration of a single oral dose of 0.5 mg macimorelin/kg body weight.

Absorption

The maximum plasma macimorelin concentrations (C) were observed between 0.5 hour and 1.5 hours following oral administration of 0.5 mg macimorelin/kg body weight to patients with AGHD under fasting for at least 8 hours. A liquid meal decreased the macimorelin C and AUC by 55% and 49%, respectively.

Elimination

An in vitro human liver microsomes study showed that CYP3A4 is the major enzyme to metabolize macimorelin.

Macimorelin was eliminated with a mean terminal half-life (T) of 4.1 hours following administration of a single oral dose of 0.5 mg macimorelin/kg body weight in healthy subjects.

Carcinogenesis

Long-term carcinogenesis studies in rodents have not been conducted.

Mutagenesis

Macimorelin did not cause mutations in bacteria under assay conditions with or without metabolic activation. There were also no mutations or clastogenic effects in mouse lymphoma cells with or without metabolic activation.

Impairment of Fertility

No studies have been conducted to assess the effect of macimorelin on fertility.

The diagnostic efficacy of the MACRILEN test was established in a randomized, open-label, single-dose, cross-over study. The objective of the study was to compare the level of agreement between MACRILEN test results and insulin tolerance test (ITT) results in adult patients with different pre-test probability of growth hormone deficiency and healthy control subjects. The four groups of individuals evaluated were:

For both the ITT and the MACRILEN test, serum concentrations of growth hormone were measured at 30, 45, 60, and 90 minutes after drug administration. The test was considered positive (i.e., growth hormone deficiency diagnosed) if the maximum serum GH level observed after stimulation was less than the pre-specified cut point value of 2.8 ng/mL for the MACRILEN test or 5.1 ng/mL for the ITT.

The level of negative and positive agreement between the results of the ITT and the MACRILEN test was used to evaluate the performance of the MACRILEN test. In the study, the ITT is used as the benchmark (i.e., a negative ITT indicates absence of disease and a positive ITT indicates presence of disease). Negative agreement is the proportion of subjects with a negative ITT (i.e., those who do not have GHD per the ITT) who also have a negative MACRILEN test. With a high level of negative agreement, the MACRILEN test will not wrongly diagnose an individual without GHD per the ITT as having GHD. Positive agreement is the proportion of subjects with a positive ITT (i.e., those who have GHD per the ITT) who also have a positive MACRILEN test. With a high level of positive agreement, the MACRILEN test will not wrongly diagnose an individual with GHD per the ITT as not having GHD. The agreement measures are defined mathematically below (see Table 2).

Table 2: Definition of Agreement between ITT and MACRILEN
Insulin Tolerance Test Total
+ -
MACRILEN + a b a+b Positive Agreement (%)=100% x a/(a+c)
- c d c+d Negative Agreement (%)=100% x d/(b+d)
Total a+c b+d a+b+c+d Overall Agreement (%)=100% x (a+d)/(a+b+c+d)

Results

One hundred and fifty-seven subjects underwent at least one of the two tests in this study, 59% were male, 41% female, and 86% of white origin. The median age was 41 years (range: 18 – 66 years) and body mass index 27.5 kg/m (range: 16 – 40 kg/m). The study relied on a cross-over design and each participant was to undergo the two diagnostic tests and serve as his or her own control. Data on both tests were available for 140 subjects; 38 (27%) in Group A, 37 (26%) in Group B, 40 (29%) in Group C, and 25 (18%) in Group D. One out of 154 MACRILEN tests (0.6%) performed failed due to a technical error and 27 out of 157 ITTs (17.2%) performed failed because induction of severe hypoglycemia (i.e., the stimulus) could not be achieved.

Two-by-two tables presenting the pre-specified primary analysis results for the ITT and MACRILEN test are shown below for all subjects (Groups A, B, C, and D combined) and for each group separately (see Table 3). The estimates for negative and positive agreement between MACRILEN and the ITT in the overall study population were 94% and 74% with lower 95% confidence interval bounds 85% and 63%, respectively. Negative and positive agreement between MACRILEN and the ITT in subjects with intermediate or low risk (Groups B and C) were 93% and 61% with lower 95% confidence interval bounds 80% and 43%, respectively. These results are based on peak GH values (maximum GH concentrations across all measurement timepoints).

Repeatability was tested in a subset of 34 subjects who underwent two MACRILEN tests. Agreement between the result of the first test and the second test was observed in 31 cases (91.2%).

Table 3: Diagnostic Outcomes for MACRILEN and the ITT in all Subjects (Groups A, B, C, and D) and in Each Group Separately
All Subjects Insulin Tolerance Test Total Agreement Between
+ - ITT and MACRILEN
MACRILEN + 55 4 59 Positive 74%
- 19 62 81 Negative 94%
Total 74 66 140 Overall 84%
Group A
High likelihood of AGHD
Insulin Tolerance Test Total
+ -
MACRILEN + 33 0 33 Positive 89%
- 4 1 5 Negative 100%
Total 37 1 38 Overall 89%
Group B
Intermediate likelihood of AGHD
Insulin Tolerance Test Total
+ -
MACRILEN + 20 1 21 Positive 67%
- 10 6 16 Negative 86%
Total 30 7 37 Overall 70%
Group C
Low likelihood of AGHD
Insulin Tolerance Test Total
+ -
MACRILEN + 2 2 4 Positive 33%
- 4 32 36 Negative 94%
Total 6 34 40 Overall 85%
Group D
Healthy control
Insulin Tolerance Test Total
+ -
MACRILEN + 0 1 1 Positive 0%
- 1 23 24 Negative 96%
Total 1 24 25 Overall 92%

MACRILEN 60 mg is supplied as white to off-white granules in an aluminum pouch. Each pouch contains 60 mg macimorelin (equivalent to 68 mg macimorelin acetate) that when reconstituted with 120 mL of water provides a 60 mg/120 mL (0.5 mg/mL) macimorelin solution.

MACRILEN is available in boxes containing 1 pouch per box (NDC 71090-002-02).

Before administration, MACRILEN for oral solution must be reconstituted by a healthcare professional [see Dosage and Administration (2.3)].

Store pouches under refrigeration at 2-8°C (36-46°F).

The solution must be used within 30 minutes after preparation. Discard unused portion.

Instruct patients to discontinue treatment with GH at least one week before administering MACRILEN. Also, instruct patients to discontinue other medications that may interfere with the diagnostic test results prior to MACRILEN administration [see Drug Interactions (7.2, 7.3)].

Instruct patients to fast for at least 8 hours before MACRILEN administration [see Dosage and Administration (2.2)].

Manufactured by:Allphamed Pharbil Arzneimittel GmbH, Goettingen, Germany

Distributed by: Strongbridge U.S. Inc., Trevose, PA 19053

MACRILEN™ is a trademark of Aeterna Zentaris GmbH, licensed exclusively in the U.S. and Canada to Strongbridge Ireland Limited.

MACRILEN is the subject of U.S. Patent Nos. 6,861,409 and 8,192,719.

STRONGBRIDGE BIOPHARMA is a registered trademark of the Strongbridge Biopharma plc. companies, which include Strongbridge Ireland Limited and Strongbridge U.S. Inc.

Revised: January 2018

Principal Display Panel - Macrilen Pouch Label

Rx only

NDC 71090-002-02

Macrilen™

(macimorelin) for oral solution

60 mg

Must administer dose within30 minutes after reconstitution.Discard unused portion.

For oral use only.

193277/1

Principal Display Panel - Macrilen Carton Label

Rx only

NDC 71090-002-02

Macrilen™

(macimorelin) for oral solution

60 mg

One Pouch

Must administer dose within 30 minutes afterreconstitution. Discard unused portion.

For oral use only.

Strongbridge Biopharma

Manufacturer

Strongbridge U.S. Inc

Active Ingredients

Source

Drugs and Medications [0 Results]

None

Clinical Trials [0 Results]

None

PubMed Articles [0 Results]

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