GIVINOSTAT: 265 Adverse Event Reports & Safety Profile

DUVYZAT (givinostat) oral suspension contains givinostat hydrochloride monohydrate, a histone deacetylase inhibitor. Givinostat hydrochloride monohydrate is designated chemically as: [6-(diethylaminomethyl)naphthalen-2-yl]methyl[4(hydroxycarbamoyl) phenyl] carbamate hydrochloride monohydrate. The molecular formula is C 24 H 27 N 3 O 4

• HCl•H 2 O and the molecular weight is 475.97 g/mol. Its structural formula is: Givinostat hydrochloride monohydrate is a white to off-white, non-hygroscopic, crystalline powder that is very slightly to slightly soluble in aqueous media and slightly soluble in ethanol. DUVYZAT contains givinostat 8.86 mg/mL (equivalent to givinostat hydrochloride monohydrate 10 mg/mL) and the following inactive ingredients: cream flavor, glycerin, non-crystallizing sorbitol solution, peach flavor, polysorbate 20, purified water, saccharin sodium, sodium benzoate, sodium hydroxide, tartaric acid, and tragacanth. Image

AND USAGE DUVYZAT is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients 6 years of age and older. DUVYZAT is a histone deacetylase inhibitor indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients 6 years of age and older. ( 1 )

AND ADMINISTRATION Obtain and evaluate baseline platelet counts and triglycerides prior to initiation of DUVYZAT. Do not initiate DUVYZAT in patients with a platelet count less than 150 x 10^9/L. ( 2.1 , 5.1 , 5.2 ) The dosage of DUVYZAT is based on patient’s body weight. ( 2.2 ) Administer orally twice daily with food. ( 2.2 ) Dosage modifications may be needed for decreased platelet counts, diarrhea, increased triglycerides, or QTc prolongation. ( 2.3 , 5.1 , 5.2 , 5.3 , 5.4 )

2.1 Recommended Evaluation and Testing Before Initiation of DUVYZAT Obtain and evaluate baseline platelet counts and triglycerides prior to initiation of DUVYZAT <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1 , 5.2) ]</span> . Do not initiate DUVYZAT in patients with a platelet count less than 150 x 10 9 /L. Monitor platelet counts and triglycerides as recommended during treatment to determine if dosage modifications are needed <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span>. In addition, in patients with underlying cardiac disease or taking concomitant medications that cause QT prolongation, obtain ECGs when initiating treatment with DUVYZAT, during concomitant use, and as clinically indicated <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) , Warnings and Precautions (5.4) , and Drug Interactions (7.2) ]</span> .

2.2 Recommended Dosage The recommended dosage of DUVYZAT is based on body weight and administered orally twice daily with food (see Table 1 ) <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span> .

Table

1: Recommended Dosage in Patients 6 Years of Age and Older for the Treatment of DMD Weight Based on actual body weight Dosage Oral Suspension Volume 10 kg to less than 20 kg 22.2 mg twice daily 2.5 mL twice daily 20 kg to less than 40 kg 31 mg twice daily 3.5 mL twice daily 40 kg to less than 60 kg 44.3 mg twice daily 5 mL twice daily 60 kg or more 53.2 mg twice daily 6 mL twice daily

2.3 Dosage Modifications for Adverse Reactions Decrease in Platelets, Diarrhea, Increase in Triglycerides DUVYZAT may cause adverse reactions <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1 , 5.2 , 5.3) ]</span>, which may necessitate a dosage modification (see Table 2 ) if the following occur: Platelet count &lt;150 x 10 9 /L verified in two assessments one week apart or Moderate or severe diarrhea or Fasting triglycerides &gt;300 mg/dL verified by two assessments one week apart Based on the severity of these adverse reactions, treatment interruption prior to dosage modification should be considered.

Table

2: Dosage Modifications for Adverse Reactions in Patients 6 Years of Age and Older for the Treatment of DMD First Dosage Modification If the adverse reaction(s) persist after the first dosage modification, proceed to the second dosage modification.

Second Dosage

Modification If the adverse reaction(s) persist after the second dosage modification, DUVYZAT should be discontinued.

Weight

Based on actual body weight Dosage Oral Suspension Volume Dosage Oral Suspension Volume 10 kg to less than 20 kg 17.7 mg twice daily 2 mL twice daily 13.3 mg twice daily 1.5 mL twice daily 20 kg to less than 40 kg 22.2 mg twice daily 2.5 mL twice daily 17.7 mg twice daily 2 mL twice daily 40 kg to less than 60 kg 31 mg twice daily 3.5 mL twice daily 26.6 mg twice daily 3 mL twice daily 60 kg or more 39.9 mg twice daily 4.5 mL twice daily 35.4 mg twice daily 4 mL twice daily QTc Interval Prolongation Withhold DUVYZAT if the QTc interval is > 500 ms or the change from baseline is > 60 ms [see Warnings and Precautions (5.4) and Drug Interactions (7.2) ].

2.4 Preparation and Administration Instructions See the Instructions for Use for further details. Before use, shake the DUVYZAT suspension for at least 30 seconds by inverting the bottle by 180°. Visually verify the homogeneity of the suspension. Using a graduated oral syringe, measure the appropriate volume of suspension corresponding to the prescribed dose of DUVYZAT. Administer orally with the provided graduated oral syringe.

2.5 Missed Dose If a dose is missed, patients should not take double or extra doses.

None. None. ( 4 )

REACTIONS The following clinically significant adverse reactions are described below and elsewhere in the labeling: Hematological Changes [see Warnings and Precautions (5.1) ]

Increased

Triglycerides [see Warnings and Precautions (5.2) ]

Gastrointestinal

Disturbances [see Warnings and Precautions (5.3) ] QTc Prolongation [see Warnings and Precautions (5.4) ] Most common adverse reactions (≥10% in DUVYZAT-treated patients) are diarrhea, abdominal pain, thrombocytopenia, nausea/vomiting, hypertriglyceridemia, and pyrexia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact ITF Therapeutics, LLC. at 1-833-582-4312 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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 controlled and uncontrolled trials in patients with confirmed DMD, 222 male patients aged 6 years and older were treated with DUVYZAT, including 210 patients treated for ≥ 6 months, 187 patients for ≥ 12 months, and 105 patients for ≥ 24 months. The safety profile of DUVYZAT is based on a double-blind, placebo-controlled, 18-month study in a total of 179 ambulant DMD patients aged 6 years or older on concomitant steroid treatment (Study 1) <span class="opacity-50 text-xs">[see Clinical Studies (14) ]</span> . The dosage in Study 1 was weight-based <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span> . Patients were excluded from the study if they had the following abnormalities at the screening visit: platelet, white blood cell, or hemoglobin counts less than the lower limit of normal, triglycerides &gt; 300 mg/dL (3.42 mmol/L) in fasting condition, or had a baseline-corrected QT interval, Fridericia’s correction (QTcF) of &gt; 450 msec (mean of 3 consecutive readings 5 minutes apart) or a history of additional risk factors for torsades de pointes (e.g., heart failure, hypokalemia, or family history of long QT syndrome). Overall, 2% of the patients discontinued the study because of adverse reactions. Adverse reactions reported in &gt;5% of DUVYZAT-treated patients at a frequency at least 5% greater than that of the placebo group are presented in Table 3 below.

Table

3.

Adverse Reactions

Reported in >5% of DUVYZAT-Treated Patients and at Least 5% Greater than Placebo in Study 1 Adverse Reaction DUVYZAT N=118 % Placebo N=61 % Diarrhea 37 20 Abdominal pain 34 25 Thrombocytopenia Thrombocytopenia includes platelet count decreased and thrombocytopenia 33 0 Nausea/Vomiting 32 18 Hypertriglyceridemia 23 7 Pyrexia 13 8 Myalgia 9 3 Rash 9 2 Arthralgia 8 2 Fatigue 8 0 Constipation 7 2 Decreased appetite 7 0 Less Common Adverse Reactions in Study 1 Adverse reactions of hypothyroidism and/or thyroid stimulating hormone (TSH) increased occurred in 5% of patients treated with DUVYZAT compared to 2% of patients who received placebo.

AND PRECAUTIONS Hematological Changes: DUVYZAT can cause dose-related thrombocytopenia and other signs of myelosuppression, including anemia and neutropenia. Monitor platelets; dosage adjustment or discontinuation may be needed. ( 2.3 , 5.1 )

Increased

Triglycerides: An increase in triglycerides can occur; dosage modification may be needed. Discontinuation may be needed. ( 2.3 , 5.2 )

Gastrointestinal

Disturbances: Adjust dosage if moderate or severe diarrhea occurs. Antiemetics or antidiarrheal medications may be considered during treatment with DUVYZAT. Discontinue DUVYZAT if the symptoms persist. ( 2.3 , 5.3 ) QTc Prolongation: Avoid use of DUVYZAT in patients who are at an increased risk for ventricular arrhythmias. ( 2.1 , 5.4 , 7.2 )

5.1 Hematological Changes DUVYZAT can cause dose-related thrombocytopenia and other signs of myelosuppression, including decreased hemoglobin and neutropenia.

In Study

1 [see Clinical Studies (14) ] , thrombocytopenia occurred in 33% of patients treated with DUVYZAT compared to no patients on placebo. The maximum decrease in platelets occurred within the first 2 months of therapy and remained low throughout the course of therapy. In a few patients, thrombocytopenia was associated with bleeding events including epistaxis, hematoma or contusions. Low platelet counts resulted in DUVYZAT dose reduction in 28% of patients. Patients with baseline platelet counts below the lower limit of normal were excluded from the study. Decreased hemoglobin and decreased neutrophils were also observed in patients treated with DUVYZAT compared to placebo. Monitor blood counts every 2 weeks for the first 2 months of treatment, at month 3, and then every 3 months thereafter. Modify the dosage of DUVYZAT for confirmed thrombocytopenia [see Dosage and Administration (2.3) ] . Treatment should be permanently discontinued if the abnormalities worsen despite dose modification. If a patient develops signs or symptoms of thrombocytopenia, obtain a platelet count as soon as possible, and hold dosing until platelet count is confirmed.

5.2 Increased Triglycerides DUVYZAT can cause elevations in triglycerides.

In Study

1 [see Clinical Studies (14) ] , hypertriglyceridemia occurred in 23% of patients treated with DUVYZAT (one of whom had familial hypertriglyceridemia) compared to 7% of patients on placebo. High triglycerides (i.e., levels greater than 300 mg/dL) resulted in discontinuation and led to dosage modification in 2% and 8%, respectively, of patients treated with DUVYZAT. Monitor triglycerides at 1 month, 3 months, 6 months, and then every 6 months thereafter. Modify the dosage if fasting triglycerides are verified > 300 mg/dL [see Dosage and Administration (2.3) ] . Treatment with DUVYZAT should be discontinued if triglycerides remain elevated despite adequate dietary intervention and dosage adjustment.

5.3 Gastrointestinal Disturbances Gastrointestinal disturbances, including diarrhea, nausea/vomiting, and abdominal pain were common adverse reactions in DUVYZAT clinical trials in DMD.

In Study

1, diarrhea was reported in 37% of patients treated with DUVYZAT (with 1 severe case reported) compared to 20% of patients on placebo. Diarrhea usually occurred within the first few weeks of initiation of treatment with DUVYZAT. Vomiting and nausea, sometimes severe and usually occurring within the first 2 months of treatment, occurred in 32% of patients treated with DUVYZAT compared to 18% of patients on placebo. Abdominal pain occurred in 34% of patients treated with DUVYZAT compared to 25% of patients on placebo. One case of abdominal pain was serious. Antiemetics or antidiarrheal medications may be considered during treatment with DUVYZAT. Fluid and electrolytes should be replaced as needed to prevent dehydration [see Warnings and Precautions (5.4) ] . Modify the dosage of DUVYZAT in patients with moderate or severe diarrhea, and treatment should be discontinued if significant symptoms persist [see Dosage and Administration (2.3) ] .

5.4 QTc Prolongation DUVYZAT can cause prolongation of QTc interval <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2) ]</span> . Avoid use of DUVYZAT in patients who are at an increased risk for ventricular arrhythmias (including torsades de pointes), such as those with congenital long QT syndrome, coronary artery disease, electrolyte disturbance <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) ]</span> , concomitant use of other medicinal products known to cause QT prolongation <span class="opacity-50 text-xs">[see Drug Interactions (7.2) ]</span> . Obtain ECGs prior to initiating treatment with DUVYZAT in patients with underlying cardiac disease or in patients who are taking concomitant medications that cause QT prolongation <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) ]</span> .

INTERACTIONS Closely monitor when DUVYZAT is used in combination with an oral CYP3A4 sensitive substrate or a sensitive substrate of the OCT2 transporter, for which a small change in substrate plasma concentration may lead to serious toxicities. ( 7.1 ) Avoid concomitant use with other drugs that prolong the QTc interval; monitor ECG if concomitant use cannot be avoided. ( 7.2 )

7.1 Effect of DUVYZAT on Other Drugs CYP3A4 Sensitive Substrates Givinostat is a weak intestinal CYP3A4 inhibitor <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Closely monitor when DUVYZAT is used in combination with orally administered CYP3A4 sensitive substrates for which a small change in substrate plasma concentration may lead to serious toxicities. OCT2 Sensitive Substrates Givinostat is a weak inhibitor of the renal uptake transporter OCT2 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Closely monitor when DUVYZAT is used in combination with drugs known as a sensitive substrate of the OCT2 transporter for which a small change in substrate plasma concentration may lead to serious toxicities.

7.2 Effect of Other Drugs on DUVYZAT Drugs that Prolong the QTc Interval Avoid concomitant use of DUVYZAT with other product(s) with a known potential to prolong the QTc interval. If concomitant use cannot be avoided, obtain ECGs when initiating, during concomitant use, and as clinically indicated <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4) ]</span> . Withhold DUVYZAT if the QTc interval is &gt; 500 ms or the change from baseline is &gt; 60 ms <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) ]</span> . DUVYZAT causes QTc interval prolongation <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2) ]</span> . Concomitant use of DUVYZAT with other products that prolong the QTc interval may result in a greater increase in the QTc interval and adverse reactions associated with QTc interval prolongation, including Torsade de pointes, other serious arrythmias, and sudden death <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4) ]</span> .