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Glasdegib Tablets

TABLE OF CONTENTS

1. DESCRIPTION 8. USE IN SPECIFIC POPULATIONS
2. INDICATIONS AND USAGE 9. OVERDOSAGE
3. DOSAGE AND ADMINISTRATION 10. MECHANISM OF ACTION
4. CONTRAINDICATIONS 11. PHARMACODYNAMICS
5. WARNINGS AND PRECAUTIONS 12. PHARMACOKINETICS
6. ADVERSE REACTIONS 13. HOW SUPPLIED/STORAGE AND HANDLING
7. DRUG INTERACTIONS

 


WARNING: EMBRYO-FETAL TOXICITY

Glasdegib can cause embryo-fetal death or severe birth defects when administered to a pregnant woman. Glasdegib is embryotoxic, fetotoxic, and teratogenic in animals [see Warnings and Precautions (5.1), Use in Specific Populations (8.1)].

Conduct pregnancy testing in females of reproductive potential prior to initiation of glasdegib treatment. Advise females of reproductive potential to use effective contraception during treatment with glasdegib and for at least 30 days after the last dose [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.3)].

Advise males of the potential risk of glasdegib exposure through semen and to use condoms with a pregnant partner or a female partner of reproductive potential during treatment with glasdegib and for at least 30 days after the last dose to avoid potential drug exposure [see Warnings and Precautions (5.1), Use in Specific Populations (8.3)].


 

1. DESCRIPTION

Glasdegib is a potent small molecule inhibitor of Smoothened (SMO) for oral use. It is formulated with the maleate salt of glasdegib. The chemical name of glasdegib maleate is 1-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea maleate. The molecular structure is shown below:

Empirical formula: C25H26N6O5 - Molecular weight: 490.51 Daltons

Glasdegib maleate is a white to pale colored powder with pKa values of 1.7 and 6.1. The aqueous solubility of glasdegib maleate is 1.7 mg/mL.

Glasdegib is supplied as a film-coated tablet for oral use containing either 100 mg glasdegib (equivalent to 131.1 mg glasdegib maleate) or 25 mg of glasdegib (equivalent to 32.8 mg glasdegib maleate) together with microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodium starch glycolate, and magnesium stearate as inactive ingredients in the tablet. The film-coating consists of Opadry II® Beige (33G170003) and Opadry II® Yellow (33G120011) containing: hypromellose, titanium dioxide, lactose monohydrate, macrogol, triacetin, iron oxide yellow, and iron oxide red.

2. INDICATIONS AND USAGE

Glasdegib is indicated, in combination with low-dose cytarabine, for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adult patients who are ≥75 years old or who have comorbidities that preclude use of intensive induction chemotherapy.

Limitation of Use: Glasdegib has not been studied in patients with the comorbidities of severe renal impairment or moderate-to-severe hepatic impairment.

3. DOSAGE AND ADMINISTRATION

3.1 Recommended Dose and Schedule

The recommended dose of glasdegib is 100 mg orally once daily on days 1 to 28 in combination with cytarabine 20 mg subcutaneously twice daily on days 1 to 10 of each 28-day cycle in the absence of unacceptable toxicity or loss of disease control. For patients without unacceptable toxicity, treat for a minimum of 6 cycles to allow time for clinical response.

Administer glasdegib with or without food. Do not split or crush glasdegib tablets. Administer glasdegib about the same time each day. If a dose of glasdegib is vomited, do not administer a replacement dose; wait until the next scheduled dose is due. If a dose of glasdegib is missed or not taken at the usual time, administer the dose as soon as possible and at least 12 hours prior to the next scheduled dose. Return to the normal schedule the following day. Do not administer 2 doses of glasdegib within 12 hours.

3.2 Monitoring and Dose Modifications

Assess complete blood counts, electrolytes, renal, and hepatic function prior to the initiation of glasdegib and at least once weekly for the first month. Monitor electrolytes and renal function once monthly for the duration of therapy. Obtain serum creatine kinase levels prior to initiating glasdegib and as indicated clinically thereafter (e.g., if muscle symptoms are reported). Monitor electrocardiograms (ECGs) prior to the initiation of glasdegib, approximately one week after initiation, and then once monthly for the next two months to assess for QTc prolongation. Repeat ECG if abnormal. Certain patients may require more frequent and ongoing ECG monitoring [see Warnings and Precautions (5.2)]. Manage any abnormalities promptly [see Adverse Reactions (6.1)].

See Table 1 for dose modification guidelines for patients who develop an adverse reaction.

Table 1. Recommended Dose Modifications for Adverse Reactions

*Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening.

4. CONTRAINDICATIONS

None.

5. WARNINGS AND PRECAUTIONS

5.1 Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal embryo-fetal developmental toxicity studies, glasdegib can cause embryo-fetal death or severe birth defects when administered to a pregnant woman.

There are no clinical data on the use of glasdegib in pregnant women. In animal embryo-fetal developmental toxicity studies, glasdegib caused embryotoxicity, fetotoxicity and teratogenicity at maternal exposures that were less than the human exposure at the recommended human dose of 100 mg [see Use in Specific Populations (8.1, 8.2), Clinical Pharmacology]. Advise pregnant women of the potential risk to the fetus.

Females of Reproductive Potential

Glasdegib is not recommended for use during pregnancy. Conduct pregnancy testing in female patients of reproductive potential prior to initiating glasdegib treatment. Advise females of reproductive potential to use effective contraception during treatment with glasdegib and for at least 30 days after the last dose. Advise women not to breastfeed during treatment with glasdegib and for at least 30 days after the last dose [see Use in Specific Populations (8.2, 8.3)].

Males

Advise male patients with female partners of the potential risk of exposure through semen and to use effective contraception, including a condom, even after vasectomy, to avoid drug exposure to a pregnant partner or a female partner of reproductive potential during treatment with glasdegib and for at least 30 days after the last dose [see Use in Specific Populations (8.3)].

Blood Donation

Advise patients not to donate blood or blood products while taking glasdegib and for at least 30 days after the last dose of glasdegib because their blood or blood products might be given to a female of reproductive potential.

5.2 QTc Interval Prolongation

Patients treated with glasdegib can develop QTc prolongation and ventricular arrhythmias, including ventricular fibrillation and ventricular tachycardia. Of the 98 evaluable patients treated with glasdegib 100 mg in combination with low-dose cytarabine in the clinical trial, 5% were found to have a QTc interval greater than 500 ms and 4% of patients had an increase from baseline QTc greater than 60 ms. The clinical trial excluded patients with baseline QTc of greater than 470 ms or with a history of long QT syndrome or uncontrolled cardiovascular disease.

Monitor electrocardiograms (ECGs) and electrolytes [see Dosage and Administration (3.2)]. Concomitant use of glasdegib with drugs known to prolong the QTc interval and CYP3A4 inhibitors may increase the risk of QTc interval prolongation [see Drug Interactions (7), Clinical Pharmacology]. In patients with congenital long QT syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval, more frequent ECG monitoring is recommended.

Interrupt glasdegib if QTc increases to greater than 500 ms. Discontinue glasdegib permanently for patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia [see Dosage and Administration (3.2)].

6. ADVERSE REACTIONS

The following clinically significant adverse reaction is described elsewhere in the labeling:

 QT Interval Prolongation [see Warnings and Precautions (5.2)]

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.

The safety profile of glasdegib is based on experience in the BRIGHT AML 1003 study for 111 adults with newly-diagnosed AML and 14 adults with other conditions for which glasdegib is not indicated [see Clinical Studies]. Patients were treated with glasdegib 100 mg daily in combination with low-dose cytarabine (N=84) or low-dose cytarabine alone (N=41). The median duration of treatment in the glasdegib with low-dose cytarabine arm was 83 days (range 3 to 972 days), and the median duration of treatment in the low-dose cytarabine alone arm was 47 days (range 6 to 239 days). The median exposure to glasdegib in the glasdegib with low-dose cytarabine arm was 76 days (range 3 to 954 days). Thirty-two patients (38%) were treated with glasdegib with low-dose cytarabine for at least 6 months and 14 patients (17%) were treated for at least 1 year.

Serious adverse reactions were reported in 79% of patients treated in the glasdegib with low-dose cytarabine arm. The most common (≥5%) serious adverse reactions in patients receiving glasdegib with low-dose cytarabine were febrile neutropenia (29%), pneumonia (23%), hemorrhage (12%), anemia (7%), and sepsis (7%).

Dose reductions associated with adverse reactions were reported in 26% of patients treated with glasdegib with low-dose cytarabine, and the most common reasons (≥2%) for dose reductions due to adverse reactions were muscle spasms (5%), fatigue (4%), febrile neutropenia (4%), anemia (2%), thrombocytopenia (2%), and ECG QT prolonged (2%). Adverse reactions leading to permanent discontinuation were reported in 36% of patients treated with glasdegib with low-dose cytarabine, and the most common (≥2%) reasons for permanent discontinuation were pneumonia (6%), febrile neutropenia (4%), sepsis (4%), sudden death (2%), myocardial infarction (2%), nausea (2%), and renal insufficiency (2%).

Adverse reactions reported in the first 90 days of therapy on the BRIGHT AML 1003 study are shown in Table 2.

Table 2. Adverse Reactions Occurring in ≥ 10% of Patientsa,b Within the First 90 Days of Therapy in BRIGHT AML 1003

Abbreviations: N = number of patients.

Preferred terms were retrieved by applying the Medical Dictionary for Regulatory Activities (MedDRA) version 19.1.

BRIGHT AML 1003 used National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

Adverse reactions include events that commenced within 28 days after the last treatment dose.

a. Adverse reactions with ≥10% incidence in the glasdegib with low-dose cytarabine arm or the low-dose cytarabine arm are included.

b. No Grade 5 events in the glasdegib with low-dose cytarabine or low-dose cytarabine alone arm.

c. Hemorrhage includes petechiae, epistaxis, hematoma, contusion, rectal hemorrhage, anal hemorrhage, ecchymosis, gingival bleeding, hematuria, mouth hemorrhage, purpura, cerebral hemorrhage, eye contusion, eye hemorrhage, gastric hemorrhage, gastrointestinal hemorrhage, hematemesis, hemoptysis, hemorrhage, implant site hematoma, injection site bruising, retroperitoneal hematoma, thrombotic thrombocytopenic purpura, tracheal hemorrhage, conjunctival hemorrhage, disseminated intravascular coagulation, eyelid hematoma, hematochezia, hemorrhage intracranial, hemorrhoidal hemorrhage, lower gastrointestinal hemorrhage, retinal hemorrhage, and subdural hematoma.

d. Fatigue includes asthenia and fatigue.

e. Edema includes edema peripheral, edema, fluid overload, fluid retention, and swelling face.

f. Mucositis includes mucosal inflammation, oropharyngeal pain, stomatitis, anal ulcer, gingival pain, laryngeal inflammation, esophagitis, oral pain, aphthous ulcer, mouth ulceration, and pharyngeal inflammation.

g. Chest pain includes chest pain and non-cardiac chest pain.

h. Musculoskeletal pain includes pain in extremity, arthralgia, back pain, myalgia, musculoskeletal pain, musculoskeletal chest pain, neck pain, and bone pain.

i. Muscle spasms includes muscle spasms and muscle tightness.

j. Abdominal pain includes abdominal pain, abdominal pain upper, and abdominal pain lower.

k. Diarrhea includes diarrhea, colitis, and gastroenteritis.

l. Dyspnea includes dyspnea, hypoxia, bronchospasm, and respiratory failure.

m. Cough includes cough and productive cough.

n. Dysgeusia includes dysgeusia and ageusia.

o. Rash includes rash, pruritus, erythema, skin ulcer, rash maculo-papular, and rash pruritic.

p. Pneumonia includes pneumonia, pneumonia aspiration, and lung infection.

q. Atrial arrhythmia includes atrial fibrillation, bradycardia, tachycardia, and sinus tachycardia.

r. Renal insufficiency includes acute kidney injury, blood creatinine increased, oliguria, and renal failure.

The adverse reactions muscle spasms (4 in 12 patients) and decreased appetite (2 in 10 patients) worsened (i.e. progressed from Grades ≤ 2 to Grade 3 or higher) after the first 90 days of therapy in BRIGHT AML 1003.

Additional clinically-significant adverse reactions occurring in < 10% of patients treated with glasdegib and low-dose cytarabine in BRIGHT AML 1003 include:

 Dental disorders: loose tooth and toothache

 Skin and subcutaneous tissue disorders: alopecia

 Cardiac disorders: QT interval prolonged

Changes in selected post-baseline laboratory values that were observed in patients with newly-diagnosed AML and other conditions for which glasdegib is not indicated in the clinical trial are shown in Table 3.

Table 3. Selected Laboratory Abnormalities (≥ 15% )a Within the First 90 Days of Therapy in BRIGHT AML 1003

Abbreviations: N = number of patients; AST = aspartate aminotransferase; ALT = alanine aminotransferase; CPK = creatinine phosphokinase.

BRIGHT AML 1003 used National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

* Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening.

a. Maximum severity based on the number of patients with available on-study laboratory data.

The following laboratory abnormalities worsened (i.e. progressed from Grades ≤ 2 to Grade 3 or higher) after the first 90 days of therapy in BRIGHT AML 1003:

 hypophosphatemia (8 in 38 patients), creatinine increased (2 in 39 patients), and ALT increased (2 in 40 patients).

7. DRUG INTERACTIONS

Table 4. Drug Interactions with Glasdegib

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on its mechanism of action and findings in animal embryo-fetal developmental toxicity studies, glasdegib can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology]. There are no clinical data on the use of glasdegib in pregnant women to inform of a drug-associated risk of major birth defects and miscarriage. Glasdegib is not recommended for use during pregnancy. Conduct pregnancy testing in female patients of reproductive potential prior to initiating treatment with glasdegib. Report pregnancy exposures to Pfizer at 1-800-438-1985.

In animal embryo-fetal developmental toxicity studies, repeat-dose oral administration of glasdegib during organogenesis at maternal exposures that were less than the human exposure at the recommended dose resulted in embryotoxicity, fetotoxicity and teratogenicity in rats and rabbits (see Data). Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

In embryo-fetal developmental toxicity studies, glasdegib was orally administered to pregnant rats and rabbits at doses up to 100 mg/kg/day during the period of organogenesis. Glasdegib resulted in embryo-fetal lethality (e.g., increased postimplantation loss and decreased numbers of live fetuses) in rats and rabbits at 50 mg/kg/day and 5 mg/kg/day, respectively, at maternal exposures approximately 4-times and 3-times the human exposure at the recommended dose [based on Cmax (rat) and AUC (rabbit)]. Doses of ≥ 10 mg/kg in rat [approximately 0.6-times the human exposure (Cmax) at the recommended dose] and ≥ 5 mg/kg in rabbit resulted in fetal developmental abnormalities and malformations consisting of craniofacial malformations, malformed limbs, paws/digits, trunk and tail, dilation of brain, malpositioned/malformed eyes, misshapen head, small tongue, absent palate, teeth and viscera, diaphragmatic hernia, edema, heart defects, rib and vertebral abnormalities, malformed or absent structures in the appendicular skeleton.

8.2 Lactation

Risk Summary

There are no data on the presence of glasdegib or its active metabolites in human milk, the effects of the drug on the breastfed child, or its effect on milk production. Because of the potential for serious adverse reactions in a breastfed child from glasdegib, advise women who are taking glasdegib not to breastfeed or provide breast milk to infants or children during treatment with glasdegib and for at least 30 days after the last dose.

8.3 Females and Males of Reproductive Potential

Glasdegib can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Conduct pregnancy testing in females of reproductive potential within 7 days prior to initiating therapy with glasdegib.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with glasdegib and at least 30 days after the last dose.

Males

It is not known if glasdegib is present in semen. Advise males of the potential risk of exposure through semen and to use effective contraception, including a condom, even after a vasectomy, to avoid drug exposure to a pregnant partner or a female partner of reproductive potential during treatment with glasdegib and for at least 30 days after the last dose. Advise males to not donate semen during treatment with glasdegib for at least 30 days after the last dose [see Nonclinical Toxicology].

Infertility

Males

Based on findings in repeat-dose animal toxicity studies in rats, glasdegib may impair fertility in males of reproductive potential. Some effects on male reproductive organs did not recover [see Nonclinical Toxicology]. Men should seek advice on effective fertility preservation before treatment.

8.4 Pediatric Use

The safety and effectiveness of glasdegib have not been established in pediatric patients. In repeat-dose toxicity studies in rats, oral administration of glasdegib resulted in adverse changes in growing bone, teeth, and testis. Effects on bone consisted of partial to complete closure of the epiphyseal plate. Effects in growing incisor teeth included degeneration/necrosis of ameloblasts, and complete tooth loss with oral ulceration. Reproductive tissue toxicity was evidenced by testicular degeneration and hypospermatogenesis. These effects in bone, teeth and testis were observed after administration of glasdegib for 26 weeks at greater than or equal to 50 mg/kg/day corresponding to approximately 6.6-times the steady state AUC in patients at the recommended human dose.

8.5 Geriatric Use

Of the total number of subjects in clinical studies of glasdegib with low-dose cytarabine (N=88), 98% of the patients were age 65 years or older and 60% of the patients were age 75 years or older. There were insufficient patients younger than age 65 years to determine differences in adverse reactions reported from patients older than 65.

9. OVERDOSAGE

There is no specific antidote for glasdegib. Management of glasdegib overdose should include symptomatic treatment and ECG monitoring.

Glasdegib has been administered in clinical studies up to a dose of 640 mg/day. At the highest dosage the adverse events reported were nausea, vomiting, dehydration, fatigue and dizziness.

10. MECHANISM OF ACTION

Glasdegib is an inhibitor of the Hedgehog pathway. Glasdegib binds to and inhibits Smoothened, a transmembrane protein involved in hedgehog signal transduction.

In a murine xenotransplant model of human AML, glasdegib in combination with low-dose cytarabine, inhibited increases in tumor size and reduced the percentage of CD45+/CD33+ blasts in the marrow to a greater extent than glasdegib or low-dose cytarabine alone.

11. PHARMACODYNAMICS

Cardiac Electrophysiology

The effect of glasdegib administration on corrected QT interval (QTc) was evaluated in a randomized, single-dose, double-blind, 4-way crossover, placebo- and open-label moxifloxacin-controlled study in 36 healthy subjects. At therapeutic plasma concentrations for the recommended dose, achieved with a single dose of 150 mg glasdegib, the largest placebo and baseline-adjusted QTc interval change was 8 ms (90% CI: 6, 10 ms). At a two-fold therapeutic plasma concentration, achieved with a single dose of 300 mg glasdegib, the QTc change was 13 ms (90% CI: 11, 16 ms). Glasdegib is associated with concentration-dependent QTc prolongation.

12. PHARMACOKINETICS

Glasdegib at 5 mg to 600 mg once daily (0.05 to 6 times the recommended dose) result in a dose proportional increase in glasdegib peak concentrations (Cmax) and area under the curve over the dosing interval (AUCtau). Steady-state plasma levels are reached by 8 days of daily dosing. The median accumulation ratio of glasdegib ranged from 1.2 to 2.5 following once-daily dosing.

At glasdegib 100 mg once daily, the geometric mean (geometric coefficient of variation, % CV) of glasdegib Cmax was 1252 ng/mL (44%) and AUCtau was 17210 ng*hr/mL (54%) in patients with cancer.

Absorption

The mean absolute bioavailability of glasdegib is 77%. Following 100 mg once daily dosing, glasdegib median time to peak concentrations (Tmax) at steady-state ranged from 1.3 hours to 1.8 hours.

Effect of Food: A high-fat, high-calorie meal (total 800-1000 calories: 500-600 fat calories, 250 carbohydrate calories and 150 protein calories) reduced area under the curve over time to infinity (AUCinf) by 16% and Cmax by 31%.

Distribution

Glasdegib is 91% bound to human plasma proteins in vitro. The geometric mean (%CV) apparent volume of distribution (Vz/F) was 188 L (20%) in patients with hematologic malignancies.

Elimination

Glasdegib has a mean ( SD) half-life of 17.4 h (3.7) and geometric mean (%CV) apparent clearance of 6.45 L/h (25%) following 100 mg once daily dosing in patients with hematologic malignancies.

Metabolism

Glasdegib is primarily metabolized by the CYP3A4 pathway, with minor contributions by CYP2C8 and UGT1A9. Glasdegib accounts for 69% of the total circulating drug related material in plasma.

Excretion

Following a single oral dose of 100 mg radiolabeled glasdegib, 49% (17% unchanged) of the administered dose was eliminated in the urine and 42% (20% unchanged) of the administered dose was eliminated in the feces.

Specific Populations

Age (25 to 92 years), sex, race (White, Black, Asian), body weight (43.5 to 145.6 kg), mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1-1.5 x ULN and any AST) or mild to moderate renal impairment (creatinine clearance [CLcr] 30-89 mL/min) did not have clinically meaningful effects on the pharmacokinetics of glasdegib. The effect of moderate (total bilirubin 1.5-3 x ULN and any AST) and severe (total bilirubin > 3 x ULN and any AST) hepatic impairment or severe renal impairment (CLcr 15-29 mL/min) on glasdegib pharmacokinetics is unknown.

Drug Interaction Studies

Clinical Studies

Effect of Strong CYP3A4 Inhibitors on Glasdegib:

Coadminstration of ketoconazole (a strong inhibitor of CYP3A4) with glasdegib increased the glasdegib AUCinf by 2.4-fold and Cmax by 1.4-fold over glasdegib given alone [see Drug Interactions (7)].

Effect of Strong CYP3A4 Inducers on Glasdegib:

Coadminstration of rifampin (a strong inducer of CYP3A4) with glasdegib decreased glasdegib AUCinf by 70% and Cmax by 35% [see Drug Interactions (7)].

Effect of Gastric Acid Reducing Agents on Glasdegib:

Coadministration of rabeprazole (a proton pump inhibitor) with glasdegib did not alter glasdegib AUCinf but decreased Cmax by 20%.

In Vitro Studies

Effect of Glasdegib on Cytochrome P450 (CYP) Substrates:

Glasdegib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A, and does not induce CYP1A2, CYP2B6, and CYP3A in vitro.

Effect of Transporters on Glasdegib:

Glasdegib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).

Effect of Glasdegib on Transporters:

Glasdegib inhibits P-gp, BCRP, multidrug and toxin extrusion (MATE) protein 1, and MATE-2K, but not organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, and organic cation transporter (OCT)2 in vitro.

13. HOW SUPPLIED/STORAGE AND HANDLING

How Supplied:

DAURISMO is supplied in the following strengths and package configurations:

Storage and Handling:

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Rx only

Rev 11/18