Actions of Dalalone DP in details
Pharmacology: Pharmacodynamics: Mechanism of Action: Dalalone DP, a potent corticosteroid, has been shown to suppress inflammation by inhibiting multiple inflammatory cytokines resulting in decreased edema, fibrin deposition, capillary leakage and migration of inflammatory cells.
Clinical Studies: The efficacy of Dalalone DP was assessed in two, multicenter, double-masked, randomized, parallel studies.
Following a single injection, Dalalone DP for the treatment of macular edema following branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO) demonstrated the following clinical results for the percent of patients with ≥15 letters of improvement from baseline in best-corrected visual acuity (BCVA): See Table 1.
In each individual study and in a pooled analysis, time to achieve ≥15 letters (3-line) improvement in BCVA cumulative response rate curves were significantly faster with Dalalone DP compared to sham (p<0.01), with Dalalone DP-treated patients achieving a 3-line improvement in BCVA earlier than sham-treated patients.
The onset of a ≥15 letter (3-line) improvement in BCVA with Dalalone DP occurs within the first two months after implantation in approximately 20-30% of subjects. The duration of effect persists approximately one to three months after onset of this effect.
Pharmacokinetics: Plasma concentrations were obtained from 21 patients in the two, 6-month phase 3 efficacy studies prior to dosing and on days 7, 30, 60, and 90 following the intravitreal implant containing 0.35 mg or 0.7 mg Dalalone DP. In both studies, the majority of plasma Dalalone DP concentrations were below the lower limit of quantitation (LLOQ=50 pg/mL). Plasma Dalalone DP concentrations from 10 of 73 samples in the 0.7 mg dose group and from 2 of 42 samples in the 0.3 mg dose group were above the LLOQ, ranging from 82 pg/mL to 94 pg/mL. The highest plasma concentration value of 94 pg/mL was observed in one subject from the 0.7 mg group. Plasma Dalalone DP concentration did not appear to be related to age, body weight, or sex of patients.
In an in vitro metabolism study, following the incubation of [14C]-Dalalone DP with human cornea, iris-ciliary body, choroid, retina, vitreous humor, and sclera tissues for 18 hours, no metabolites were observed.
Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: No adequate studies in animals have been conducted to determine whether Dalalone DP (Dalalone DP intravitreal implant) has the potential for carcinogenesis.
Although no adequate studies have been conducted to determine the mutagenic potential of Dalalone DP, Dalalone DP has been shown to have no mutagenic effects in bacterial and mammalian cells in vitro or in the in vivo mouse micronucleus test.
How should I take Dalalone DP?
Dalalone DP is injected into a muscle or a vein. A healthcare provider will give you this injection.
Dalalone DP is usually given by injection only if you are unable to take the medicine by mouth.
Your dose needs may change due to surgery, illness, stress, or a medical emergency. Tell your doctor about any such situation that affects you.
Dalalone DP can affect the results of certain medical tests. Tell any doctor who treats you that you are using Dalalone DP.
You may have withdrawal symptoms if you stop using Dalalone DP suddenly after long-term use. Ask your doctor before stopping the medicine.
Store at room temperature away from moisture and heat.
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Dalalone DP administration
Oral: Administer with meals to help prevent GI upset. May administer antacids between meals to help prevent peptic ulcers.
Oral concentrate: Use only the calibrated dropper provided. Draw dose into dropper; squeeze dropper contents into a liquid or semi-solid food (water, juice, soda or soda-like beverage, applesauce, pudding). Gently stir for a few seconds. Administer the entire mixture immediately. Do not store for future use.
IV: May administer 4 mg/mL or 10 mg/mL concentration undiluted over ≤1 minute (Gahart 2015). Rapid administration may be associated with perineal irritation (especially with higher doses); consider further dilution and administration by IV intermittent infusion over 5 to 15 minutes (Allan 1986; Neff 2002; Perron 2003; Singh 2011).
IM: Administer 4 mg/mL or 10 mg/mL concentration by deep IM injection.
Intra-articular or soft tissue injection: Note: Dalalone DP sodium phosphate (a short-acting solution) in the 4 mg/mL concentration is the only formulation available for intra-articular or soft tissue injections. Dalalone DP acetate (a long-acting suspension) is not available in the United States or Canada. Therefore, other glucocorticoids, such as triamcinolone acetonide or methylprednisolone acetate, are used more commonly for intra-articular or soft-tissue injection (Centeno 1994; Roberts 2019).
Intra-articular: Administer into affected joint using the 4 mg/mL concentration only.
Soft tissue: Administer into affected tissue using the 4 mg/mL concentration only.
Intralesional injection: Note: Dalalone DP sodium phosphate (a short-acting solution) in the 4 mg/mL concentration is the only formulation available for intralesional injections. Another glucocorticoid, triamcinolone acetonide, is used more commonly for intralesional injection (Mathes 2019).
Intralesional: Administer into affected area using the 4 mg/mL concentration only.
Dalalone DP pharmacology
Mechanism of Action
Dalalone DP is a corticosteroid with anti-inflammatory effects and low mineralocorticoid activity. The precise mechanism of action in multiple myeloma is unknown. Dalalone DP induces apoptosis of multiple myeloma cells.
Pharmacodynamics
Following oral administration of a single dose of Dalalone DP tablet to healthy subjects, the decrease in mean baseline cortisol concentration was maximal by 12 hours post-dose, with mean cortisol concentrations returning to near baseline approximately 3 days after drug administration.
Pharmacokinetics
The pharmacokinetics of oral Dalalone DP were dose proportional between single dose of 0.5 to 40 mg. Following a single Dalalone DP dose of 20 mg, the geometric mean (coefficient of variation, %CV) Dalalone DP peak concentrations (Cmax) was 247 ng/mL (31%) and area under the curve over time to infinity (AUCinf) was 1271 ng.hr/mL (31%) in subjects.
Absorption
Following 20 mg dose of Dalalone DP, Dalalone DP median time to peak concentrations (Tmax) was 1 hour (range: 0.5 to 4 hours).
Effect of Food
A high-fat, high-calorie (total 800-1000 calories: approximately 60% from fat, 25% from carbohydrate and 15% from protein) meal had no effect on AUCinf and decreased Cmax by 23% of a single 20 mg dose of Dalalone DP.
Distribution
Dalalone DP is about 77% bound to human plasma proteins in vitro.
Elimination
The mean terminal half-life (coefficient of variation) of Dalalone DP is 4 hours (18%) and oral clearance (CL/F) was 15.7 L/hr following a single dose of Dalalone DP.
Metabolism
Dalalone DP is metabolized by CYP3A4.
Excretion
Renal excretion of Dalalone DP is less than 10% of total body clearance. Less than 10% of Dalalone DP is excreted in the urine.
Specific Populations
The effect of baseline renal and hepatic impairment on the pharmacokinetics of Dalalone DP has not been studied.
Drug Interactions Studies
Effect of Strong and Moderate CYP3A4 Inhibitors
Coadministration of itraconazole (strong CYP3A4 inhibitor: 200 mg once daily x 4 days) with a single dose of oral Dalalone DP (4.5 mg) increased Dalalone DP AUCinf by 3.7-fold.
Coadministration of aprepitant (moderate CYP3A4 inhibitor: 125 mg on Day 1, and 80 mg once daily on Days 2 to 5) with oral Dalalone DP (20 mg on Day 1, and 8 mg once daily on Day 2-5) increased Dalalone DP AUCinf by 2.2 -fold on Day 1 and 5.
Effects of Other Anti-Myeloma Products
Coadministration of thalidomide, lenalidomide, pomalidomide, ixazomib, bortezomib or carfilzomib with Dalalone DP is not expected to affect the pharmacokinetics of Dalalone DP.
Effect on Other Anti-Myeloma Products
Coadministration of Dalalone DP had no effect on the mean AUCinf of lenalidomide, pomalidomide, ixazomib, and bortezomib.
Coadministration of Dalalone DP with carfilzomib or thalidomide is not expected to affect the pharmacokinetics of these drugs, as these drugs are not primarily metabolized by CYP3A4 in vitro.
For additional information on the drug interaction studies with Dalalone DP and other anti-myeloma products, refer to the Prescribing Information of the other anti-myeloma products.
References
- DailyMed. "DEXAMETHASONE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
- NCIt. "Dexamethasone: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
- EPA DSStox. "Dexamethasone: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).
Reviews
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Information checked by Dr. Sachin Kumar, MD Pharmacology
