Active IngredientTADALAFIL

NDA filling and Orange book information

Drug Name FDA Application No. Company Dosage Form;Route Strength RLD Strength Original Approval or
Tentative Approval Date
Exclusivity
Expiration
(NCE)
Exclusivity
Expiration
(ODE)
Chemical
Type
Review
Classification
Marketing
Status
TE Code
CIALIS NDA#021368 LILLY TABLET;ORAL 2.5MG, 5MG, 10MG, 20MG 2.5MG, 5MG, 10MG, 20MG November 21, 2003 - - 1 New molecular entity (NME) STANDARD Prescription None

API Information

Parameters Details
Structural Formula structural formula
Chemical NamePyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione,6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-,(6R-trans)-(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-[3,4-(methylenedioxy)phenyl]-pyrazino[1',2':1,6] pyrido [3,4-b]indole-1,4-dione
CAS No171596-29-5
Molecular Formula C22H19N3O4
Molecular Weight389.41
Appearancecrystalline solid
SolubilityIt is practically insoluble in water and very slightly soluble in ethanol. It does not possess any ionisable groups in the pH range of 1-11 and, subsequently, does not demonstrate any changes in solubility in aqueous buffers in that range. It is freely soluble only in solvents such as dimethylsulfoxide and dimethylformamide.
Water Solubility0.25 mg/mL
PolymorphismThis molecule has 2 chiral centres, and therefore four different stereoisomers may be found. The molecule obtained in the process described is in the RR form.. Crystallization studies show that tadalafil does not exhibit polymorphism.
pKa (Strongest Acidic)15.17
pKa (Strongest Basic)-4.2
Log P1.7
IdentificationIR, HPLC
DegradationNo degradation or physical changes were observed in tadalafil at its solid state under heat, humidity and light exposure. However, degradation was observed in solutions and suspensions of the active substance at different pH values, light and oxidative conditions.
HygroscopicHygroscopic
Photostability study-
Melting Point301-302 °C
BCS ClassII
Manufacture of APITadalafil drug substance is synthesised by a 3-step process, with purifications following each step. After the final drying, the resulting solid is milled to meet the established particle size specification.”

Label Information

Parameters Details
Indications and Usage CIALIS® is indicated for the treatment of erectile dysfunction (ED).
CIALIS is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH).
Limitation of Use: If CIALIS is used with finasteride to initiate BPH treatment, such use is recommended for up to 26 weeks because the incremental benefit of CIALIS decreases from 4 weeks until 26 weeks, and the incremental benefit of CIALIS beyond 26 weeks is unknown.
Dosage and Administration The recommended starting dose for Erectile Dysfunction 10 mg, taken prior to anticipated sexual activity. The dose may be increased to 20 mg or decreased to 5 mg, based on individual efficacy and tolerability. The maximum recommended dosing frequency is once per day in most patients.
The recommended dose of CIALIS for once daily use in Benign Prostatic Hyperplasia is 5 mg, taken at approximately the same time every day.
CIALIS may be taken without regard to food.
Refer FDA Label for more information.
Mechanism of action CIALIS (tadalafil) is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).
Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosal smooth muscle. This response is mediated by the release of nitric oxide (NO) from
nerve terminals and endothelial cells, which stimulates the synthesis of cGMP in smooth muscle cells. Cyclic GMP causes smooth muscle relaxation and increased blood flow into the corpus cavernosum. The inhibition of phosphodiesterase type 5 (PDE5) enhances erectile function by increasing the amount of cGMP. Tadalafil inhibits PDE5. Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibition of PDE5 by tadalafil has no effect in the absence of sexual stimulation.
The effect of PDE5 inhibition on cGMP concentration in the corpus cavernosum and pulmonary arteries is also observed in the smooth muscle of the prostate, the bladder and their vascular supply. The mechanism for reducing BPH
symptoms has not been established.
Studies in vitro have demonstrated that tadalafil is a selective inhibitor of PDE5. PDE5 is found in the smooth muscle of the corpus cavernosum, prostate, and bladder as well as in vascular and visceral smooth muscle, skeletal muscle, urethra, platelets, kidney, lung, cerebellum, heart, liver, testis, seminal vesicle, and pancreas.
Absorption Over a dose range of 2.5 to 20 mg, tadalafil exposure (AUC) increases proportionally with dose in healthy subjects. Steady-state plasma concentrations are attained within 5 days of once per day dosing and exposure is approximately 1.6-fold greater than after a single dose.
After single oral-dose administration, the maximum observed plasma concentration (Cmax) of tadalafil is achieved between 30 minutes and 6 hours (median time of 2 hours). Absolute bioavailability of tadalafil following oral dosing has not been determined.
Food Effect The rate and extent of absorption of tadalafil are not influenced by food; thus CIALIS may be taken with or without food.
Distribution The mean apparent volume of distribution following oral administration is approximately 63 L, indicating that tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil in plasma is bound to proteins.
Less than 0.0005% of the administered dose appeared in the semen of healthy subjects.
Metabolism Tadalafil is predominantly metabolized by CYP3A4 to a catechol metabolite. The catechol metabolite undergoes extensive methylation and glucuronidation to form the methylcatechol and methylcatechol glucuronide conjugate, respectively. The major circulating metabolite is the methylcatechol glucuronide. Methylcatechol concentrations are less than 10% of glucuronide concentrations. In vitro data suggests that metabolites are not expected to be pharmacologically active at observed metabolite concentrations.
Elimination The mean oral clearance for tadalafil is 2.5 L/hr and the mean terminal half-life is 17.5 hours in healthy subjects. Tadalafil is excreted predominantly as metabolites, mainly in the feces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose).
Peak plasma time (Tmax)2 hours
Half life17.5 hours
Bioavailability-
Age, gender Healthy male elderly subjects (65 years or over) had a lower oral clearance of tadalafil, resulting in 25% higher exposure (AUC) with no effect on Cmax relative to that observed in healthy subjects 19 to 45 years of age. No dose adjustment is warranted based on age alone. However, greater sensitivity to medications in some older individuals should be considered.

API Drug Master File

DMF Status Type Submit Date Holder
20640 A II June 15, 2007 MYLAN LABORATORIES LTD
20884 A II September 26, 2007 TEVA PHARMACEUTICAL INDUSTRIES LTD
20962 A II October 22, 2007 ORCHID PHARMA LTD
21209 A II January 7, 2008 DR REDDYS LABORATORIES LTD
22530 A II February 16, 2009 GLENMARK PHARMACEUTICALS LTD
22707 A II March 31, 2009 ALEMBIC PHARMACEUTICALS LTD
22771 I II May 13, 2009 SUN PHARMACEUTICAL INDUSTRIES LTD
24206 A II September 28, 2010 SMS PHARMACEUTICALS LTD
24590 A II January 31, 2011 ZAKLADY FARMACEUTYCZNE POLPHARMA SA
25355 I II October 5, 2011 AMI LIFE SCIENCES PRIVATE LTD
25513 A II November 15, 2011 MSN ORGANICS PRIVATE LTD
25694 A II January 18, 2012 AUROBINDO PHARMA LTD
25815 A II February 22, 2012 APOTEX PHARMACHEM INDIA PVT LTD
26139 A II April 5, 2013 MACLEODS PHARMACEUTICALS LTD
26786 A II February 8, 2013 MSN ORGANICS PRIVATE LTD
27246 A II June 28, 2013 JUBILANT GENERICS LTD
27479 A II September 27, 2013 ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
29027 A II February 3, 2015 UNICHEM LABORATORIES LTD
29316 A II June 24, 2015 SUN PHARMACEUTICAL INDUSTRIES LTD
29595 A II September 30, 2015 GLENMARK PHARMACEUTICALS LTD
29765 A II December 4, 2015 HONOUR LAB LTD
30608 A II June 10, 2016 AMOLI ORGANICS PVT LTD
30860 A II September 5, 2016 QILU TIANHE PHARMACEUTICAL CO LTD

Innovator Formulation Information

Parameters Details
Strength 2.5MG 5MG 10MG 20MG
Excipients used croscarmellose sodium, hydroxypropyl cellulose,
lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, talc
Composition of coating material lactose monohydrate,
hypromellose, triacetin, titanium dioxide (E171), iron oxide yellow (E172), iron oxide red (E172), talc.
lactose monohydrate,
hypromellose, triacetin,
titanium dioxide (E171),
iron oxide yellow (E172),
talc.
Composition of caspule shell -
Pharmaceutical Development The development pharmaceutics have taken into consideration the physicochemical characteristics of
the active drug substance such as poor aqueous solubility, hygroscopic properties, stability, particle size, and biopharmaceutical issues such as dissolution rate.
The formulation contains stable, milled tadalafil drug substance and incorporated into a wet granulation to consistently produce tablets with good homogeneity and the desired dissolution characteristics. To achieve a dosage form with a rapid therapeutic onset, the excipients included in the formulation were selected and adjusted to promote rapid absorption. This combination of ingredients has produced a material (free-flowing, easily wetted and compressible) as well as tablets that possess the desired physical characteristics of low friability, acceptable hardness and rapid disintegration.
Manufacture of the product The process for the manufacturing of the finished product follows conventional pharmaceutical practices, which includes aqueous wet granulation, sizing, and drying steps of tadalafil with hydrophilic excipients, followed by dry sizing of the granulate and then blending with additional excipients. The final blend is compressed into tablets, which are subsequently coated.
Validation of the manufacturing process was performed on 3 full-scale batches. For each one of those batches, specific conditions at each stage were investigated (mixing speeds, times, screen size, temperature, rotation speeds, etc.). Results indicate that the process is adequately validated and controlled.
Tablet / Capsule Image 2.5MG 5MG 10MG 20MG
Appearance Almond-shaped, tablets debossed with “C 2 1/2” on one side and plain on other side. Almond-shaped, tablets debossed with “C 5” on one side and plain on other side. Almond-shaped, tablets debossed with “C 10” on one side and plain on other side. Almond-shaped, tablets debossed with “C 20” on one side and plain on other side.
Imprint code / Engraving / Debossment "C 2 1/2" "C 5" "C 10" "C 20"
Score no score no score no score no score
Color Yellow Yellow Yellow Yellow
Shape OVAL (Almond) OVAL (Almond) OVAL (Almond) OVAL (Almond)
Dimension - - 11mm 12mm
Mfg by Eli Lilly and Company (US, EU)
Mfg for Eli Lilly and Company (US, EU)
Marketed by Eli Lilly and Company (US, EU)
Distributed by Eli Lilly and Company (US, EU)

Orange Book Listed Patent

Application No. Prod No Patent No Patent Expiration Drug Substance Claim Drug Product Claim Patent Use Code Delist Requested Link
N021368 4 5859006 21-Nov-17 DS DP - - Download
N021368 4 6140329 11-Jul-16 - DP U-155 - Download
N021368 4 6821975 19-Nov-20 DS DP U-533 U-614 - Download
N021368 4 6943166 26-Apr-20 - - U-155 - Download
N021368 4 7182958 26-Apr-20 - DP U-155 - Download

Office of Generic Drug Media

USP Apparatus Speed (RPMs) Medium Volume (mL) Recommended Sampling Times (minutes) Date Updated
II (Paddle) 50 0.5% Sodium Lauryl Sulfate 1000 10, 20, 30 and 45 January 26, 2006

Packaging System

Market EU US
Strength Packaging System
2.5MG Aluminium/PVC blisters in cartons of 28 film-coated tablets. Blisters of 2 x 15
5MG Aluminium/PVC blisters in cartons of 14, 28 or 84 film-coated tablets Bottles of 30
Blisters of 2 x 15
10MG Aluminium/PVC blisters in cartons of 4 film-coated tablets. Bottles of 30
20MG Aluminium/PVC blisters in cartons of 2, 4, 8, 10 and 12 film-coated tablets. Bottles of 30
Storage Store in the original package in order to protect from moisture. Do not store above 30°C. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep out of reach of children.

Innovator Product Information

Label Link
FDA label Download
FDA chemistry review Download
FDA Pharmacology Review(s) Download
FDA Clinical Pharmacology Biopharmaceutics Review(s) Download
FDA BE Recommendation Download
European Public Assessment Report Download

Product Available

Territory Brand name / Generic company name Link
EU CIALIS Download
UK CIALIS Download
US ALEMBIC PHARMS LTD (ANDA #204809)
US AUROBINDO PHARMA LTD (ANDA #206285)
US CIALIS Download
US SUN PHARMA GLOBAL (ANDA #208934)
US SYNTHON PHARMS (ANDA #200630)
US WATSON LABS INC (ANDA #205885)

Remarks

-

References

www.accessdata.fda.gov, www.drugbank.ca, www.ema.europa.eu, www.medicines.org.uk, dailymed.nlm.nih.gov

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