Archive for August, 2015

Atorvastatin

Aug 16 2015 Published by under Medicines

What is Atorvastatin (Lipitor)?

Atorvastatin is an anticholesteremic pharmaceutical compound, which aids to reduce blood cholesterol and triglycerides (fatty acids) levels.

Atorvastatin : Structure and chemical information..

Atorvastatin : Structure and chemical information.

What is the generic and brand name of Drug?

  • The drug is available under generic name Atorvastatin and brand name Lipitor.
  • The drug was originally discovered by Bruce Roth and coworkers at Parke-Davis.
  • Pfizer is responsible for the manufacture and distribution of Atorvastatin. During 1996-2012, Atorvastatin (Liptor) became the world’s best-selling drug and acquired more than US $125 billion.
  • Pfizer’s patent expired in 2011 and then two other pharmaceuticals companies, Watson Pharmaceuticals and Ranbaxy Laboratories have started manufacturing of the Atorvastatin.

What is the source of the drug (natural or synthetic)?

  • Atorvastatin is a synthetic (man-made) pharmaceutical anti-hyperlipidemic/ anticholesteremic drug commonly known as Statins.

Why is this medication prescribed?

  • Atorvastatin is an anti-hyperlipidemic (lipid lowering) class of drug which reduces the amount of fatty or lipid substances such as cholesterol and triglycerides from the body.
  • Usually, Atorvastatin is used in combination of low fat diet or exercise or other drugs as adjunctive therapy to reduce elevated total cholesterol, low-density lipoproteins (LDL) cholesterol and triglycerides in the blood and to increase the amount of HDL (high-density lipoprotein; a type of fatty substance that decreases the risk of heart disease) in the blood.
  • Atorvastatin is used in primary prevention in individuals with multiple risk factors for coronary heart disease (CHD) and as secondary prevention in individuals with CHD to decrease the risk of heart attack, stroke, myocardial infarction, unstable angina, and revascularization.
  • The drug is usually prescribed for adult patients with primary hypercholesterolemia or mixed dyslipidemia (Fredrickson Types IIa and IIb) and hypertriglyceridemia (Fredrickson Types IV).
  • Atorvastatin is also prescribed for the treatment of dysbetalipoproteiemia (Fredrickson Types III) and combined hyperlipidemia.
  • It is also used in prophylaxis of myocardial infarction and stroke in patients with type II diabetes.
  • Unique structure, hepatic selectivity and long half-life provide greater LDL-lowering potency to Atorvastatin in comparison with other HMG-CoA reductase inhibitors. By decreasing LDL-C and TG and increasing HDL-C, Atorvastatin significantly lowers the risk of cardiovascular morbidity and mortality.

Pharmacophore structure: Information about the chemical structure of the drug?

Atorvastatin chemically belongs to the class of organic compounds known as Diphenylpyrroles, a heterocyclic aromatic molecule which contains pyrrole ring attached to two phenyl groups. The detailed chemical classification of Atorvastatin is as follows.

Kingdom Organic compounds
Super Class Organoheterocyclic compounds
Class Pyrroles
Sub Class Substituted Pyrroles
Direct Parent Diphenylpyrroles

Chemical information of the drug

  • Atorvastatin selectively brings about the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.
  • Atorvastatin is a synthetic aromatic heteromonocyclic compound with a molecular formula C33H34FN2O5 and molecular weight of 63Da.
  • Chemically, Atorvastatin is known as 7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-(propan-2-yl)-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate.
  • Atorvastatin is available as a calcium trihydrate salt known as Atorvastatin calcium.
  • Atorvastatin calcium is chemically known as 7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-(propan-2-yl)-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate, calcium salt (2:1) trihydrate.
  • Chemically Atorvastatin calcium is represented by the empirical formula of (C33H34FN2O5)2Ca•3H2O and molecular weight of 42 Da.
  • Atorvastatin calcium is a white to off-white, crystalline powder and has a water solubility of 000495 mg/mL.
  • Atorvastatin calcium is very slightly soluble in acetonitrile and distilled water, slightly soluble in ethanol while freely soluble in methanol.
  • The melting point of Atorvastatin is 2-160.7°C.

What is the available strength of the drug?

  • Atorvastatin is available for oral administration in tablet form.
  • It is available in different dosage strength of 10 mg, 20 mg, 40 mg and 80 mg/tablet.
  • The tablet is white in colour, film coated and elliptical in shape.
  • Atorvastatin tablets of 10 mg, 20 mg, 40 mg and 80 mg are coded with “10”, “20”, “40” and “80” on one side responding to the dose of the drug and “PD 155”, “PD 156”, “PD 157” and “PD 158” on another side respectively.
  • Each tablet contains Atorvastatin calcium as an active component and inactive ingredients such as calcium carbonate, USP; croscarmellose sodium, NF; candelilla wax, FCC; microcrystalline cellulose, NF; magnesium stearate, NF; hydroxypropyl cellulose, NF; lactose monohydrate, NF; Opadry White YS-1-7040 ((hypromellose, polyethylene glycol, talc, titanium dioxide); polysorbate 80, NF; simethicone emulsion.

How the medicine works (mode of action)?

  • Atorvastatin primarily acts in the liver, where it increases the hepatic uptake of dietary cholesterol and reduces the hepatic cholesterol levels and plasma cholesterol levels.
  • Atorvastatin is a selective, competitive inhibitor of the HMG-CoA reductase enzyme of cholesterol biosynthesis pathway.
  • HMG-CoA reductase is involved in the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate. It is the key rate-limiting enzyme in cholesterol biosynthesis via the mevalonate pathway.
  • Due to the inhibition of HMG-CoA reductase, hepatic cholesterol level decreases which stimulate the upregulation of hepatic low-density lipoproteins cholesterol (LDL-C) receptors on cell surface.
  • As a result hepatic uptake of low-density lipoproteins cholesterol increases and serum LDL cholesterol concentration decreases. Atorvastatin also decreases the level of very low density lipoprotein cholesterol (VLDL-C) and triglycerides (TG) and produce variable increase in high density lipoprotein cholesterol (HDL-C) and apolipoprotein A-1.
Atorvastatine mode of action.

Atorvastatine mode of action.

What are the recommended doses of Atorvastatin?

Atorvastatin is available in tablet form and the dosage varies depending upon the diseases status.

Adult dose:

  • Prevention of cardiovascular diseases:
  • 10 mg-80 mg once a day orally.
  • Primary hypercholesterolemia (heterozygous familial and non-familial):
  • Initial dose: 10 mg-20 mg once a daily or 40 mg once daily for those patients who require large reduction in LDL-C.
  • Maintenance dose: 10 mg-80 mg once a day depending on the condition of the disease.
  • Homozygous familial hypercholesterolemia:
  • 10 mg-80 mg once a daily.
  • Dyslipidemia (Fredrickson type IIa and IIb):
  • Initial dose: 10 mg-20 mg once a daily.
  • Maintenance dose: 10 mg-80 mg once a day depending on the condition of disease.
  • Hypertriglyceridemia (Fredrickson type IV):
  • Initial dose: 10 mg once a day.
  • Maintenance dose: 10 mg-80 mg once a day.
  • Primary dysbetalipoproteinemia (Fredrickson type III):
  • 10 mg-80 mg once a day orally.

Paediatric dose:

  • Heterozygous Familial Hypercholesterolemia:
  • <10 years: Not recommended.
  • ≥10 years: 10 mg once a day orally (maximum 20 mg).
  • Heterozygous Familial Hypercholesterolemia:
  • <10 years: Not recommended.
  • ≥10 years: 10 mg-40 mg once a day orally.

However, the represented dose schedule can vary according to patient response and can change on the basis of repeated lipid determinations at 4 to 8 weeks interval. Treatment should continue until disease progression or unacceptable toxicity occurs.

When should I discontinue, withhold or modify the dose of Atorvastatin?

  • Do not use the medicine if you are allergic to Atorvastatin or any of the ingredients present in the Atorvastatin product.
  • The use of Atorvastatin is contraindicated or temporarily withheld in case of severe renal impairment.
  • The drug is also not recommended in patients with hepatic encephalopathy, hepatitis, cholestasis and jaundice.
  • Atorvastatin is contraindicated with the use of drugs that decrease the level of endogenous steroid hormone such as Ketoconazole, Cimetidine and Spironolactone.
  • Atorvastatin also contraindicated with HIV protease inhibitor drugs (Darunavir, Lopinavir, Ritonavir, Nelfinavir, Fosamprenavir, Saquinavir and Tiiprenevir), oral contraceptives and cholesterol lowering medications (Fenofibrate, Gemfibrozil and Niacin).
  • Dose of Atorvastatin should be adjusted in medications that suppress immune system such as Cyclosporine, Rifampin, Telaprevir and Spironolactone.

What are the pharmacokinetic properties of the drug?

  • Pharmacokinetic studies suggested that after oral administration, Atorvastatin is rapidly absorbed and has a bio-availability of approximately 14% and systemic availability of HMG-CoA reductase inhibitory activity is 30%.
  • It has been observed that following a single dose of maximum (or peak) plasma concentration is achieved in 60-120 minutes in the fasted state.
  • Following absorption the majority (>98%) of the drug is bound to plasma proteins.
  • The drug is extensively metabolized to parahydroxylate and ortho derivatives and various betaoxidation Atorvastatin metabolism is also facilitated by the hepatic enzyme CYP3A4.
  • The average median half-life of Atorvastatin is 14 hours while on the other hand, due to the longer lived active metabolites, half-life of HMG-CoA inhibitory activity is 20-30 hours.
  • Atorvastatin is primarily eliminated in the hepatic biliary excretion after hepatic or extra-hepatic metabolism and very little amount in the urine (<2%).
  • The average steady state volume of distribution of the drug is 381

Which pregnancy category (A; B; C; D; X) has been assigned to Atorvastatin?

  • The Atorvastatin is classified by US FDA pregnancy category: X
  • Due to lack of adequate and well-controlled studies the use and safety of Atorvastatin in pregnant women is contraindicated and recommended only when benefit justifies the risk.
  • Laboratory animal studies have revealed fetal abnormalities and positive evidence of fetus damage.
  • No adequate data is available on excretion of Atorvastatin into human breast milk. However, the use of drug is not recommended in nursing mothers.
  • Despite these facts caution should be exercised when taking Atorvastatin.

How to use the drugs?

  • Atorvastatin is available in tablet form for oral administration by mouth with or without food.
  • Atorvastatin tablets are not chewed, split or crushed. Whole tablet should be swallowed.
  • It is advisable not to take more than one tablet daily.
  • It is also recommended to take drug at almost the same time every day.
  • Follow the instructions carefully as directed on prescription leaflet and take Atorvastatin exactly as directed by your health care professional.
  • Do not change the dose of the drug as prescribed by your doctor as your doctor may decrease the dose of Atorvastatin depending upon adverse side effects or medication response.
  • If you have any queries about the drug immediately consult to your doctor to get explained any part you do not understand.

How to store the drug?

  • Atorvastatin is stored at room temperature at 20° to 25°C (68° to 77°F).
  • The container should be tightly closed and kept away from excess heat, direct sun light and reach of children.

How to dispose the medicine?

  • Throw away unused and opened, outdated or no longer used container.
  • Also dispose the old medicine after the expiration date.
  • Talk to your pharmacist about the proper disposal of your medication.

Does Atorvastatin has approval from government / FDA /or any other related agencies?

  • Atorvastatin has received its official approval from US Food and Drug Administration (FDA) in December, 1996.
  • Atorvastatin is approved to treat medical complications such as primary hypercholesterolemia, mixed dyslipidemia (Fredrickson Types IIa and IIb) and hypertriglyceridemia.

Other uses of the drug.

  • Atorvastatin is also used in the patients with acute coronary syndrome and thrombotic stroke.
  • Atorvastatin may also be used for other uses not listed here. It is advisable to ask your doctor or pharmacist for more detailed information regarding its use.

What special dietary precautions should I follow?

  • It is generally recommended to avoid high fat/cholesterol diet and follow a routinely exercise regimen.
  • Follow a routine diet as prescribed by your dietician and avoid spicy foods.
  • For more detailed information about the dietary plan please visit the National Cholesterol Education Program (NCEP) website for additional dietary information at http://www.nhlbi.nih.gov/health/public/heart/chol/chol_tlc.pdf.
  • Avoid grapefruit juice and drinking in large amounts while taking Atorvastatin.

What special precautions should I follow? / What should I avoid while using Atorvastatin?

  • Consult with your doctor and pharmacist about what prescription and non-prescription medications, vitamins, and nutritional supplements you are taking or plan to take.
  • Avoid the use of alcohol; it may increase the risk of serious side effects.
  • Use of high fat and high cholesterol diet should be avoided.
  • Inform your doctor if you are breastfeeding or pregnant or plan to become pregnant.
  • Grapefruit juice is also avoided because its components are known inhibitors of intestinal CYP3A4.
  • Use of vitamin D supplements should also be avoided. These supplements reduce the concentration of Atorvastatin and active metabolites.
  • Inform your doctor if you are alcoholic and have diabetes or hypothyroidism.

What are the possible side effects of this drug?

In addition to the associated benefits, Atorvastatin also is accompanied with the side effects some of which are more common, others less common whereas some that fade away with time while you take the drug. It is always recommended to consult a doctor if you encounter any of the side effects.

There are some adverse effects that disappear while consuming the drug with time. But, if any of them keep on persisting, consult your doctor.

Less commonly occurring side effects include:

  • Back pain
  • Constipation
  • Excessive gas or belching
  • Feeling of discomfort or illness
  • Indigestion
  • Lack or loss of strength and appetite
  • Nausea
  • Pain in abdomen or stomach
  • Shivering
  • Sleeplessness
  • Stomach discomfort
  • Sweating
  • Vomiting

More common side effects include:

  • Difficult or painful urination
  • Headache
  • Hoarseness
  • Pain in lower back or side
  • Runny nose
  • Tenderness around the eyes and cheekbones

Some of the commonly occurring side effects that require medical attention is outlined as:

  • Chest tightness
  • Difficulty with swallowing
  • Fast heartbeat
  • Fever and cough
  • Light-headedness
  • Muscle cramps, stiffness, pain, swelling, or weakness
  • Puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
  • Skin rash and itching
  • Unusual tiredness or weakness

Besides these, Atorvastatin may also be associated with some other side effects. These include:

  • Cardiovascular effects: chest pain, angioneurotic edema, peripheral edema, haemorrhagic stroke.
  • Dermatologic effects: rashes, dermatomyositis.
  • Endocrine effect: gynecomastia, thyroid dysfunction, hypospermia, acid maltase deficiency.
  • Gastrointestinal effects: constipation, dyspepsia, flatulence, anorexia, vomiting, diarrhea, abdominal pain.
  • Genitourinary effects: hematuria, erectile dysfunction, impotence and testicular pain.
  • Haematological effect: thrombocytopenia, leukopenia, haemolytic anemia.
  • Hepatic effect: choestatic jaundice, fatty changes in the liver, cirrhosis, fulminant hepatic necrosis.
  • Hypersensitivity effects: allergic reactions, chills, angioedema, anaphylaxis, flushing, dyspnea, epidermal necrolysis.
  • Musculoskeletal effects: severe myopathy.
  • Nervous system effects: headache, dizziness, fatigue, memory loss, vertigo, paresthesias, peripheral neuropathy, cranial nerve dysfunction, drowsiness, decline in cognitive function, peripheral nerve palsy.
  • Ocular effects: ocular myasthenia, reversible ophthalmoplegia, blurred vision.
  • Renal effects: rhabdomyolysis, acute renal failure.
  • Respiratory effects: pharyngitis, rhinitis, bronchitis, sinusitis.

What should I do in case of overdose?

  • Overdose usually occurs when someone by mistake or deliberately takes more than the prescribed limit of this medication.
  • If you overdose the drug contact with your doctor or pharmacist for symptomatic and supportive measures.
  • Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

 What should I do in case of missed a dose?

  • In case of missed dosage, take it as soon as you remember and maintain a regular dosing schedule.
  • Skip the missed dose if it is almost time for your next scheduled dose. Keep in mind to not use a double dose to make up a missed dose.

Does Atorvastatin have any interaction with drugs?

The concurrent use of Statin such as Atorvastatin with acid derivatives, lipid modifying doses of niacin, cyclosporine, or strong CYP 3A4 inhibitors (e.g. itraconazole, HIV protease inhibitors, and clarithromycin) is contraindicated.

  • Strong Inhibitors of CYP 3A4: Cytochrome P450 3A4 brings about the metabolization of Atorvastatin. In presence of strong inhibitors of CYP 3A4, Atorvastatin plasma concentration is increased.
  • Clarithromycin: Atorvastatin exposure is significantly increased when given concomitantly with Clarithromycin as compared to that of Atorvastatin alone.
  • Itraconazole: Atorvastatin AUC gets significantly enhanced with concomitant administration of LIPITOR 40 mg and Itraconazole 200 mg. Therefore, in patients taking Itraconazole, caution should be used when the LIPITOR dose exceeds 20 mg.
  • Combination of Protease Inhibitors: Co-administration of the drug with a variety of combinations of HIV protease inhibitors and also hepatitis C protease inhibitor Telaprevir causes an increase in the Atorvastatin AUC. It is, therefore, recommended to avoid the use of Atorvastatin in patients consuming HIV protease inhibitor Tipranavir and Ritonavir, or the hepatitis C protease inhibitor Telaprevir. Caution is required while taking HIV protease inhibitors Saquinavir plus Ritonavir; Darunavir plus Ritonavir; Lopinavir plus Ritonavir; Fosamprenavir, or Fosamprenavir plus Ritonavir.
  • Cyclosporine: Atorvastatin and Atorvastatin-metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1 (e.g., Cyclosporine) can increase the bioavailability of Atorvastatin. In cases where co-administration of LIPITOR with cyclosporine is necessary, the dose of LIPITOR should not exceed 10 mg.
  • Rifampin or other Inducers of Cytochrome P450 3A4: Co-administration of Atorvastatin with inducers of cytochrome P450 3A4 such as Efavirenz, or Rifampin may bring about variable reductions in Atorvastatin plasma concentrations. It is usually recommended to co-administer Atorvastatin and Rifampin simultaneously to avid reduction in the plasma levels of Atorvastatin.
  • Oral Contraceptives: Concomitant use of Atorvastatin and an oral contraceptive causes a rise in AUC values for Norethindrone and Ethinyl estradiol. Hence, careful selection of the oral contraceptive is required for the women who are taking Atorvastatin.
  • Colchicine: Co-administration of Atorvastatin with Colchicine results in increased cases of myopathy, including rhabdomyolysis and caution should be exercised when prescribing these drugs together.
  • Digoxin: The steady state plasma concentration of Digoxin gets increased by 20 % in cases of multiple co-administration doses of Atorvastatin and Digoxin. Hence, patients taking Digoxin should be monitored appropriately.
  • Grapefruit Juice: The grape juice contains one or more components that inhibit CYP 3A4 and can increase plasma concentrations of Atorvastatin, especially with excessive grapefruit juice consumption (>1.2 liters per day).
  • Warfarin: Atorvastatin shows no clinically significant effect on prothrombin time when given to patients who are receiving warfarin treatment.
  • Niacin: Dose adjustment is required in case of concomitant use of Atorvastatin and Niacin due to the enhanced risk of skeletal muscle effects.
  • Gemfibrozil: Atorvastatin may result in an increased risk of myopathy/rhabdomyolysis when co-administered with Gemfibrozil. It is therefore recommended to avoid the use Atorvastatin when the patient is taking Gemfibrozil.
  • Other Fibrates: Atorvastatin use should be done very cautiously in case of co-administration with Gemfibrozil or other fibrates as the risk of myopathyis greatly enhanced.

    Atorvastatin Drugs Interaction.

    Atorvastatin Drugs Interaction.

Does Atorvastatin have any interaction with Diseases?

Before you begin to take Atorvastatin, it is necessary to discuss any medical condition or allergies you have or any other significant medical fact. It has been observed that following conditions may interact with Atorvastatin:

  • Geriatric population: Older people have higher levels of Atorvastatin in plasma as compared to young ones. Hence, the chances of lowering of LDL at any dose are greater in older ones in comparison to young population.
  • Gender: Although the plasma concentration of Atorvastatin varies between men and women but the LDL-C lowering effect of the drug do not show clinically significant difference.
  • Pediatric population: The effect of the drug has not been evaluated in the pediatric population.
  • Pregnancy and Lactation: Atorvastatin brings about inhibition of HMG-CoA reductase and thereby decreases the synthesis of cholesterol and other biologically active components obtained from cholesterol which are essential for fetal development. The drug is therefore contraindicated in pregnant women and nursing women as it may harm the fetus.
  • Hemodialysis: Hemodialysis in patients of advanced renal dysfunction does not significantly enhance the clearance of the drug Atorvastatin due to its extensive binding to the plasma proteins.
  • Renal Insufficiency: No dose adjustment is required in patients suffering from renal dysfunction as the condition neither influences the plasma concentration nor the LDL-C lowering effect of Atorvastatin.
  • Hepatic Insufficiency: Plasma concentration of Atorvastatin and its exposure time is greatly enhanced in the patients with hepatic dysfunction.
  • Liver Dysfunction: Atorvastatin causes biochemical abnormalities of liver function by bringing about an increase in serum transaminases and hence should be used with caution in patients with liver disease.
  • Endocrine Function: Atorvastatin interferes with cholesterol synthesis and decreases adrenal and/or gonadal steroid production. The drug does not lower basal plasma cortisol concentration or impair adrenal reserve. No adequate data is available on the effects of Atorvastatin on male fertility. Atorvastatin should be administered cautiously in case of concomitant use with drugs that decreases the levels or activity of endogenous steroid hormones including cimetidine, spironolactone, and ketoconazole.
  • CNS Toxicity: Brain hemorrhage and optic nerve vacuolation have been observed in animal studies.  However, no CNS lesions were seen in mice and rats after chronic treatment for a period of 2 years at doses of 400 mg/kg/day or 100 mg/kg/day respectively. Other members of this class of drug or a chemically similar drug have been associated with CNS vascular lesions and optic nerve degeneration respectively in dogs.
  • Skeletal Muscle: Atorvastatin has been associated with rhabdomyolysis (breakdown of muscle tissue leading to the release of muscle fiber in the blood stream), myalgia (muscle pain) and myoglobinuria (presence of myoglobin in the urine). Atorvastatin therapy should be stopped promptly in case of elevation of CPK (creatine phosphokinase) levels or myopathy.
  • Carcinogenesis, Mutagenesis, Impairment of Fertility: In vivo studies in rats represent 2 rare types of muscle tumors namely, rhabdomyosarcoma and, fibrosarcoma. Similar studies in mice have shown cases of liver adenomas and liver carcinomas. However, in vitro studies do not show any mutagenic or clastogenic effect.

Where can I get more information?

Your pharmacist can provide more information about Atorvastatin.

Clinical research and current scenario of the drug.

  • Clinical studies indicate the effectiveness of Atorvastatin in bringing about reductions in cardiovascular events in patients with and without Coronary heart diseases (CHD).
  • Studies indicate the use of high-dose of Atorvastatin in arresting and reversing the progression of atherosclerosis.
  • Clinical studies in diabetic patients showed the decrease in the occurrence of stroke, acute CHD events, and coronary revascularizations via Atorvastatin.
  • Atorvastatin has also been found to be effective in decreasing nonfatal myocardial infarctions and fatal CHD in hypertensive patients.
  • Clinical trials indicate the effectiveness of high doses of Atorvastatin in reducing risk of stroke in patients with prior cerebrovascular events, benefiting patients suffering from recent acute coronary syndrome, and in slowing cognitive decline in preliminary studies of Alzheimer’s patients.
  • Studies indicate the association of Atorvastatin with decreased progression of mild chronic kidney dysfunction and no significant benefit in patients on hemodialysis with advanced renal dysfunction.
References from chemical, biological and toxicological databases.

How does tadalafil work for Benign Prostatic Hyperplasia?

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Tadalafil

Aug 05 2015 Published by under Medicines

What is Tadalafil (Cialis)?

  • Tadalafil is a drug that is used for the treatment of erectile dysfunction (inability to attain penile erection during sexual activity).
Tadalafil : Structure and chemical information.

Tadalafil : Structure and chemical information.

What is the generic and brand name of the drug?

  • The drug is available under generic name Tadalafil and brand names Cialis and Adcirca.
  • Tadalafil was initially developed by the Biotechnology Company ICOS and subsequently redeveloped and marketed by Lilly ICOS, LLC, the joint venture of ICOS Corporation and Eli Lilly and Company.
  • In late November 2008, the exclusive rights to commercialize Tadalafil in United State were sold to United Therapeutics by Eli Lilly.
  • An Indian pharmaceutical company Cipla also manufacture and distribute Tadalafil under the brand name

What is the source of the drug (natural or synthetic)?

  • Tadalafil is a synthetic (man-made) pharmaceutical phosphodiesterase (PDE) inhibitors class of

Why is this medication prescribed?

  • Tadalafil acts as a muscle relaxant and increases blood flow to specific areas of the body.
  • Tadalafil (under brand name Cialis) is used to treat erectile dysfunction or impotence (complications related to condition, where person is unable to get or keep penis erection during the sexual activity).
  • Tadalafil acts by enhancing blood flow to the male penis and helps in attaining and keeping erection. However, this drug does not provide any protection against sexually transmitted diseases like syphilis, HIV, hepatitis B etc.
  • Tadalafil (under brand name Cialis) is also prescribed for the treatment of the Benign Prostatic Hyperplasia (a disease condition which is characterized by enlargement of the prostate gland, painful urination, inability to pass urine, and urinary frequency and exigency in adult men.
  • Tadalafil under brand name Adrica is used to improve the exercise capacity in people (men and women) suffering from Pulmonary Arterial Hypertension (an abnormal constriction of pulmonary arteries (vessels that carrying blood to the lungs) which results in high blood pressure). The drug acts on the blood vessels in the lungs, relaxing them and allow blood to flow more easily.

Pharmacophore structure: Information about the chemical structure of the drug.

Tadalafil chemically belongs to the class of organic compounds which are known as Beta carbolines characterized by a 9H-pyrido [3, 3-b] indole moiety. The detailed chemical classification of Tadalafil is described below:

  Kingdom Organic compounds 
Super Class Organoheterocyclic compounds
Class Indoles and derivatives
Sub Class Pyridoindoles
Direct Parent Beta carbolines

 Chemical information of the drug.

  • It is a synthetic pharmaceutical aromatic heteropolycyclic compound with a molecular formula C22H19N3O4 and molecular weight of 389.403 Da.
  • Chemically, Tadalafil is known as (2R,8R)-2-(2H-1,3-benzodioxol-5-yl)-6-methyl-3,6,17-triazatetracyclo[8.7.0.0³,⁸.0¹¹,¹⁶]heptadeca-1(10),11,13,15-tetraene-4,7-dione.
  • Tadalafil is available as a monohydrochloride salt.
  • It is white crystalline powder and practically insoluble in water and slightly soluble in ethanol.
  • The water solubility of Tadalafil is 0.25 mg/mL and melting point is 301°C -302°C.

What is the available strength of the drug?

  • Tadalafil is available in tablet form for oral administration.
  • It is available in different dosage strength of 2.5, 5, 10 and 20 mg/tablet.
  • The tablet is yellow in colour, film coated, almond shaped embossed with “C 2.1/2”, “C 5”, “C 10”, and “C 20” on one side, which is corresponding to the different doses of the drug.
  • Each Tadalafil tablet contains active Tadalafil HCl and inactive ingredients such as hydroxypropyl cellulose, croscarmellose sodium, titanium dioxide, microcrystalline cellulose, lactose monohydrate, iron oxide, magnesium stearate, hypromellose, sodium lauryl sulphate, triacetin.

How Tadalafil (Cialis) works (mode of action)?

  • The mode of action of Tadalafil is same as that of other drugs used for the treatment of erectile dysfunction such as Sildenafil and Vardenafil.
  • Tadalafil has a longer half-life (17.5 hours) in comparison with other erectile dysfunction medications such as Viagra and Levitra (4-5 hours). This longer half-life results in a longer duration of action that provides Tadalafil a nickname of the “weekend pill.
  • During sexual stimulation, nitric oxide (NO) is released in the corpus cavernosum (a pair of sponge-like areas of erectile tissue, which hold blood in the penis during an erection) located around the penis.
  • The nitric oxide in turn activates the enzyme guanylate cyclase which results in increased levels of cyclic guanosine monophosphate (cGMP). The increased level of cGMP causes relaxation of penile arteries and corpus cavernosal smooth muscles, resulting in increased inflow of blood and penile erection.
  • Tadalafil selectively brings about the inhibition of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type (PDE5), which is responsible for degradation of cGMP (cyclic guanosine monophosphate) in the corpus cavernosum of the penis.
  • The inhibition of PDE5 by Tadalafil causes increased and constantly maintained levels of cGMP under normal sexual stimulation in the corpus cavernosum, which leads to better penile erections.
  • The inhibition of phosphodiesterase type 5 (PDE5) by Tadalafil enhances erectile function by increasing the amount of cGMP.
  • However, the drug will not work in the absence of sexual stimulation and activation of the NO/cGMP system.
Tadalafil : Mode of Action.

Tadalafil : Mode of Action.

What are the recommended doses of Tadalafil?

  • The drug can be taken orally either in presence or absence of food. The recommended dose of the drug for adults with erectile dysfunction is usually 10 mg once a day which has to be taken 30 minutes before the sexual intercourse.
  • However, the dose may be increased to a maximum of 40 mg or decreased to 2.5 mg depending upon the efficiency or the side effects of the drug.
  • The prescribed dose of Tadalafil varies depending upon the age and diseased state of the patient. The dosing recommendations are as follows:
    • Adult Dose:
      • Erectile Dysfunction (ED):
        • Dosing of ED when needed: Initial dose 10 mg once a day orally before sexual activity followed by 5 to 20 mg based on effectiveness and tolerability
        • Dosing for ED once daily: Initial dose is 2.5 mg once a day without concerning to sexual activity followed by 2.5 to 5 mg based on effectiveness and tolerability.
      • Pulmonary arterial hypertension: 40 mg orally once a day with or without food.
      • Benign prostatic hyperplasia: 5 mg orally once a day with or without food.
    • Geriatric dose:
      • Erectile Dysfunction:
        • Dosing of ED when needed: Initial dose is 10 mg once a day before sexual activity followed by 5 to 20 mg based on effectiveness and tolerability
        • Dosing for once daily: Initial dose is 2.5 mg once a day without concerning to sexual activity followed by 2.5 to 5 mg based on effectiveness and tolerability.
      • Pulmonary arterial hypertension: 40 mg orally once a day with or without food.
      • Benign prostatic hyperplasia: 5 mg orally once a day with or without food. Dose adjustment is required in case of renal and hepatic impairment.
    • Dose adjustments:
      1. Hepatic impairment:
        • Dosing for ED when needed: Mild to moderate hepatic impairment: 10 mg orally once a day. Severe hepatic impairment: Not recommended.
        • Dosing for ED once daily: Mild to moderate hepatic impairment: use with caution. Severe hepatic impairment: Not recommended.
        • Pulmonary Arterial Hypertension: Mild to moderate hepatic impairment: 20 mg orally once a day. Severe hepatic impairment: must be avoided.
      2. Renal impairment:
        • Dosing of ED when needed: CrCl 30-50 mL/min: 5mg orally once a day. CrCl less than 30 mL/min: 5 mg once in every 72 hours.
        • Dosing for ED once daily: CrCl 30-50 mL/min: no data available. CrCl less than 30 mL/min: not recommended.
        • Pulmonary Arterial Hypertension: CrCl 30-50 mL/min: 20 mg orally once a day. CrCl less than 30 mL/min: should be avoided.
        • Benign Prostatic Hyperplasia: CrCl 30-50 mL/min: 2.5 mg orally once a day. CrCl less than 30 mL/min: not recommended.
        • In erectile dysfunction with alpha blocker: 2.5 mg once a day orally with or without food.
        • In erectile dysfunction with CYP450 3A4:
        • Dosing of ED when needed: maximum10 mg once in every 72 hours orally.
        • Dosing for ED once daily: maximum 2.5 mg once a day orally.
        • Co-administration of Tadalafil in patients on Ritonavir: 20 mg once a day orally with or without food.
        • Co-administration of Ritonavir in patients on Tadalafil: Adcirca is discontinued before 24 hours to start Ritonavir. Adcirca is continued after 1 week following the beginning of Ritonavir.

        When should I discontinue, withhold or modify the dose of Tadalafil?

        • The usual dosing of the drug (i.e. 2.5 mg per day) may vary depending upon the efficiency and side effects of the drug in a particular individual.
        • Dosage adjustment is not required in case of geriatric population.
        • No dosage adjustment is necessary in renal impairment (mild or moderate) patients and patients with mild hepatic impairment. Tadalafil is not recommended for patients with severe renal or hepatic impairment.
        • Tadalafil use should be withheld in case of sudden vision loss.
        • Co-administration of Tadalafil with poppers (such as amyl nitrate, butyl nitrate) and nitrates (such as isosorbide dinitrate or isosorbide mononitrate) is contraindicated.
        • The dosage of the drug has to be adjusted in case you are taking alpha blocker such as Doxazosin or Tamsulosin.
        • The dosage of the Tadalafil has to be adjusted in case you are taking CYP3A4 inhibitor.

        What are the pharmacokinetic properties of the drug?

        • It has been observed that following administration of single oral-dose of Tadalafil maximum (or peak) plasma concentration (Cmax) of Tadalafil is achieved between 30 minutes and 6 hours (median time of 2 hours).
        • Absolute bioavailability following oral dosing of Tadalafil has not been studied in detail.
        • Following absorption the majority (94%) of the drug is bound to plasma proteins.
        • The drug is mainly metabolized by the hepatic enzyme CYP3A4 into catechol metabolite.
        • The average median half-life of Tadalafil is 17.5 hours.
        • Tadalafil is mainly excreted as metabolites in the feces (approximately 61%), while some amount is excreted in the urine (36%).
        • The average steady state volume of distribution of the drug is 62.6 litres.

        Which pregnancy category (A; B; C; D; X) has been assigned to Tadalafil?

        • Tadalafil is classified by US FDA pregnancy category: B.
        • Due to lack of adequate and well-controlled studies the use of Tadalafil in pregnant women is contraindicated and recommended only when benefit justifies the risk.
        • Laboratory animal studies have shown no damage to the fetus.
        • Studies support the excretion of the drug into animal milk. However, no adequate data is available on excretion of Tadalafil into human breast milk.
        • Despite these facts caution should be exercised when taking Tadalafil.

        How to use the drug?

        • Tadalafil is available in tablet form for oral administration by mouth with or without food.
        • Tadalafil can be taken in two different ways, either as daily dose or as need basis.
        • Consult your doctor or physician about the suitable dosing schedule based on your condition.
        • If you are following the regular schedule of Tadalafil, it is recommended to take the drug at around the same time every day.
        • It is recommended to take the drug about 30 minutes before sexual intercourse. It is advisable not to take more than one recommended dose daily.
        • The time duration between the drug uses should be at least 24 hours.
        • Follow the instructions carefully as directed on prescription leaflet and take Tadalafil exactly as directed.
        • Do not change the dose of the drug as prescribed by your doctor as the dosage is based on patient medical condition, treatment responses and usage with other drugs.

        How to store the drug?

        • Tadalafil is stored at 25°C (77°F) and excursion permitted to 15-30°C (59-86°F).
        • Store the medicine away from light and moisture.
        • Medicine should not be stored in the bathroom.
        • The drug should be kept away from children and pets.

        How to dispose the medicine?

        • Throw away unused and opened, outdated or no longer used container.
        • Also dispose the old medicine after the expiration date.
        • Talk to your pharmacist about the proper disposal of your medication.

        Does Tadalafil has approval from government / FDA /or any other related agencies?

        • Tadalafil has received its official approval from US Food and Drug Administration (FDA) in November 2003 as third ED prescription drug pill (after sildenafil citrate (Viagra) and vardenafil hydrochloride (Levitra)) for the treatment of erectile dysfunction.
        • In May 2009, US Food and Drug Administration (FDA) approved Tadalafil for the treatment of Pulmonary Arterial Hypertension.
        • Tadalafil was also approved by FDA in 2011 for the treatment of Benign Prostatic Hyperplasia (BPH).
        • Tadalafil received its official approval from US Food and Drug Administration (FDA) in October 2011 for treatment of signs and symptoms of Benign Prostatic Hyperplasia (BPH) as well as a combination of BPH and erectile dysfunction (ED), when the conditions coincide.

        Other uses of the drug

        • Tadalafil is also used to treat the combination of Erectile Dysfunction (ED) and Benign Prostatic Hyperplasia (BPH).
        • Tadalafil may also be used for other uses not listed here. It is advisable to ask your doctor or pharmacist for more information.

        What special dietary precautions should I follow?

        • Grapes and its juice are known to interact with Tadalafil and increase its adverse effects via increasing the levels of the drug in the blood.
        • Consult your doctor or pharmacist regarding the use of grapefruit products.
        • Alcohol consumption can also enhance some side effects of the drug.

        What special precautions should I follow/ What should I avoid while using Tadalafil?

        • Do not use the medicine if you are hypersensitive or allergic to any of the ingredients.
        • Before taking Tadalafil, tell your doctor about your medical history preferentially if you have any kind of liver disease, heart disease, kidney disease, eye disorders, bleeding disorders, or blood pressure problems.
        • It is usually recommended to avoid driving, use of machinery or any chore requiring alertness or clear vision.
        • Consult with your doctor and pharmacist if you are taking any prescription and non-prescription medications, vitamins, nutritional supplements or herbal products (especially St. John’s wort) or plan to take.
        • Consult your doctor in case of any query. Avoid use of other drugs used for the treatment of impotence.
        • Inform your doctor if you smoke or had diarrhea, vomiting, have ever had an erection that lasted more than 4 hours, or not been drinking enough fluids.
        • Also tell your doctor if you have or have ever had chest pain during sexual activity, ; high or low blood pressure; irregular heartbeat, pulmonary veno-occlusive disease , diabetes; high cholesterol; any condition that affects the shape of the penis; ulcers in the stomach; a bleeding disorder; blood circulation problems.
        • Inform your doctor if you are breastfeeding or pregnant or plan to become pregnant.
        • Inform your doctor about the use of alcoholic beverages during treatment with Tadalafil. Drinking a large amount of alcohol can result in experience of certain side effects of Tadalafil such as headache, fast heartbeat, dizziness, and low blood pressure.
        • Inform your doctor about the use of Tadalafil if you are having surgery, including dental surgery.

        What are the possible side effects of this drug?

        In addition to the associated benefits, Tadalafil also is accompanied with the side effects some of which are more common, others less common whereas some that fade away with time while you take the drug. It is always recommended to consult a doctor if you encounter any of the side effects.

        Some of the less commonly occurring side effects but requiring medical attention is outlined as:

        • Blurred vision
        • Chills
        • Cold sweats
        • Confusion
        • Discomfort or pain in chest
        • Dizziness
        • Fainting
        • Fast or irregular heartbeat
        • Headache
        • Hearing loss
        • Irregular heartbeat
        • Light-headedness when getting up suddenly from a lying or sitting position
        • Nausea
        • Nervousness
        • Pain in arm, back, or jaw
        • Pain in neck
        • Pounding in the ears
        • Shortness of breath
        • Tightness or heaviness of chest
        • Uneasiness in the arms, jaw or back
        • Unusual tiredness or weakness
        • Vomiting

        In some cases the incidence are rarely known such as hearing loss. There are some adverse effects that disappear while consuming the drug with time. But, if any of them keep on persisting, consult your doctor.

        More common side effects include:

        • Belching
        • Discomfort or pain in stomach
        • Heartburn
        • Indigestion
        • Sour stomach

        Less commonly occurring side effects include:

        • Aching or cramping in muscle
        • Bloody nose
        • Burning and pain in the throat
        • Changes in voice
        • Congestion
        • Difficulty with moving, sleeping and swallowing
        • Feeling of burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling
        • Feeling of warmth, constant movement of self or surroundings
        • Fever
        • Hoarseness
        • Increased erection
        • Itching eyes
        • Loss of strength
        • Mouth dryness
        • Nasal congestion
        • Pain in body or body aches
        • Pain in eye, neck, arms and legs
        • Pain in upper abdomen or stomach
        • Pain, redness, swelling of the eye, eyelid, or inner lining of the eyelid
        • Puffiness or swelling of the eyes or face
        • Redness of the face, neck, arms and occasionally, upper chest
        • Reduced sensitivity to touch
        • Sleeplessness
        • Soreness or dryness of the throat
        • Spinning sensation
        • Spontaneous penile erection
        • Stiffness muscle
        • Swelling of the eyelids
        • Swollen glands in the neck and joints
        • Tenderness in the stomach area
        • Unnecessary eye discharge
        • Unusual drowsiness
        • Watering of the eye

        Besides these, Tadalafil may also be associated with some long term effects. These include:

        • Hypersensitivity effects: allergic reactions.
        • Nervous system effects: headache, dizziness, transient global amnesia, transient ischemic attacks.
        • Genitourinary effects: hematospermia, penile hemorrhage, increased erection.
        • Ocular effects: eye discomfort, pain, eyelid edema, change in color vision, visual field defect, retinal vein occlusion and retinal artery occlusion.
        • Cardiovascular effects: myocardial infarction, chest pain, hypertension, tachycardia, sudden cardiac death and palpitation.
        • Respiratory effects: nasopheryngitis, nasal congestion, cough, rhinitis, pulmonary hypertension.
        • Dermatologic effects: rashes, sweating, urticaria, angioedema.
        • Renal effects: hematuria (blood in urine).
        • Gastrointestinal effects: constipation, diarrhea, gastroesophageal reflux disease, abdominal pain.
        • Musculoskeletal effects: back pain, myalgia, pain in limbs, musculoskeletal stiffness.

        What should I do in case of overdose?

        • Overdose usually occurs when someone by mistake or deliberately takes more than the prescribed limit of this medication.
        • In case of overdose, contact with your doctor or pharmacist for symptomatic and supportive measures.
        • Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

        What should I do in case of missed a dose?

        • In case of missed dosage, take it as soon as you remember and maintain a regular dosing schedule.
        • Skip the missed dose if it is almost time for your next scheduled dose. Keep in mind to not use a double dose to make up a missed

        Does Tadalafil have any interaction with other drugs?

        It has been observed that Tadalafil may interact with or increase or decrease the effect of certain drugs. It is therefore recommended not to start or stop any medication or change the dosage of any drug. Caution should be taken when co administrating Tadalafil with one of the following drugs as it may lead to very serious or sometimes fatal interaction:

        • Drugs for heart conditions (Nicorandil or Nitrates): Organic nitrate in any form is contraindicated in patients who are taking Tadalafil as the drug potentiates the hypotensive effects of nitrates.
        • Antacids: Co-administration of an antacid such as magnesium hydroxide or aluminum hydroxide and Tadalafil result in decreased uptake of Tadalafil.
        • Alpha blockers (used to treat high blood pressure, enlarged prostate or heart failure): PDE5 inhibitors (such as Tadalafil) and alpha-adrenergic blocking agents (like Tamsulosin, Alfuzosin, or Doxazosin) when given simultaneously lead to an additive blood lowering effect as both are vasodilators and hence should not be given together.
        • Antihypertensives: Tadalafil (PDE5 inhibitors), a mild systemic vasodilators when co-administered with specific antihypertensive drugs such as Angiotensin II receptor blockers, Bendrofluazide, Metoprolol, and Enalapril etc. brings about a small reduction in blood pressure.
        • HIV protease inhibitor: Ritonavir and other HIV protease inhibitors increase the exposure of Tadalafil.
        • Cytochrome P450 Inhibitors: Tadalafil is primarily metabolized by CYP3A4. Hence, co-administration of Tadalafil with drugs that are inhibitors of CYP3A4 such as Ketoconazole, Erythromycin, Itraconazole, and Grapefruit juice result in an increase in Tadalafil exposure.
        • Cytochrome P450 Inducers: Concomitant use of Tadalafil with drugs that induce CYP3A4 such as Rifampin, Carbamazepine, Phenytoin, and Phenobarbital results in decreased exposure and hence efficacy of Tadalafil.

        There are certain drugs whose co-administration with Tadalafil may not result in much change in the pharmacokinetics.

        • P-glycoprotein (e.g. Digoxin): Coadministration of Tadalafil does not affect the pharmacokinetics of Digoxin.
        • Cytochrome P450 Substrates: Tadalafil does not cause any significant inhibition or induction of the clearance of drugs metabolized by isoforms of cytochrome P450 such as Theophylline, Warfarin, Midazolam or Lovastatin.
        • Aspirin: Tadalafil does not potentiate the increase in bleeding time brought about by aspirin.
        • H2 Antagonists (e.g. Nizatidine): The co-administration of Nizatidine (results in increase in gastric pH) with Tadalafil does not affect the pharmacokinetic properties of Tadalafil.

        This list does not contain all the possible drug interactions of Tadalafil. Therefore, before using Tadalafil, it is recommended to discuss with your doctor or pharmacist about the medications you are taking or plan to take.

        Does Tadalafil have any interaction with diseases?

        Before you begin to take Tadalafil, it is necessary to discuss any medical condition or allergies you have or any other significant medical fact. It has been observed that following medical conditions (disease) may interact with Tadalafil:

        • Allergy: People who are allergic to Tadalafil or any of its ingredients are recommended to take the drug with caution and only under the prescription of the doctor.
        • Surgery: The effectiveness of Tadalafil has not been established in patients in case of pelvic surgery or radical non-nerve-sparing prostatectomy. It is therefore recommended to use the drug with high caution.
        • Cardiac disease: The use of Tadalafil is contradicted in patients with cardiac disease for whom the sexual activity is generally not recommended. The doctors should consider the cardiac risk of sexual activity which may lead to sudden cardiac death, chest pain, stroke, unstable angina pectoris, ventricular arrhythmia, palpitations, transient ischaemic attacks, myocardial infarction, and tachycardia.
        • Optic disorders: Certain visual defects and non-arteritic anterior ischaemic optic neuropathy (NAION) (i.e. loss of vision in one eye) have been encountered with intake of Tadalafil. It is therefore advised to stop the intake of the drug and consult the doctor immediately in case the patient faces sudden optical defect.
        • Hypertension: Concomitant use of Tadalafil in patients who are on antihypertensive medication may result in a decrease in blood pressure decrease. Therefore, an adjustment in dose of the medicine should be considered while co-administering Tadalafil and anti-hypertensive drugs.
        • Renal and hepatic impairment: Use of Tadalafil is usually not recommended in patients suffering from severe renal or hepatic impairment due to increased exposure of the drug and limited clinical data.
        • Lactose intolerance: The patients suffering from rare hereditary problems of glucose-galactose malabsorption, galactose intolerance, or the Lapp lactase deficiency are generally advised to avoid the consumption of the drug as it contains lactose.
        • Other treatment of erectile dysfunction or benign prostatic hyperplasia: Concomitant use of Tadalafil and other PDE5 inhibitors or other treatments for erectile dysfunction have not been evaluated. Hence, the patients are informed not to take Tadalafil in such combinations. In case of benign prostatic hyperplasia, administration of Tadalafil is recommended only after careful examination of the cardiovascular conditions and ruling out the possibility of the prostate carcinoma. The use of the drug for the treatment of erectile dysfunction or benign prostatic hyperplasia in patients with hepatic insufficiency should be carefully evaluated for the associated benefits or risks.
        • Priapism (persistent and painful erection of the penis) and anatomical deformation of the penis: Tadalafil should be used with high caution in patients with conditions such as multiple myeloma, leukaemia, or sickle cell anaemia that predispose them to priapism as it may lead to penile tissue damage and permanent loss of potency. Also the use of the drug should be considered under doctor’s supervision with high caution in patients with anatomical deformation of the penis including Peyronie’s disease, cavernosal fibrosis, or angulation.
        Tadalafil : Disease Interaction.

        Tadalafil : Disease Interaction.

        Where can I get more information?

        Your pharmacist or health care provider can provide more information about Tadalafil.

        Clinical research and current scenario of the drug.

        • Clinical studies indicate comparable exposure of Tadalafil in patients with mild or moderate hepatic impairment (Child-Pugh Class A or B) and healthy subjects at a dose of 10 mg.
        • Studies utilizing single-dose Tadalafil (5 to 10 mg) indicated double Tadalafil exposure in subjects with creatinine clearance of 30 to 80 mL/min.
        • Administration of Tadalafil at a dose of 20 mg to healthy male subjects resulted in no significant difference as compared to placebo in systolic and diastolic blood pressure and no significant effect on heart rate.
        • Clinical pharmacology studies suggest the potential of Tadalafil (5- 20 mg) to potentiate the hypotensive effect of nitrates.
        • Studies to assess the potential effect on sperm characteristics of Tadalafil at varying doses and duration showed no adverse effects on sperm morphology or sperm motility.
        • Studies indicated no adverse effect of a single dose of Tadalafil (40 mg) on intraocular pressure, pupilometry, or visual acuity.
        • Animal studies involving Tadalafil administration up to 400 mg/kg/day suggested no effects on fertility, reproductive performance or reproductive organ.
        • Tadalafil has been shown to be effective in treating ED (erectile dysfunction) in patients with Diabetes Mellitus.
        • Studies indicate the effectiveness and safety of Tadalafil in patients for the treatment of ED (erectile dysfunction), or/and the signs and symptoms of BPH (benign prostatic hyperplasia).
        References from chemical, biological and toxicological database.

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