Tadagra Overdose

Did you have any side effects with this medicine?
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What happens if I overdose Tadagra?

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include chest pain; fainting; prolonged erection; severe dizziness; severe or persistent back or muscle pain; severe or persistent vision changes.

Proper storage of Tadagra:

Store Tadagra at 77 degrees F (25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Tadagra out of the reach of children and away from pets.

Overdose of Tadagra in details

When a dose is taken in higher dose than the recommended doses, it is called Overdose. Overdose always needs a clinical supervision. Any medicine or drug when consumed in Overdose produces untoward side effects on one or various organs in the body. A medicine is excreted in the kidney or metabolized in the liver most of the times. This process goes without any hurdles when taken in normal dose, but when taken in an overdose, the body is not able to metabolize it or send it out properly which causes the effects of anoverdose.
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Single doses up to 500 mg have been given to healthy male subjects, and multiple daily doses up to 100 mg have been given to male patients with erectile dysfunction. Adverse reactions were similar to those seen at lower doses. Doses greater than 40 mg have not been studied in patients with pulmonary arterial hypertension. In cases of overdose, standard supportive measures should be adopted as needed. Hemodialysis contributes negligibly to Tadagra elimination.

What should I avoid while taking Tadagra?

Drinking alcohol can increase certain side effects of Tadagra.

Grapefruit and grapefruit juice may interact with Tadagra and lead to potentially dangerous effects. Discuss the use of grapefruit products with your doctor.

Avoid using other medicines to treat erectile dysfunction, such as sildenafil (Viagra) or vardenafil (Levitra) while you are taking Tadagra.

Tadagra warnings

Warnings are a mix of Precautions. Contraindications and interactions and serious harmful effects associated with the medicine intake. A diabetic or Hypertensive patient need to be warned about few drug interactions. A known hypersensitivity patient needs to be careful about the reactions or anaphylactic shock. A pregnant woman or a breastfeeding woman should be warned of certain medications. A Hepatitis [liver disease] patient or a cardiac patient should avoid few drugs.

Evaluation of erectile dysfunction and BPH should include an appropriate medical assessment to identify potential underlying causes, as well as treatment options.

Before prescribing Tadagra, it is important to note the following:

Cardiovascular

Physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity. Therefore, treatments for erectile dysfunction, including Tadagra, should not be used in men for whom sexual activity is inadvisable as a result of their underlying cardiovascular status. Patients who experience symptoms upon initiation of sexual activity should be advised to refrain from further sexual activity and seek immediate medical attention.

Physicians should discuss with patients the appropriate action in the event that they experience anginal chest pain requiring nitroglycerin following intake of Tadagra. In such a patient, who has taken Tadagra, where nitrate administration is deemed medically necessary for a life-threatening situation, at least 48 hours should have elapsed after the last dose of Tadagra before nitrate administration is considered. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring. Therefore, patients who experience anginal chest pain after taking Tadagra should seek immediate medical attention..

Patients with left ventricular outflow obstruction, (e.g., aortic stenosis and idiopathic hypertrophic subaortic stenosis) can be sensitive to the action of vasodilators, including PDE5 inhibitors.

The following groups of patients with cardiovascular disease were not included in clinical safety and efficacy trials for Tadagra, and therefore until further information is available, Tadagra is not recommended for the following groups of patients:

As with other PDE5 inhibitors, Tadagra has mild systemic vasodilatory properties that may result in transient decreases in blood pressure. In a clinical pharmacology study, Tadagra 20 mg resulted in a mean maximal decrease in supine blood pressure, relative to placebo, of 1.6/0.8 mm Hg in healthy subjects. While this effect should not be of consequence in most patients, prior to prescribing Tadagra, physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects. Patients with severely impaired autonomic control of blood pressure may be particularly sensitive to the actions of vasodilators, including PDE5 inhibitors.

Potential for Drug Interactions When Taking Tadagra for Once Daily Use

Physicians should be aware that Tadagra for once daily use provides continuous plasma Tadagra levels and should consider this when evaluating the potential for interactions with medications (e.g., nitrates, alpha-blockers, anti-hypertensives and potent inhibitors of CYP3A4) and with substantial consumption of alcohol.

Prolonged Erection

There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for this class of compounds. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention.

Tadagra should be used with caution in patients who have conditions that might predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia), or in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie's disease).

Effects on the Eye

Physicians should advise patients to stop use of all phosphodiesterase type 5 (PDE5) inhibitors, including Tadagra, and seek medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition and a cause of decreased vision, including permanent loss of vision, that has been reported rarely postmarketing in temporal association with the use of all PDE5 inhibitors. Based on published literature, the annual incidence of NAION is 2.5-11.8 cases per 100,000 in males aged ≥50. An observational study evaluated whether recent use of PDE5 inhibitors, as a class, was associated with acute onset of NAION. The results suggest an approximate 2-fold increase in the risk of NAION within 5 half-lives of PDE5 inhibitor use. From this information, it is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or other factors.

Physicians should consider whether their patients with underlying NAION risk factors could be adversely affected by use of PDE5 inhibitors. Individuals who have already experienced NAION are at increased risk of NAION recurrence. Therefore, PDE5 inhibitors, including Tadagra, should be used with caution in these patients and only when the anticipated benefits outweigh the risks. Individuals with "crowded" optic disc are also considered at greater risk for NAION compared to the general population; however, evidence is insufficient to support screening of prospective users of PDE5 inhibitors, including Tadagra, for this uncommon condition.

Patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in the clinical trials, and use in these patients is not recommended.

Sudden Hearing Loss

Physicians should advise patients to stop taking PDE5 inhibitors, including Tadagra, and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including Tadagra. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors.

Alpha-blockers and Antihypertensives

Physicians should discuss with patients the potential for Tadagra to augment the blood-pressure-lowering effect of alpha-blockers and antihypertensive medications.

Caution is advised when PDE5 inhibitors are coadministered with alpha-blockers. PDE5 inhibitors, including Tadagra, and alpha-adrenergic blocking agents are both vasodilators with blood-pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some patients, concomitant use of these two drug classes can lower blood pressure significantly, which may lead to symptomatic hypotension (e.g., fainting). Consideration should be given to the following:

ED

.

BPH

Renal Impairment

Tadagra for Use as Needed

Tadagra should be limited to 5 mg not more than once in every 72 hours in patients with creatinine clearance less than 30 mL/min or end-stage renal disease on hemodialysis. The starting dose of Tadagra in patients with creatinine clearance 30 – 50 mL/min should be 5 mg not more than once per day, and the maximum dose should be limited to 10 mg not more than once in every 48 hours..

Tadagra for Once Daily Use

ED

Due to increased Tadagra exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis, Tadagra for once daily use is not recommended in patients with creatinine clearance less than 30 mL/min.

BPH and ED/BPH

Due to increased Tadagra exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis, Tadagra for once daily use is not recommended in patients with creatinine clearance less than 30 mL/min. In patients with creatinine clearance 30 – 50 mL/min, start dosing at 2.5 mg once daily, and increase the dose to 5 mg once daily based upon individual response.

Hepatic Impairment

Tadagra for Use as Needed

In patients with mild or moderate hepatic impairment, the dose of Tadagra should not exceed 10 mg. Because of insufficient information in patients with severe hepatic impairment, use of Tadagra in this group is not recommended.

Tadagra for Once Daily Use

Tadagra for once daily use has not been extensively evaluated in patients with mild or moderate hepatic impairment. Therefore, caution is advised if Tadagra for once daily use is prescribed to these patients. Because of insufficient information in patients with severe hepatic impairment, use of Tadagra in this group is not recommended.

Alcohol

Patients should be made aware that both alcohol and Tadagra, a PDE5 inhibitor, act as mild vasodilators. When mild vasodilators are taken in combination, blood-pressure-lowering effects of each individual compound may be increased. Therefore, physicians should inform patients that substantial consumption of alcohol (e.g., 5 units or greater) in combination with Tadagra can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache.

Concomitant Use of Potent Inhibitors of Cytochrome P450 3A4 (CYP3A4)

Tadagra is metabolized predominantly by CYP3A4 in the liver. The dose of Tadagra for use as needed should be limited to 10 mg no more than once every 72 hours in patients taking potent inhibitors of CYP3A4 such as ritonavir, ketoconazole, and itraconazole. In patients taking potent inhibitors of CYP3A4 and Tadagra for once daily use, the maximum recommended dose is 2.5 mg.

Combination With Other PDE5 Inhibitors or Erectile Dysfunction Therapies

The safety and efficacy of combinations of Tadagra and other PDE5 inhibitors or treatments for erectile dysfunction have not been studied. Inform patients not to take Tadagra with other PDE5 inhibitors, including Tadagra.

Effects on Bleeding

Studies in vitro have demonstrated that Tadagra is a selective inhibitor of PDE5. PDE5 is found in platelets. When administered in combination with aspirin, Tadagra 20 mg did not prolong bleeding time, relative to aspirin alone. Tadagra has not been administered to patients with bleeding disorders or significant active peptic ulceration. Although Tadagra has not been shown to increase bleeding times in healthy subjects, use in patients with bleeding disorders or significant active peptic ulceration should be based upon a careful risk-benefit assessment and caution.

Counseling Patients About Sexually Transmitted Diseases

The use of Tadagra offers no protection against sexually transmitted diseases. Counseling patients about the protective measures necessary to guard against sexually transmitted diseases, including Human Immunodeficiency Virus (HIV) should be considered.

Consideration of Other Urological Conditions Prior to Initiating Treatment for BPH

Prior to initiating treatment with Tadagra for BPH, consideration should be given to other urological conditions that may cause similar symptoms. In addition, prostate cancer and BPH may coexist.

What should I discuss with my healthcare provider before taking Tadagra?

You should not take Tadagra if you are allergic to it.

Tadagra should not be used together with nitrate medication, such as nitroglycerin (Nitro Dur, Nitrolingual, Nitrostat, Transderm Nitro, and others), isosorbide dinitrate (Dilatrate, Isordil, Isochron), isosorbide mononitrate (Imdur, ISMO, Monoket), or recreational drugs such as amyl nitrate or nitrite ("poppers"). Taking Tadagra with a nitrate medicine for chest pain or heart problems can cause a sudden and serious decrease in blood pressure.

To make sure you can safely take Tadagra, tell your doctor if you have any of these other conditions:

Tadagra can decrease blood flow to the optic nerve of the eye, causing sudden vision loss. This has occurred in a small number of people taking Tadagra, most of whom also had heart disease, diabetes, high blood pressure, high cholesterol, or certain pre-existing eye problems, and in those who smoke or are over 50 years old.

It is not clear whether Tadagra is the actual cause of vision loss. Stop using Tadagra and get emergency medical help if you have sudden vision loss.

FDA pregnancy category B. Tadagra is not expected to harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment with Tadagra.

It is not known whether Tadagra passes into breast milk or if it could harm a nursing baby. Do not use Tadagra without telling your doctor if you are breast-feeding a baby.

Tadagra precautions

Certain people who are very sick or very old or who are sensitive show an exacerbation of side effect of the drug which can turn dangerous at times. So, it is very important to remember the precautions while taking the medicine. Pregnancy and Breastfeeding are also special categories wherein extra care or precaution is needed when taking a drug. Few patients may have a hypersensitivity reaction to few medications, and that can be life-threatening rarely. Penicillin hypersensitivity is one example. Diarrhea, rashes are few other symptoms which need a watch. A patient with other co-existing diseases like liver disease, heart disease, kidney disease should take special precautions.
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Cardiovascular Effects

Discuss with patients the appropriate action to take in the event that they experience anginal chest pain requiring nitroglycerin following intake of Tadagra. At least 48 hours should elapse after the last dose of Tadagra before taking nitrates. If a patient has taken Tadagra within 48 hours, administer nitrates under close medical supervision with appropriate hemodynamic monitoring. Patients who experience anginal chest pain after taking Tadagra should seek immediate medical attention.

PDE5 inhibitors, including Tadagra, have mild systemic vasodilatory properties that may result in transient decreases in blood pressure. Prior to prescribing Tadagra, carefully consider whether patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects. Patients with severely impaired autonomic control of blood pressure or with left ventricular outflow obstruction, (e.g., aortic stenosis and idiopathic hypertrophic subaortic stenosis) may be particularly sensitive to the actions of vasodilators, including PDE5 inhibitors.

Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary venoocclusive disease (PVOD). Since there are no clinical data on administration of Tadagra to patients with veno-occlusive disease, administration of Tadagra to such patients is not recommended. Should signs of pulmonary edema occur when Tadagra is administered, the possibility of associated PVOD should be considered.

There is a lack of data on safety and efficacy in the following groups who were specifically excluded from the PAH clinical trials:

Use with Alpha Blockers and Antihypertensives

PDE5 inhibitors, including Tadagra, and alpha–adrenergic blocking agents are vasodilators with blood pressure– lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some patients, concomitant use of these two drug classes can lower blood pressure significantly, which may lead to symptomatic hypotension (e.g., fainting). Safety of combined use of PDE5 inhibitors and alpha blockers may be affected by other variables, including intravascular volume depletion and use of other antihypertensive drugs.

Use with Alcohol

Both alcohol and Tadagra are mild vasodilators. When mild vasodilators are taken in combination, blood pressure-lowering effects are increased.

Use With Potent CYP3A Inhibitors Or Inducers

Co-administration of Tadagra in Patients on Ritonavir

In patients receiving ritonavir for at least one week, start Tadagra at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Co-administration of Ritonavir in Patients on Tadagra

Avoid use of Tadagra during the initiation of ritonavir. Stop Tadagra at least 24 hours prior to starting ritonavir. After at least one week following the initiation of ritonavir, resume Tadagra at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Other Potent Inhibitors of CYP3A

Tadagra is metabolized predominantly by CYP3A in the liver. In patients taking potent inhibitors of CYP3A such as ketoconazole and itraconazole, avoid use of Tadagra.

Potent Inducers of CYP3A

For patients chronically taking potent inducers of CYP3A, such as rifampin, avoid use of Tadagra.

Use In Renal Impairment

In Patients With Mild Or Moderate Renal Impairment

Start dosing at 20 mg once daily. Increase the dose to 40 mg once daily based upon individual tolerability.

In patients with severe renal impairment

Avoid use of Tadagra because of increased Tadagra exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis.

Use In Hepatic Impairment

In Patients With Mild To Moderate Hepatic Cirrhosis (Child-Pugh Class A and B)

Because of limited clinical experience in patients with mild to moderate hepatic cirrhosis, consider a starting dose of 20 mg once daily Tadagra.

In Patients With Severe Hepatic Cirrhosis (Child-Pugh Class C)

Patients with severe hepatic cirrhosis have not been studied. Avoid use of Tadagra.

Visual Loss

Physicians should advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non–arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision, including permanent loss of vision, that has been reported postmarketing in temporal association with the use of all PDE5 inhibitors. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION, including but not necessarily limited to: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking. Based on published literature, the annual incidence of NAION is 2.5-11.8 cases per 100,000 in males aged ≥ 50 in the general population. An observational study evaluated whether recent episodic use of PDE5 inhibitors, as a class, typical of erectile dysfunction treatment, was associated with acute onset of NAION. The results suggest an approximate 2-fold increase in the risk of NAION within 1 to 4 days of PDE5 inhibitor use.

It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or other factors. Physicians should also discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators such as PDE5 inhibitors.

Patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in the clinical trials, and use in these patients is not recommended.

Hearing Impairment

Physicians should advise patients to seek immediate medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including Tadagra. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors.

Combination With Other PDE5 Inhibitors

Tadagra is also marketed as Tadagra. The safety and efficacy of taking Tadagra together with Tadagra or other PDE5 inhibitors have not been studied. Inform patients taking Tadagra not to take Tadagra or other PDE5 inhibitors.

Prolonged Erection

There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for this class of compounds. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention.

Tadagra should be used with caution in patients who have conditions that might predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia), or in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie's disease).

Effects On Bleeding

PDE5 is found in platelets. When administered in combination with aspirin, Tadagra 20 mg did not prolong bleeding time, relative to aspirin alone. Tadagra has not been administered to patients with bleeding disorders or significant active peptic ulceration. Although Tadagra has not been shown to increase bleeding times in healthy subjects, use in patients with bleeding disorders or significant active peptic ulceration should be based upon a careful risk-benefit assessment.

Patient Counseling Information

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Tadagra was not carcinogenic to rats or mice when administered daily for 2 years at doses up to 400 mg/kg/day. Systemic drug exposures, as measured by AUC of unbound Tadagra, were approximately 5–fold for mice, and 7– and 14–fold for male and female rats, respectively, the exposures at the maximum recommended human dose (MRHD) of 40 mg.

Mutagenesis

Tadagra was not mutagenic in the in vitro bacterial Ames assays or the forward mutation test in mouse lymphoma cells. Tadagra was not clastogenic in the in vitro chromosomal aberration test in human lymphocytes or the in vivo rat micronucleus assays.

Impairment of Fertility

There were no effects on fertility, reproductive performance or reproductive organ morphology in male or female rats given oral doses of Tadagra up to 400 mg/kg/day, a dose producing AUCs for unbound Tadagra of 6–fold for males or 17–fold for females the exposures at the MRHD of 40 mg. In beagle dogs given Tadagra daily for 3 to 12 months, there was treatment–related non–reversible degeneration and atrophy of the seminiferous tubular epithelium in the testes in 20–100% of the dogs that resulted in a decrease in spermatogenesis in 40–75% of the dogs at doses of ≥ 10 mg/kg/day. Systemic exposure (based on AUC) at no–observed–adverse-effect–level (NOAEL) (10 mg/kg/day) for unbound Tadagra was similar to that expected in humans at the MRHD of 40 mg.

There were no treatment–related testicular findings in rats or mice treated with doses up to 400 mg/kg/day for 2 years.

Use In Specific Populations

Pregnancy

Pregnancy Category B

Animal reproduction studies in rats and mice revealed no evidence of fetal harm. There are, however, no adequate and well-controlled studies of Tadagra in pregnant women. Because animal reproduction studies are not always predictive of human response, Tadagra should be used during pregnancy only if clearly needed.

Non–teratogenic effects

Animal reproduction studies showed no evidence of teratogenicity, embryotoxicity, or fetotoxicity when Tadagra was given to pregnant rats or mice at unbound Tadagra exposures up to 7 times the maximum recommended human dose (MRHD) of 40 mg/day during organogenesis. In one of two perinatal/postnatal developmental studies in rats, postnatal pup survival decreased following maternal exposure to unbound Tadagra concentrations greater than 5 times the MRHD based on AUC. Signs of maternal toxicity occurred at doses greater than 8 times the MRHD based on AUC. Surviving offspring had normal development and reproductive performance.

Nursing Mothers

It is not known whether Tadagra is excreted into human milk. While Tadagra or some metabolite of Tadagra was excreted into rat milk, drug levels in animal breast milk may not accurately predict levels of drug in human breast milk. Because many drugs are excreted in human milk, caution should be exercised when Tadagra is administered to a nursing woman.

Pediatric Use

Safety and effectiveness of Tadagra in pediatric patients have not been established.

Geriatric Use

Of the total number of subjects in the clinical study of Tadagra for pulmonary arterial hypertension, 28 percent were 65 and over, while 8 percent were 75 and over. No overall differences in safety were observed between subjects over 65 years of age compared to younger subjects or those over 75 years of age. No dose adjustment is warranted based on age alone; however, a greater sensitivity to medications in some older individuals should be considered..

Renal Impairment

For patients with mild or moderate renal impairment, start Tadagra at 20 mg once daily. Increase the dose to 40 mg once daily based upon individual tolerability.

In patients with severe renal impairment, avoid use of Tadagra because of increased Tadagra exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis.

Hepatic Impairment

Because of limited clinical experience in patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A or B), consider a starting dose of Tadagra 20 mg once daily. Patients with severe hepatic cirrhosis (Child-Pugh Class C) have not been studied, thus avoid use of Tadagra in such patients.

What happens if I miss a dose of Tadagra?

When you miss a dose, you should take it as soon as you remember, but you should take care that it should be well spaced from the next dose. You should not take an extra dose at the time of the second dose as it will become a double dose. The double dose can give unwanted side effects, so be careful. In chronic conditions or when you have a serious health issue, if you miss a dose, you should inform your health care provider and ask his suggestion.

If Tadagra is used as needed, you are not likely to be on a dosing schedule.

If you take Tadagra every day and you miss a dose, take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.


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References

  1. DailyMed. "TADALAFIL: 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).
  2. DrugBank. "Tadalafil". http://www.drugbank.ca/drugs/DB00820 (accessed September 17, 2018).
  3. MeSH. "Vasodilator Agents". https://www.ncbi.nlm.nih.gov/mesh/68... (accessed September 17, 2018).

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