Malegra Dxt Plus

Uses

Duloxetine Hydrochloride is used for the-

• Treatment of Major Depressive Disorder (MDD)
• Management of neuropathic pain associated with diabetic peripheral neuropathy.
• Chronic Musculoskeletal Pain
• Urinary stress incontinence.

Sildenafil Citrate is used for the treatment of Erectile Dysfunction.

Malegra Dxt Plus is also used to associated treatment for these conditions: Back Pain Lower Back Chronic, Chemotherapy-induced Peripheral Neuropathy (CIPN), Chronic Musculoskeletal Pain, Diabetic Peripheral Neuropathy (DPN), Fibromyalgia, Generalized Anxiety Disorder (GAD), Major Depressive Disorder (MDD), Osteoarthritis of the Knee, Stress Urinary Incontinence (SUI)Erectile Dysfunction, NYHA Functional Class II-III Pulmonary arterial hypertension, Premature Ejaculation, Symptomatic pulmonary arterial hypertension (PAH)

How Malegra Dxt Plus works

Duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors.

Action on the external urinary sphincter is mediated via duloxetine's CNS effects. Increased serotonin and norepinephrine concentrations in Onuf's nucleus leads to increased activation of 5-HT₂, 5-HT₃, and α₁ adrenergic receptors. 5-HT₂ and α₁ are both G_q coupled and their activation increases the activity of the inositol trisphosphate/phospholipase C (IP₃/PLC) pathway. This pathway leads to release of intracellular calcium stores, increasing intracellular calcium concentrations, and facilitating neuronal excitability. 5-HT₃ functions as a ligand-gated sodium channel which allows sodium to flow into the neuron when activated. Increased flow of sodium into the neuron contributes to depolarization and activation of voltage gated channels involved in action potential generation. The combined action of these three receptors contributes to increased excitability of the pudendal motor nerve in response to glutamate.

Also related to duloxetine's action at the spinal cord is its modulation of pain. Increasing the concentration of serotonin and norepinephrine in the dorsal horn of the spinal cord increases descending inhibition of pain through activation of 5-HT_1A, 5-HT_1B, 5-HT_1D, 5-HT₂, 5-HT₃, α₁-adrenergic, and α₂-adrenergic receptors. 5-HT₂, 5-HT₃, and α₁-adrenergic mediate neuronal activation as described above. The activated neuron in this case is the GABAergic inhibitory interneuron which synapses onto the nociceptive projection neuron to inhibit the transmission of painful stimuli to the brain. The 5-HT₁ and α₂ receptors are G_i/G_o coupled and their activation leads to increased potassium current through inward rectifier channels and decreased adenylyl cyclase/protein kinase A signaling which contributes to neuronal inhibition. These inhibitory receptors are present on the projection neuron itself as well as the dorsal root ganglion which precedes it and serves to directly suppress the transmission of painful stimuli.

The mechanisms involved in duloxetine's benefits in depression and anxiety have not been fully elucidated. Dysfunctional serotonin and norepinephrine signaling are thought to be involved and increases in the availability of these neurotransmitters at the synaptic cleft thought to mediate a therapeutic effect. It is postulated that the involvement of serotonin and norepinephrine in area responsible for emotional modulation such as the limbic system contributes to the effects in mood disorders specifically but this has yet to be confirmed.

Duloxetine's hypertensive effect is related to its intended pharmacological effect. Increased availability of norepinephrine leads to activation of adrenergic receptors on the vascular endothelium. Since the action of α₁ receptors predominates, vasoconstriction results as the G_q coupled receptor mediates calcium release from the sarcoplasmic reticulum to facilitate smooth muscle contraction.

Sildenafil is an oral therapy for erectile dysfunction . In the natural setting, i.e. with sexual stimulation, it restores impaired erectile function by increasing blood flow to the penis .

The physiological mechanism responsible for the erection of the penis involves the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation . Nitric oxide then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood .

Sildenafil is a potent and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum, where PDE5 is responsible for degradation of cGMP . Sildenafil has a peripheral site of action on erections . Sildenafil has no direct relaxant effect on isolated human corpus cavernosum but potently enhances the relaxant effect of NO on this tissue . When the NO/cGMP pathway is activated, as occurs with sexual stimulation, inhibition of PDE5 by sildenafil results in increased corpus cavernosum levels of cGMP . Therefore sexual stimulation is required in order for sildenafil to produce its intended beneficial pharmacological effects .

Moreover, apart from the presence of PDE5 in the corpus cavernosum of the penis, PDE5 is also present in the pulmonary vasculature . Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation . In patients with pulmonary arterial hypertension, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation .

Dosage

Malegra Dxt Plus dosage

Major Depressive Disorder (MDD): Starting dose- 20-30 mg b.i.d or 60 mg once daily, Target dose- 60 mg once daily, max. dose- 60 mg once daily

Diabetic peripheral neuropathy: Starting dose- 60 mg/day (once daily), Target dose- 60 mg once daily, max. dose- 60 mg once daily

Chronic Musculoskeletal Pain: Starting dose- 30 mg/day, Target dose- 60 mg once daily, max. dose- 60 mg once daily

Urinary stress incontinence: Starting dose- 40 mg /day, Target dose- 80 mg/day (twice daily, max. dose- 80 mg/day (twice daily).

The usual starting dose of Sildenafilis 50 mg once daily. lt should be taken before 30-40 minutes of intercourse. Depending on effectiveness and tolerance; the dose may be increased to a maximum recommended dose of 100 mg or decreased to 25 mg. The maximum dosing frequency is once per day.

Some factors are associated with increased plasma levels of sildenafil: age>65, hepatic impairment, severe renal impairment and concomitant use of ketoconazole, itraconazole, erythromycin. Since higher plasma levels may increase both the efficacy and incidence of adverse events, a starting dose of 25 mg should be considered in these patients.

Sildenafil may takes longer time to work if you take it with a heavy meal.

Side Effects

The most commonly observed adverse events in Duloxetine hydrochloride treated patients were nausea, dizziness, dry mouth, constipation, decreased appetite, fatigue, somnolence, increased sweating, hyperhidrosis and asthenia. It may slightly increase blood pressure. No clinically significant differences were observed for QT, PR, and QRS intervals between Duloxetine -treated and placebo-treated patients.

Like all medicines, Sildenafil can cause side effects although not everybody gets them.The side effects reported in association with the use of Sildenafil are usually mild to moderate and of a short duration. All medicines including Sildenafil can cause allergic reactions.

Contact with doctors immediately if experiences any of the following symptoms after taking Sildenafil: sudden wheeziness, difficulty in breathing or dizziness, swelling of the eyelids, face, lips or throat. Common side effect includes headache, facial flushing, indigestion, effects on vision, light sensitivity, blurred vision or reduced, stuffy nose and dizziness. Uncommon side effect includes vomiting, skin rash, bleeding at the back of the eye, red eyes, eye pain, double vision, abnormal sensation in the eye, irregular or rapid heartbeat, muscle pain, feeling sleepy, reduced sense of touch, vertigo, ringing in the ears, nausea, dry mouth, chest pain & feeling tired.

Toxicity

Overdose

Fatalities have been reported with doses of 1000mg involving both mixed drugs as well as duloxetine alone. Signs and symptoms of overdose include: somnolence, coma, serotonin syndrome, seizure, syncope, hypo- or hypertension, tachycardia, and vomiting. No antidote exists and the drug is unlikely to be cleared by hemodialysis. Supportive care is recommended along with activated charcoal and gastric lavage to reduce absorption. If serotonin syndrome occurs specific treatment such as temperature control or cyproheptadine may be initiated.

Carcinogenicity & Mutagenicity

Increased incidence of hepatocellular carcinomas and adenomas were reported in female mice fed 140 mg/kg/day duloxetine for 2 years, equivalent to 6 times the maximum recommended human dose (MRHD). No effect was reported with doses of 50mg/kg/day (2 time MRHD) in females or 100 mg/kg/day in males (4 times MRHD). Similar investigation in rats produced no carcinogenicity at doses of 27 mg/kg/day (2 times MRHD)in females and 36 mg/kg/day in males (4 times MRHD).

No mutagenicity, clastogenicity, induction of sister chromatid exchange, or genotoxicity has been observed in toxicology investigations.

Reproductive Toxicity

Neither male or female rats displayed adverse reproductive effects at doses up to 45 mg/kg/day (4 times MRHD).

Lactation

An estimated 25% of plasma duloxetine appears in breast milk with the estimated daily infant dose being 0.14% of the maternal dose. Breast milk concentrations have been observed to peak 3 hours after administration.

In single-dose volunteer studies of doses up to 800 mg, adverse reactions were similar to those seen at lower doses, but the incidence rates and severities were increased . Doses of 200 mg did not result in increased efficacy but the incidence of adverse reaction (headache, flushing, dizziness, dyspepsia, nasal congestion, altered vision) was increased .

Due to the lack of data on the effect of sildenafil indicated for the treatment of pulmonary arterial hypertension (PAH) in pregnant women, sildenafil is not recommended for women of childbearing potential unless also using appropriate contraceptive measures .

The safety and efficacy of sildenafil indicated for treating PAH in a woman during labor and delivery have not been studied . Caution should ultimately be exercised when sildenafil is administered to nursing women as it is not known if sildenafil or its metabolites are excreted in human breast milk .

The safety and efficacy of sildenafil for the treatment of PAH in children below 1 year of age has not been established as no data is available .

Clinical experience with the elderly population in the use of sildenafil for the treatment of PAH has been varied. Some reports suggest that there are no identified differences in responses between elderly and younger patients while others have documented that clinical efficacy as measured by 6-minute walk distance could be less in elderly patients . In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy .

Conversely, when sildenafil was used to treat erectile dysfunction in healthy elderly volunteers (65 years or over), a reduced clearance of sildenafil was observed . This reduction resulted in about 90% higher plasma concentrations of sildenafil and the active N-desmethyl metabolite compared to those seen in healthy younger volunteers (18-45 years) . Due to age-differences in plasma protein binding, the corresponding increase in free sildenafil plasma concentration was approximately 40% .

Sildenafil was not carcinogenic when administered to rats for 24 months at a dose resulting in total systemic drug exposure (AUCs) for unbound sildenafil and its major metabolite of 29- and 42- times, for male and female rats, respectively, the exposures observed in human males given the Maximum Recommended Human Dose (MRHD) of 100 mg . Sildenafil was not carcinogenic when administered to mice for 18-21 months at dosages up to the Maximum Tolerated Dose (MTD) of 10 mg/kg/day, approximately 0.6 times the MRHD on a mg/m2 basis .

Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity .

There was no impairment of fertility in rats given sildenafil up to 60 mg/kg/day for 36 days to females and 102 days to males, a dose producing an AUC value of more than 25 times the human male AUC .

Precaution

Duloxetine hydrochloride should ordinarily not be prescribed to patients with substantial alcohol use. Blood pressure should be measured prior to initiating treatment and periodically measured throughout treatment. It should be used cautiously in patients with a history of mania, seizure disorder and controlled narrow-angle glaucoma.

Warnings: In patients with preexisting cardiovascular disease, there is a potential risk in sexual activity. Sildenafil should not be generally used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status. Sildenafil has systemic vasodilatory properties (mean maximum decrease of 8.4/5.5 mmHg). Patients with left ventricular outflow obstruction (e.g. aortic stenosis, idiopathic hypertrophic subaortic stenosis) and those with severely impaired autonomic control of blood can be particularly sensitive to the actions of vasodilators including Sildenafil.There is no controlled clinical data on the safety or efficacy of Sildenafil in Patients who have suffered from a myocardial infarction, stroke, or life-threatening arrhythmia within the last 6 months. Caution should be taken in patients with resting hypotension (BP <90/50) or hypertension (BP >170/110), cardiac failure or coronary artery disease causing unstable angina, retinitis pigmentosa. Prolonged erection greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported infrequently since market approval of Sildenafil. In this situation, patient should seek immediate medical assistance.

Precautions: Please tell your doctor or pharmacist if you are taking or have recently taken other medicines, including medicines obtained without prescription. Sildenafil tablets may interfere with some medicines, especially those used to treat chest pain. In the event of a medical emergency, you should tell the healthcare professional treating your condition that you have taken Sildenafil and if you did, do not take Sildenafil with other medicines unless your doctor tells you can.You should not take Sildenafil if you are taking medicines called nitrates as the combination of these products may cause a potentially dangerous decrease in your blood pressure. Always tell your doctor or pharmacist if you are taking any of these medicines that are often used for the relief of angina pectoris (or chest painJ.You should not take Sildenafil if you are using any of the drugs known as nitric oxide donors such as amyl nitrite as the combination may also lead to potentially dangerous decrease in your blood pressure. If you are taking medicines known as protease inhibitors, such as for the treatment of HIV, your doctor may start you on the lowest dose (25 mg) of Sildenafil. Some patients who take alpha-blocker therapy for the treatment of high blood pressure or prostate enlargement may experience dizziness or light-headedness, which may be caused by low blood pressure upon sitting or standing up quickly. Certain patients have experienced these symptoms when taking Sildenafil with alpha-blocker. This is most likely to occur within 4 hours after taking Sildenafil. In order to reduce the likelihood of these symptoms occur,you should be on a regular daily dose of your alpha-blocker before you start Sildenafil. Your doctor may start you on a lower dose (2S mg) of Sildenafil if you have hypotension (avoid if systolic blood pressure below 90 mmHg), recent stroke, unstable angina & myocardial infarction. Drinking alcohol can temporally impair your ability to get an erection, to get the maximum benefit from your medicine; you are advised not to drink excessive amounts of alcohol before taking Sildenafil.

Interaction

Monoamine oxidase inhibitors (MAOIs): Due to the risk of serotonin syndrome, Duloxetine should not be used in combination with non selective, irreversible monoamine oxidase inhibitors (MAOIs), or within at least 14 days of discontinuing treatment with an MAOI.

Inhibitors of CYP1A2: Because CYP1A2 is involved in Duloxetine metabolism, concomitant use with potent inhibitors of CYP1A2 is likely to result in higher concentrations of Duloxetine. Therefore, Duloxetine should not be administered in combination with potent inhibitors of CYP1A2 like fluvoxamine.

CNS medicinal products: Caution is advised when Duloxetine is taken in combination with other centrally acting medicinal products or substances, including alcohol and sedative medicinal products (e.g., benzodiazepines, morphinomimetics, antipsychotics, phenobarbital, sedative antihistamines).

Inhibitors of CYP3A4 such as cimetidine and erythromycin are likely to reduce sildenafil clearance. CYP3A4 inducers such as rifampicin may decrease the plasma concentrations of sildenafil. Symptomatic hypotension when used with α-blockers. Plasma concentrations are increased by ritonavir.

Volume of Distribution

Apparent Vd of 1620-1800 L. Duloxetine crosses the blood-brain barrier and collects in the cerebral cortex at a higher concentration than the plasma.

The mean steady-state volume of distribution documented for sildenafil is approximately 105 L - a value which suggests the medication undergoes distribution into the tissues .

Elimination Route

Duloxetine is incompletely absorbed with a mean bioavailability of 50% although there is wide variability in the range of 30-80%. The population absorption constant (ka) is 0.168 h^{-1 Administering duloxetine with food 3 hour delay in Tmax along with an 10% decrease in AUC. Similarly, administering the dose at bedtime produces a 4 hour delay and 18% decrease in AUC with a 29% reduction in Cmax. These are attributed to delayed gastric emptying in both cases but are not expected to impact therapy to a clinically significant degree.}

Sildenafil is known to be quickly absorbed, with maximum plasma concentrations being observed within 30-120 minutes (with a median of 60 minutes) of oral administration in a fasting patient . Moreover, the mean absolute bioavailability observed for sildenafil is about 41% (from a range of 25-63%) . In particular, after oral three times a day dosing of sildenafil, the AUC and Cmax increase in proportion with dose over the recommended dosage range of 25-100 mg .

When used in pulmonary arterial hypertension patients, however, the oral bioavailability of sildenafil after a dosing regimen of 80 mg three times a day, was on average 43% greater than compared to the lower doses .

Finally, if sildenafil is administered orally with food, the rate of absorption is observed to be decreased with a mean delay in Tmax of about 60 minutes and a mean decrease in Cmax of approximately 29% . Regardless, the extent of absorption is not observed to be significantly affected as the recorded AUC decreased by only about 11 % .

Half Life

Mean of 12 h with a range of 8-17.

The terminal phase half-life observed for sildenafil is approximately 3 to 5 hours .

Clearance

There is a large degree of interindividual variation reported in the clearance of duloxetine with values ranging from 57-114 L/h. Steady state concentrations have still been shown to be dose proportional with a doubling of dose from 30 to 60 mg and from 60 to 120 mg producing 2.3 and 2.6 times the Css respectively.

The total body clearance documented for sildenafil is 41 L/h .

Elimination Route

About 70% of duloxetine is excreted in the urine mainly as conjugated metabolites. Another 20% is present in the feces as the parent drug, 4-hydroxy metabolite, and an uncharacterized metabolite. Biliary secretion is thought to play a role due to timeline of fecal excretion exceeding the time expected of normal GI transit.

After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose) .

Pregnancy & Breastfeeding use

Pregnancy: Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women; therefore, Duloxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery: The effect of Duloxetine on labor and delivery in humans is unknown. Duloxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.

Lactation: It is unknown whether or not Duloxetine and/or it's metabolites are excreted into human milk, but nursing while on Duloxetine is not recommended.

Sildenafil is not indicated for use in newborns, children & women.

Contraindication

Duloxetine is contraindicated in patients with a known hypersensitivity to this drug or any of the inactive ingredients. Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated. It should be avoided in patients with uncontrolled narrow-angle glaucoma.

Sildenafil was shown to potentiate the hypotensive effects of nitrates and its administration to patients who are using organic nitrates, either regularly and or intermittently, in any form is therefore contraindicated.

Special Warning

Use in children: Safety and efficacy in pediatric patients have not been established.

Acute Overdose

There is limited clinical experience with Duloxetine overdose in humans. There is no specific antidote to Duloxetine. In case of acute overdose, treatment should consist of those general measures employed in the management of overdose with any drug. An adequate airway, oxygenation, and ventilation should be assured, and cardiac rhythm and vital signs should be monitored. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal may be useful in limiting absorption of Duloxetine from the gastrointestinal tract.

In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses but incidence rates and severities were increased. In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine.

Storage Condition

Store in a cool and dry place, protected from light and moisture.

Store below 30° C. Protect from light and moisture. Keep out of reach of children.

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