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Nitrofurantoin is specifically indicated for the treatment & prophylaxis of urinary tract infections caused by susceptible strains of Escherichia coli, Enterococci, Staphylococcus aureus, Staphylococcus saprophyticus and certain susceptible strains of Klebsiella and Enterobacter species.

Systemic Urinary Anti- infective

Nitrofurantoin is an antibacterial agent specific for urinary tract infections. Nitrofurantoin is highly soluble in urine, to which it may impart a brown color. Nitrofurantoin inactivates or alters bacterial ribosomal proteins and other macromolecules. Nitrofurantoin has been shown to be active against the following bacteria: Gram-Positive Aerobes Staphylococcus saprophyticus, Coagulase-negative staphylococci (including Staphylococcus epidermidis), Enterococcus faecalis, Staphylococcus aureus, Streptococcus agalactiae, Group D streptococci, Viridans group streptococci. Gram-Negative Aerobes- Escherichia coli, Citrobacter amalonaticus, Citrobacter diversus, Citrobacter freundii, Klebsiella oxytoca, Klebsiella ozaenae.

Nitrofurantoin tablet (In adults):

• Uncomplicated urinary tract infections: 50-100 mg four times a day- the lower dosage level is recommended. Therapy should be continued for one week or for at least 3 days after sterility of the urine is obtained.
• For long-term suppressive therapy: In adults, a reduction of dosage to 50-100 mg at bedtime may be adequate.

Nitrofurantoin capsule (In adults):

• Acute Uncomplicated Urinary Tract Infections (UTIs): 50 mg four times daily for 7 days.
• Long term suppression: 50-100 mg once a day.
• Prophylaxis: 50 mg four times daily for the duration of procedure and for three days thereafter.

Nitrofurantoin SR capsule:

• Adults and Children over 12 years: One 100 mg capsule every 12 hours for seven days.
• Genito-urinary surgical prophylaxis: One capsule twice daily on day of procedure and for next 3 days.

Nitrofurantoin suspension: Children: 5-7 mg/kg/day in four divided doses (contraindicated under one month of age). The average dose of Nintoin suspension for pediatric patients are as follows-

• 7 to 11 kg: ½ (2.5 ml) teaspoonfuls 4 times daily.
• 12 to 21 kg: 1 (5 ml) teaspoonfuls 4 times daily.
• 22 to 30 kg: 1½ (7.5 ml) teaspoonfuls 4 times daily.
• 31 to 41 kg: 2 (10 ml) teaspoonfuls 4 times daily.

Therapy should be continued for one week or for at least 3 days after sterility of the urine is obtained. For long-term suppressive therapy in children, doses as low as 1 mg/kg per 24 hours, given in a single dose or in two divided doses, may be adequate.

Nitrofurantoin should be taken with food.

The most frequent clinical adverse events are nausea, headache, and flatulence. Other less occurred adverse events are diarrhea, dyspepsia, abdominal pain, constipation, emesis, dizziness and drowsiness.

Anuria, oliguria or significant impairment of renal function are contraindications. This drug is contraindicated in pregnant patients at 38-42 weeks, during labor and delivery. Nitrofurantoin is also contraindicated in those patients with known hypersensitivity to Nitrofurantoin.

If acute, sub-acute or chronic pulmonary reactions occur, Nitrofurantoin should be discontinued. Antacid preparations containing magnesium trisilicate should not be taken while taking Nitrofurantoin.

Antacids containing Magnesium Trisilicate, when administered concomitantly with Nitrofurantoin, reduce both the rate and extent of absorption of Uricosuric drugs, such as Probenecid and Sulfinpyrazone, can inhibit renal tubular secretion of Nitrofurantoin.

Pregnancy Category B. There are no adequate and well-controlled studies in pregnant women. This drug should be used during pregnancy only if clearly needed. Nitrofurantoin has been detected in human breast milk in trace amounts. Because of the potential for serious adverse reactions from Nitrofurantoin in nursing infants under one month of age, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Occasional incidents of acute overdosage of Nitrofurantoin have not resulted in any specific symptoms other than vomiting. Induction of emesis is recommended.

Do not store above 30°C. Keep away from light and out of the reach of children.

Nitrofurantoin is specifically indicated for the treatment & prophylaxis of urinary tract infections caused by susceptible strains of Escherichia coli, Enterococci, Staphylococcus aureus, Staphylococcus saprophyticus and certain susceptible strains of Klebsiella and Enterobacter species.

Systemic Urinary Anti- infective

Nitrofurantoin is an antibacterial agent specific for urinary tract infections. Nitrofurantoin is highly soluble in urine, to which it may impart a brown color. Nitrofurantoin inactivates or alters bacterial ribosomal proteins and other macromolecules. Nitrofurantoin has been shown to be active against the following bacteria: Gram-Positive Aerobes Staphylococcus saprophyticus, Coagulase-negative staphylococci (including Staphylococcus epidermidis), Enterococcus faecalis, Staphylococcus aureus, Streptococcus agalactiae, Group D streptococci, Viridans group streptococci. Gram-Negative Aerobes- Escherichia coli, Citrobacter amalonaticus, Citrobacter diversus, Citrobacter freundii, Klebsiella oxytoca, Klebsiella ozaenae.

Nitrofurantoin tablet (In adults):

• Uncomplicated urinary tract infections: 50-100 mg four times a day- the lower dosage level is recommended. Therapy should be continued for one week or for at least 3 days after sterility of the urine is obtained.
• For long-term suppressive therapy: In adults, a reduction of dosage to 50-100 mg at bedtime may be adequate.

Nitrofurantoin capsule (In adults):

• Acute Uncomplicated Urinary Tract Infections (UTIs): 50 mg four times daily for 7 days.
• Long term suppression: 50-100 mg once a day.
• Prophylaxis: 50 mg four times daily for the duration of procedure and for three days thereafter.

Nitrofurantoin SR capsule:

• Adults and Children over 12 years: One 100 mg capsule every 12 hours for seven days.
• Genito-urinary surgical prophylaxis: One capsule twice daily on day of procedure and for next 3 days.

Nitrofurantoin suspension: Children: 5-7 mg/kg/day in four divided doses (contraindicated under one month of age). The average dose of Nintoin suspension for pediatric patients are as follows-

• 7 to 11 kg: ½ (2.5 ml) teaspoonfuls 4 times daily.
• 12 to 21 kg: 1 (5 ml) teaspoonfuls 4 times daily.
• 22 to 30 kg: 1½ (7.5 ml) teaspoonfuls 4 times daily.
• 31 to 41 kg: 2 (10 ml) teaspoonfuls 4 times daily.

Therapy should be continued for one week or for at least 3 days after sterility of the urine is obtained. For long-term suppressive therapy in children, doses as low as 1 mg/kg per 24 hours, given in a single dose or in two divided doses, may be adequate.

Nitrofurantoin should be taken with food.

The most frequent clinical adverse events are nausea, headache, and flatulence. Other less occurred adverse events are diarrhea, dyspepsia, abdominal pain, constipation, emesis, dizziness and drowsiness.

Anuria, oliguria or significant impairment of renal function are contraindications. This drug is contraindicated in pregnant patients at 38-42 weeks, during labor and delivery. Nitrofurantoin is also contraindicated in those patients with known hypersensitivity to Nitrofurantoin.

If acute, sub-acute or chronic pulmonary reactions occur, Nitrofurantoin should be discontinued. Antacid preparations containing magnesium trisilicate should not be taken while taking Nitrofurantoin.

Antacids containing Magnesium Trisilicate, when administered concomitantly with Nitrofurantoin, reduce both the rate and extent of absorption of Uricosuric drugs, such as Probenecid and Sulfinpyrazone, can inhibit renal tubular secretion of Nitrofurantoin.

Pregnancy Category B. There are no adequate and well-controlled studies in pregnant women. This drug should be used during pregnancy only if clearly needed. Nitrofurantoin has been detected in human breast milk in trace amounts. Because of the potential for serious adverse reactions from Nitrofurantoin in nursing infants under one month of age, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Occasional incidents of acute overdosage of Nitrofurantoin have not resulted in any specific symptoms other than vomiting. Induction of emesis is recommended.

Do not store above 30°C. Keep away from light and out of the reach of children.

Mirabegron is indicated for the symptomatic treatment of urgency, increased micturition frequency and urgency incontinence as may occur in adult patients with overactive bladder (OAB) syndrome.

BPH/ Urinary retention/ Urinary incontinence

Mirabegron is the first beta-3 adrenoceptor agonist. Mirabegron exerts its effect via a dual mechanism, both directly acts on the bladder smooth muscle and also via the sensory nervous system, it increases the levels of cyclic adenosine monophosphate (cyclic AMP) and leads to relaxation of the detrusor smooth muscle during storage phase of urinary bladder fill-void cycle by activation of beta-3 adrenoceptor which increase bladder capacity.

Adults including elderly: The recommended starting dose is Mirabegron 25 mg tablet once daily with or without food. Based on individual patient efficacy and tolerability the dose may be increased to Mirabegron 50 mg tablet once daily.

Renal or hepatic impairment:

• Patients with severe renal impairment (ClCr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m2) or moderate hepatic impairment (Child-Pugh Class B), the daily dose of Mirabegron should not exceed 25 mg tablet once daily.
• Mirabegron has not been studied in patients with end stage renal disease (GFR <15 mL/min/1.73 m2 or patients requiring haemodialysis) or severe hepatic impairment (Child Pugh Class C) and it is therefore not recommended for use in these patient populations.

Gender: No dose adjustment is necessary according to gender.

Paediatric population: The safety and efficacy of Mirabegron in children below 18 years of age have not yet been established.

Mirabegron tablet is to be taken once daily, with liquids, swallowed whole and is not to be chewed, divided, or crushed.

The most common side effects reported for patients treated with Mirabegron 50 mg during the three 12-week phase 3 double blind, placebo controlled studies are tachycardia and urinary tract infections. The frequency of tachycardia was 1.2% in patients receiving Mirabegron 50 mg. Tachycardia led to discontinuation in 0.1% patients receiving Mirabegron 50 mg. The frequency of urinary tract infections was 2.9% in patients receiving Mirabegron 50 mg. Urinary tract infections led to discontinuation in none of the patients receiving Mirabegron 50 mg. Serious adverse reactions included atrial fibrillation (0.2%).

Mirabegron is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients and severe uncontrolled hypertension defined as systolic blood pressure 180 mm Hg and/or diastolic blood pressure 110 mm Hg.

Renal impairment: Mirabegron has not been studied in patients with end stage renal disease (GFR <15 mL/min/1.73 m2 or patients requiring haemodialysis) and therefore, it is not recommended for use in this patient population. Data are limited in patients with severe renal impairment (GFR 15 to 29 mL/min/1.73 m2); based on a pharmacokinetic study a dose reduction to 25 mg is recommended in this population. Mirabegron is not recommended for use in patients with severe renal impairment (GFR 15 to 29 mL/min/1.73 m2) concomitantly receiving strong CYP3A inhibitors.

Hepatic impairment: Mirabegron has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and, therefore, it is not recommended for use in this patient population. Mirabegron is not recommended for use in patients with moderate hepatic impairment (Child-Pugh Class B) concomitantly receiving strong CYP3A inhibitors.

Hypertension: Mirabegron can increase blood pressure. Blood pressure should be measured at baseline and periodically during treatment with Mirabegron, especially in hypertensive patients. Data are limited in patients with stage 2 hypertension (systolic blood pressure 160 mm Hg or diastolic blood pressure 100 mm Hg).

Patients with congenital or acquired QT prolongation: Caution should be exercised when administering Mirabegron in patients with congenital or acquired QT prolongation.

Patients with bladder outlet obstruction and patients taking antimuscarinics medications for OAB: A controlled clinical safety study in patients with bladder outlet obstruction (BOO) did not demonstrate increased urinary retention in patients treated with Mirabegron; however, Mirabegron should be administered with caution to patients with clinically significant bladder outlet obstruction. Mirabegron should also be administered with caution to patients taking antimuscarinic medications for the treatment of OAB.

Effect of enzyme inhibitors: Mirabegron exposure (AUC) was increased 1.8-fold in the presence of the strong inhibitor of CYP3A/P-gp ketoconazole in healthy volunteers. No dose adjustment is needed when Mirabegron is combined with inhibitors of CYP3A and/or P-gp. However, in patients with mild to moderate renal impairment or mild hepatic impairment concomitantly receiving strong CYP3A inhibitors, such as itraconazole, ketoconazole, ritonavir and clarithromycin, the recommended dose is 25 mg once daily with or without food. Mirabegron is not recommended in patients with severe renal impairment or patients with moderate hepatic impairment concomitantly receiving strong CYP3A inhibitors.

Effect of enzyme inducers: Substances that are inducers of CYP3A or P-gp decrease the plasma concentrations of Mirabegron. No dose adjustment is needed for Mirabegron when administered with therapeutic doses of rifampicin or other CYP3A or P-gp inducers.

Effect of Mirabegron on CYP2D6 substrates: In healthy volunteers, the inhibitory potency of Mirabegron towards CYP2D6 is moderate and the CYP2D6 activity recovers within 15 days after discontinuation of Mirabegron. Multiple once daily dosing of Mirabegron IR resulted in a 90% increase in Cmax and a 229% increase in AUC of a single dose of metoprolol. Multiple once daily dosing of Mirabegron resulted in a 79% increase in Cmax and a 241% increase in AUC of a single dose of desipramine. Caution is advised if Mirabegron is co-administered with medicinal products with a narrow therapeutic index and significantly metabolised by CYP2D6, such as thioridazine, Type 1 C antiarrhythmics (e.g., flecainide, propafenone) and tricyclic antidepressants (e.g., imipramine, desipramine). Caution is also advised if Mirabegron is co-administered with CYP2D6 substrates that are individually dose titrated.

Effect of Mirabegron on transporters: Mirabegron is a weak inhibitor of P-gp. Mirabegron increased Cmax and AUC by 29% and 27%, respectively, of the P-gp substrate digoxin in healthy volunteers. For patients who are initiating a combination of Mirabegron and digoxin, the lowest dose for digoxin should be prescribed initially. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.

Other interactions: No clinically relevant interactions have been observed when Mirabegron was co-administered with therapeutic doses of solifenacin, tamsulosin, warfarin, metformin or a combined oral contraceptive medicinal product containing ethinylestradiol and levonorgestrel. Dose-adjustment is not recommended.

There are limited amount of data from the use of Mirabegron in pregnant women. Studies in animals have shown reproductive toxicity. Mirabegron is not recommended during pregnancy and in women is planning to be pregnant. Mirabegron is excreted in the milk of rodents and therefore is predicted to be present in human milk. No studies have been conducted to assess the impact of Mirabegron on milk production in humans, its presence in human breast milk, or its effects on the breast-fed child. Mirabegron should not be administered during breast-feeding. There were no treatment-related effects of Mirabegron on fertility in animals. The effect of Mirabegron on human fertility has not been established.

Mirabegron has been administered to healthy volunteers at single doses up to 400 mg. At this dose, adverse events reported included palpitations and increased pulse rate exceeding 100 beats per minute (bpm). Multiple doses of Mirabegron up to 300 mg daily for 10 days showed increases in pulse rate and systolic blood pressure when administered to healthy volunteers. Treatment for overdose should be symptomatic and supportive. In the event of overdose, pulse rate, blood pressure, and ECG monitoring is recommended.

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

Mirabegron is indicated for the symptomatic treatment of urgency, increased micturition frequency and urgency incontinence as may occur in adult patients with overactive bladder (OAB) syndrome.

BPH/ Urinary retention/ Urinary incontinence

Mirabegron is the first beta-3 adrenoceptor agonist. Mirabegron exerts its effect via a dual mechanism, both directly acts on the bladder smooth muscle and also via the sensory nervous system, it increases the levels of cyclic adenosine monophosphate (cyclic AMP) and leads to relaxation of the detrusor smooth muscle during storage phase of urinary bladder fill-void cycle by activation of beta-3 adrenoceptor which increase bladder capacity.

Adults including elderly: The recommended starting dose is Mirabegron 25 mg tablet once daily with or without food. Based on individual patient efficacy and tolerability the dose may be increased to Mirabegron 50 mg tablet once daily.

Renal or hepatic impairment:

• Patients with severe renal impairment (ClCr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m2) or moderate hepatic impairment (Child-Pugh Class B), the daily dose of Mirabegron should not exceed 25 mg tablet once daily.
• Mirabegron has not been studied in patients with end stage renal disease (GFR <15 mL/min/1.73 m2 or patients requiring haemodialysis) or severe hepatic impairment (Child Pugh Class C) and it is therefore not recommended for use in these patient populations.

Gender: No dose adjustment is necessary according to gender.

Paediatric population: The safety and efficacy of Mirabegron in children below 18 years of age have not yet been established.

Mirabegron tablet is to be taken once daily, with liquids, swallowed whole and is not to be chewed, divided, or crushed.

The most common side effects reported for patients treated with Mirabegron 50 mg during the three 12-week phase 3 double blind, placebo controlled studies are tachycardia and urinary tract infections. The frequency of tachycardia was 1.2% in patients receiving Mirabegron 50 mg. Tachycardia led to discontinuation in 0.1% patients receiving Mirabegron 50 mg. The frequency of urinary tract infections was 2.9% in patients receiving Mirabegron 50 mg. Urinary tract infections led to discontinuation in none of the patients receiving Mirabegron 50 mg. Serious adverse reactions included atrial fibrillation (0.2%).

Mirabegron is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients and severe uncontrolled hypertension defined as systolic blood pressure 180 mm Hg and/or diastolic blood pressure 110 mm Hg.

Renal impairment: Mirabegron has not been studied in patients with end stage renal disease (GFR <15 mL/min/1.73 m2 or patients requiring haemodialysis) and therefore, it is not recommended for use in this patient population. Data are limited in patients with severe renal impairment (GFR 15 to 29 mL/min/1.73 m2); based on a pharmacokinetic study a dose reduction to 25 mg is recommended in this population. Mirabegron is not recommended for use in patients with severe renal impairment (GFR 15 to 29 mL/min/1.73 m2) concomitantly receiving strong CYP3A inhibitors.

Hepatic impairment: Mirabegron has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and, therefore, it is not recommended for use in this patient population. Mirabegron is not recommended for use in patients with moderate hepatic impairment (Child-Pugh Class B) concomitantly receiving strong CYP3A inhibitors.

Hypertension: Mirabegron can increase blood pressure. Blood pressure should be measured at baseline and periodically during treatment with Mirabegron, especially in hypertensive patients. Data are limited in patients with stage 2 hypertension (systolic blood pressure 160 mm Hg or diastolic blood pressure 100 mm Hg).

Patients with congenital or acquired QT prolongation: Caution should be exercised when administering Mirabegron in patients with congenital or acquired QT prolongation.

Patients with bladder outlet obstruction and patients taking antimuscarinics medications for OAB: A controlled clinical safety study in patients with bladder outlet obstruction (BOO) did not demonstrate increased urinary retention in patients treated with Mirabegron; however, Mirabegron should be administered with caution to patients with clinically significant bladder outlet obstruction. Mirabegron should also be administered with caution to patients taking antimuscarinic medications for the treatment of OAB.

Effect of enzyme inhibitors: Mirabegron exposure (AUC) was increased 1.8-fold in the presence of the strong inhibitor of CYP3A/P-gp ketoconazole in healthy volunteers. No dose adjustment is needed when Mirabegron is combined with inhibitors of CYP3A and/or P-gp. However, in patients with mild to moderate renal impairment or mild hepatic impairment concomitantly receiving strong CYP3A inhibitors, such as itraconazole, ketoconazole, ritonavir and clarithromycin, the recommended dose is 25 mg once daily with or without food. Mirabegron is not recommended in patients with severe renal impairment or patients with moderate hepatic impairment concomitantly receiving strong CYP3A inhibitors.

Effect of enzyme inducers: Substances that are inducers of CYP3A or P-gp decrease the plasma concentrations of Mirabegron. No dose adjustment is needed for Mirabegron when administered with therapeutic doses of rifampicin or other CYP3A or P-gp inducers.

Effect of Mirabegron on CYP2D6 substrates: In healthy volunteers, the inhibitory potency of Mirabegron towards CYP2D6 is moderate and the CYP2D6 activity recovers within 15 days after discontinuation of Mirabegron. Multiple once daily dosing of Mirabegron IR resulted in a 90% increase in Cmax and a 229% increase in AUC of a single dose of metoprolol. Multiple once daily dosing of Mirabegron resulted in a 79% increase in Cmax and a 241% increase in AUC of a single dose of desipramine. Caution is advised if Mirabegron is co-administered with medicinal products with a narrow therapeutic index and significantly metabolised by CYP2D6, such as thioridazine, Type 1 C antiarrhythmics (e.g., flecainide, propafenone) and tricyclic antidepressants (e.g., imipramine, desipramine). Caution is also advised if Mirabegron is co-administered with CYP2D6 substrates that are individually dose titrated.

Effect of Mirabegron on transporters: Mirabegron is a weak inhibitor of P-gp. Mirabegron increased Cmax and AUC by 29% and 27%, respectively, of the P-gp substrate digoxin in healthy volunteers. For patients who are initiating a combination of Mirabegron and digoxin, the lowest dose for digoxin should be prescribed initially. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.

Other interactions: No clinically relevant interactions have been observed when Mirabegron was co-administered with therapeutic doses of solifenacin, tamsulosin, warfarin, metformin or a combined oral contraceptive medicinal product containing ethinylestradiol and levonorgestrel. Dose-adjustment is not recommended.

There are limited amount of data from the use of Mirabegron in pregnant women. Studies in animals have shown reproductive toxicity. Mirabegron is not recommended during pregnancy and in women is planning to be pregnant. Mirabegron is excreted in the milk of rodents and therefore is predicted to be present in human milk. No studies have been conducted to assess the impact of Mirabegron on milk production in humans, its presence in human breast milk, or its effects on the breast-fed child. Mirabegron should not be administered during breast-feeding. There were no treatment-related effects of Mirabegron on fertility in animals. The effect of Mirabegron on human fertility has not been established.

Mirabegron has been administered to healthy volunteers at single doses up to 400 mg. At this dose, adverse events reported included palpitations and increased pulse rate exceeding 100 beats per minute (bpm). Multiple doses of Mirabegron up to 300 mg daily for 10 days showed increases in pulse rate and systolic blood pressure when administered to healthy volunteers. Treatment for overdose should be symptomatic and supportive. In the event of overdose, pulse rate, blood pressure, and ECG monitoring is recommended.

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

Mirabegron is indicated for the symptomatic treatment of urgency, increased micturition frequency and urgency incontinence as may occur in adult patients with overactive bladder (OAB) syndrome.

BPH/ Urinary retention/ Urinary incontinence

Mirabegron is the first beta-3 adrenoceptor agonist. Mirabegron exerts its effect via a dual mechanism, both directly acts on the bladder smooth muscle and also via the sensory nervous system, it increases the levels of cyclic adenosine monophosphate (cyclic AMP) and leads to relaxation of the detrusor smooth muscle during storage phase of urinary bladder fill-void cycle by activation of beta-3 adrenoceptor which increase bladder capacity.

Adults including elderly: The recommended starting dose is Mirabegron 25 mg tablet once daily with or without food. Based on individual patient efficacy and tolerability the dose may be increased to Mirabegron 50 mg tablet once daily.

Renal or hepatic impairment:

• Patients with severe renal impairment (ClCr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m2) or moderate hepatic impairment (Child-Pugh Class B), the daily dose of Mirabegron should not exceed 25 mg tablet once daily.
• Mirabegron has not been studied in patients with end stage renal disease (GFR <15 mL/min/1.73 m2 or patients requiring haemodialysis) or severe hepatic impairment (Child Pugh Class C) and it is therefore not recommended for use in these patient populations.

Gender: No dose adjustment is necessary according to gender.

Paediatric population: The safety and efficacy of Mirabegron in children below 18 years of age have not yet been established.

Mirabegron tablet is to be taken once daily, with liquids, swallowed whole and is not to be chewed, divided, or crushed.

The most common side effects reported for patients treated with Mirabegron 50 mg during the three 12-week phase 3 double blind, placebo controlled studies are tachycardia and urinary tract infections. The frequency of tachycardia was 1.2% in patients receiving Mirabegron 50 mg. Tachycardia led to discontinuation in 0.1% patients receiving Mirabegron 50 mg. The frequency of urinary tract infections was 2.9% in patients receiving Mirabegron 50 mg. Urinary tract infections led to discontinuation in none of the patients receiving Mirabegron 50 mg. Serious adverse reactions included atrial fibrillation (0.2%).

Mirabegron is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients and severe uncontrolled hypertension defined as systolic blood pressure 180 mm Hg and/or diastolic blood pressure 110 mm Hg.

Renal impairment: Mirabegron has not been studied in patients with end stage renal disease (GFR <15 mL/min/1.73 m2 or patients requiring haemodialysis) and therefore, it is not recommended for use in this patient population. Data are limited in patients with severe renal impairment (GFR 15 to 29 mL/min/1.73 m2); based on a pharmacokinetic study a dose reduction to 25 mg is recommended in this population. Mirabegron is not recommended for use in patients with severe renal impairment (GFR 15 to 29 mL/min/1.73 m2) concomitantly receiving strong CYP3A inhibitors.

Hepatic impairment: Mirabegron has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and, therefore, it is not recommended for use in this patient population. Mirabegron is not recommended for use in patients with moderate hepatic impairment (Child-Pugh Class B) concomitantly receiving strong CYP3A inhibitors.

Hypertension: Mirabegron can increase blood pressure. Blood pressure should be measured at baseline and periodically during treatment with Mirabegron, especially in hypertensive patients. Data are limited in patients with stage 2 hypertension (systolic blood pressure 160 mm Hg or diastolic blood pressure 100 mm Hg).

Patients with congenital or acquired QT prolongation: Caution should be exercised when administering Mirabegron in patients with congenital or acquired QT prolongation.

Patients with bladder outlet obstruction and patients taking antimuscarinics medications for OAB: A controlled clinical safety study in patients with bladder outlet obstruction (BOO) did not demonstrate increased urinary retention in patients treated with Mirabegron; however, Mirabegron should be administered with caution to patients with clinically significant bladder outlet obstruction. Mirabegron should also be administered with caution to patients taking antimuscarinic medications for the treatment of OAB.

Effect of enzyme inhibitors: Mirabegron exposure (AUC) was increased 1.8-fold in the presence of the strong inhibitor of CYP3A/P-gp ketoconazole in healthy volunteers. No dose adjustment is needed when Mirabegron is combined with inhibitors of CYP3A and/or P-gp. However, in patients with mild to moderate renal impairment or mild hepatic impairment concomitantly receiving strong CYP3A inhibitors, such as itraconazole, ketoconazole, ritonavir and clarithromycin, the recommended dose is 25 mg once daily with or without food. Mirabegron is not recommended in patients with severe renal impairment or patients with moderate hepatic impairment concomitantly receiving strong CYP3A inhibitors.

Effect of enzyme inducers: Substances that are inducers of CYP3A or P-gp decrease the plasma concentrations of Mirabegron. No dose adjustment is needed for Mirabegron when administered with therapeutic doses of rifampicin or other CYP3A or P-gp inducers.

Effect of Mirabegron on CYP2D6 substrates: In healthy volunteers, the inhibitory potency of Mirabegron towards CYP2D6 is moderate and the CYP2D6 activity recovers within 15 days after discontinuation of Mirabegron. Multiple once daily dosing of Mirabegron IR resulted in a 90% increase in Cmax and a 229% increase in AUC of a single dose of metoprolol. Multiple once daily dosing of Mirabegron resulted in a 79% increase in Cmax and a 241% increase in AUC of a single dose of desipramine. Caution is advised if Mirabegron is co-administered with medicinal products with a narrow therapeutic index and significantly metabolised by CYP2D6, such as thioridazine, Type 1 C antiarrhythmics (e.g., flecainide, propafenone) and tricyclic antidepressants (e.g., imipramine, desipramine). Caution is also advised if Mirabegron is co-administered with CYP2D6 substrates that are individually dose titrated.

Effect of Mirabegron on transporters: Mirabegron is a weak inhibitor of P-gp. Mirabegron increased Cmax and AUC by 29% and 27%, respectively, of the P-gp substrate digoxin in healthy volunteers. For patients who are initiating a combination of Mirabegron and digoxin, the lowest dose for digoxin should be prescribed initially. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.

Other interactions: No clinically relevant interactions have been observed when Mirabegron was co-administered with therapeutic doses of solifenacin, tamsulosin, warfarin, metformin or a combined oral contraceptive medicinal product containing ethinylestradiol and levonorgestrel. Dose-adjustment is not recommended.

There are limited amount of data from the use of Mirabegron in pregnant women. Studies in animals have shown reproductive toxicity. Mirabegron is not recommended during pregnancy and in women is planning to be pregnant. Mirabegron is excreted in the milk of rodents and therefore is predicted to be present in human milk. No studies have been conducted to assess the impact of Mirabegron on milk production in humans, its presence in human breast milk, or its effects on the breast-fed child. Mirabegron should not be administered during breast-feeding. There were no treatment-related effects of Mirabegron on fertility in animals. The effect of Mirabegron on human fertility has not been established.

Mirabegron has been administered to healthy volunteers at single doses up to 400 mg. At this dose, adverse events reported included palpitations and increased pulse rate exceeding 100 beats per minute (bpm). Multiple doses of Mirabegron up to 300 mg daily for 10 days showed increases in pulse rate and systolic blood pressure when administered to healthy volunteers. Treatment for overdose should be symptomatic and supportive. In the event of overdose, pulse rate, blood pressure, and ECG monitoring is recommended.

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

Mirabegron is indicated for the symptomatic treatment of urgency, increased micturition frequency and urgency incontinence as may occur in adult patients with overactive bladder (OAB) syndrome.

BPH/ Urinary retention/ Urinary incontinence

Mirabegron is the first beta-3 adrenoceptor agonist. Mirabegron exerts its effect via a dual mechanism, both directly acts on the bladder smooth muscle and also via the sensory nervous system, it increases the levels of cyclic adenosine monophosphate (cyclic AMP) and leads to relaxation of the detrusor smooth muscle during storage phase of urinary bladder fill-void cycle by activation of beta-3 adrenoceptor which increase bladder capacity.

Adults including elderly: The recommended starting dose is Mirabegron 25 mg tablet once daily with or without food. Based on individual patient efficacy and tolerability the dose may be increased to Mirabegron 50 mg tablet once daily.

Renal or hepatic impairment:

• Patients with severe renal impairment (ClCr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m2) or moderate hepatic impairment (Child-Pugh Class B), the daily dose of Mirabegron should not exceed 25 mg tablet once daily.
• Mirabegron has not been studied in patients with end stage renal disease (GFR <15 mL/min/1.73 m2 or patients requiring haemodialysis) or severe hepatic impairment (Child Pugh Class C) and it is therefore not recommended for use in these patient populations.

Gender: No dose adjustment is necessary according to gender.

Paediatric population: The safety and efficacy of Mirabegron in children below 18 years of age have not yet been established.

Mirabegron tablet is to be taken once daily, with liquids, swallowed whole and is not to be chewed, divided, or crushed.

The most common side effects reported for patients treated with Mirabegron 50 mg during the three 12-week phase 3 double blind, placebo controlled studies are tachycardia and urinary tract infections. The frequency of tachycardia was 1.2% in patients receiving Mirabegron 50 mg. Tachycardia led to discontinuation in 0.1% patients receiving Mirabegron 50 mg. The frequency of urinary tract infections was 2.9% in patients receiving Mirabegron 50 mg. Urinary tract infections led to discontinuation in none of the patients receiving Mirabegron 50 mg. Serious adverse reactions included atrial fibrillation (0.2%).

Mirabegron is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients and severe uncontrolled hypertension defined as systolic blood pressure 180 mm Hg and/or diastolic blood pressure 110 mm Hg.

Renal impairment: Mirabegron has not been studied in patients with end stage renal disease (GFR <15 mL/min/1.73 m2 or patients requiring haemodialysis) and therefore, it is not recommended for use in this patient population. Data are limited in patients with severe renal impairment (GFR 15 to 29 mL/min/1.73 m2); based on a pharmacokinetic study a dose reduction to 25 mg is recommended in this population. Mirabegron is not recommended for use in patients with severe renal impairment (GFR 15 to 29 mL/min/1.73 m2) concomitantly receiving strong CYP3A inhibitors.

Hepatic impairment: Mirabegron has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and, therefore, it is not recommended for use in this patient population. Mirabegron is not recommended for use in patients with moderate hepatic impairment (Child-Pugh Class B) concomitantly receiving strong CYP3A inhibitors.

Hypertension: Mirabegron can increase blood pressure. Blood pressure should be measured at baseline and periodically during treatment with Mirabegron, especially in hypertensive patients. Data are limited in patients with stage 2 hypertension (systolic blood pressure 160 mm Hg or diastolic blood pressure 100 mm Hg).

Patients with congenital or acquired QT prolongation: Caution should be exercised when administering Mirabegron in patients with congenital or acquired QT prolongation.

Patients with bladder outlet obstruction and patients taking antimuscarinics medications for OAB: A controlled clinical safety study in patients with bladder outlet obstruction (BOO) did not demonstrate increased urinary retention in patients treated with Mirabegron; however, Mirabegron should be administered with caution to patients with clinically significant bladder outlet obstruction. Mirabegron should also be administered with caution to patients taking antimuscarinic medications for the treatment of OAB.

Effect of enzyme inhibitors: Mirabegron exposure (AUC) was increased 1.8-fold in the presence of the strong inhibitor of CYP3A/P-gp ketoconazole in healthy volunteers. No dose adjustment is needed when Mirabegron is combined with inhibitors of CYP3A and/or P-gp. However, in patients with mild to moderate renal impairment or mild hepatic impairment concomitantly receiving strong CYP3A inhibitors, such as itraconazole, ketoconazole, ritonavir and clarithromycin, the recommended dose is 25 mg once daily with or without food. Mirabegron is not recommended in patients with severe renal impairment or patients with moderate hepatic impairment concomitantly receiving strong CYP3A inhibitors.

Effect of enzyme inducers: Substances that are inducers of CYP3A or P-gp decrease the plasma concentrations of Mirabegron. No dose adjustment is needed for Mirabegron when administered with therapeutic doses of rifampicin or other CYP3A or P-gp inducers.

Effect of Mirabegron on CYP2D6 substrates: In healthy volunteers, the inhibitory potency of Mirabegron towards CYP2D6 is moderate and the CYP2D6 activity recovers within 15 days after discontinuation of Mirabegron. Multiple once daily dosing of Mirabegron IR resulted in a 90% increase in Cmax and a 229% increase in AUC of a single dose of metoprolol. Multiple once daily dosing of Mirabegron resulted in a 79% increase in Cmax and a 241% increase in AUC of a single dose of desipramine. Caution is advised if Mirabegron is co-administered with medicinal products with a narrow therapeutic index and significantly metabolised by CYP2D6, such as thioridazine, Type 1 C antiarrhythmics (e.g., flecainide, propafenone) and tricyclic antidepressants (e.g., imipramine, desipramine). Caution is also advised if Mirabegron is co-administered with CYP2D6 substrates that are individually dose titrated.

Effect of Mirabegron on transporters: Mirabegron is a weak inhibitor of P-gp. Mirabegron increased Cmax and AUC by 29% and 27%, respectively, of the P-gp substrate digoxin in healthy volunteers. For patients who are initiating a combination of Mirabegron and digoxin, the lowest dose for digoxin should be prescribed initially. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.

Other interactions: No clinically relevant interactions have been observed when Mirabegron was co-administered with therapeutic doses of solifenacin, tamsulosin, warfarin, metformin or a combined oral contraceptive medicinal product containing ethinylestradiol and levonorgestrel. Dose-adjustment is not recommended.

There are limited amount of data from the use of Mirabegron in pregnant women. Studies in animals have shown reproductive toxicity. Mirabegron is not recommended during pregnancy and in women is planning to be pregnant. Mirabegron is excreted in the milk of rodents and therefore is predicted to be present in human milk. No studies have been conducted to assess the impact of Mirabegron on milk production in humans, its presence in human breast milk, or its effects on the breast-fed child. Mirabegron should not be administered during breast-feeding. There were no treatment-related effects of Mirabegron on fertility in animals. The effect of Mirabegron on human fertility has not been established.

Mirabegron has been administered to healthy volunteers at single doses up to 400 mg. At this dose, adverse events reported included palpitations and increased pulse rate exceeding 100 beats per minute (bpm). Multiple doses of Mirabegron up to 300 mg daily for 10 days showed increases in pulse rate and systolic blood pressure when administered to healthy volunteers. Treatment for overdose should be symptomatic and supportive. In the event of overdose, pulse rate, blood pressure, and ECG monitoring is recommended.

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

Tamsulosin Hydrochloride is indicated for the treatment of functional symptoms of Benign Prostatic Hyperplasia (BPH).

BPH/ Urinary retention/ Urinary incontinence

Tamsulosin, a selective alpha1 adrenoceptor blocking agent, exhibits its selectivity for alpha1 A adrenoceptors in human prostate. Blockade of these adrenoceptors can cause smooth muscle in the bladder neck and prostate to relax, resulting in an improvement in urine flow rate and a reduction in symptoms of BPH. Absorption of Tamsulosin hydrochloride capsule 0.4mg is essentially complete (90%) following oral administration under fasting conditions. The time to maximum concentration (Tmax) is reached by four to five hours under fasting conditions and by six to seven hours when administered with food. Tamsulosin hydrochloride is extremely bound to human plasma protein (94% to 99%). Tamsulosin hydrochloride is extensively metabolized by cytochrome P 450 enzymes in the liver and less than 10% of the dose is excreted in urine as unchanged form. Following intravenous or oral administration of an immediate-release formulation the elimination half-life of Tamsulosin hydrochloride in plasma ranges from five to seven hours. Because of the absorption rate controlled pharmacokinetics with Prostam capsules, the apparent half-life of Tamsulosin hydrochloride is approximately 9 to 13 hours in healthy volunteers and 14 to 15 hours in the target population.

Tamsulosin Hydrochloride 0.4 mg (one capsule) daily, to be taken after meal at night. The dose may be increased after 2 to 4 weeks, if necessary, to Tamsulosin Hydrochloride 0.8 mg (two capsules) once daily. If Tamsulosin Hydrochloride administration is discontinued or interrupted for several days at either the 0.4 mg or 0.8 mg dose, therapy should be started again with the Tamsulosin Hydrochloride 0.4 mg (one capsule) once daily dose. The capsule should be swallowed whole with a glass of water (about 150 ml) in the standing or sitting position. The capsule should not be crunched or chewed, as this will interfere with the modified release of the active ingredient.

The following adverse reactions have been reported during the use of Tamsulosin: dizziness, abnormal ejaculation and; less frequently headache, asthenia, postural hypotension and palpitations.

Tamsulosin hydrochloride is contraindicated in patients with hypersensitivity to it; history of orthostatic hypotension; severe hepatic insufficiency.

As with other alpha1 blockers, a reduction in blood pressure can occur in individual cases during treatment with Tamsulosin, as a result of which, rarely, syncope can occur, at the first signs of orthostatic hypotension (dizziness, weakness) the patient should sit or lie down until the symptoms have disappeared. And they should be cautioned to avoid situations where injury could result (like driving, operating machinery or performing hazardous tasks).

Before therapy with Tamsulosin is initiated the patient should be examined in order to exclude the presence of other conditions which can cause the same symptoms as Benign Prostatic hyperplasia. Digital rectal examination and when the necessary determination of Prostate Specific Antigen (PSA) should be performed before treatment and at regular intervals afterwards.

Rarely, transient postural symptoms have occurred during orthostatic provocation testing after the first dose. Use in patients with micturition syncope is not advised.

Effects on ability to drive and use machines: No data is available on whether Tamsulosin adversely affects the ability to drive or operate machines. However, in this respect, patients should be aware of the fact that dizziness can occur.

Concurrent administration of other alfa1-adrenoceptor antagonists could lead to hypotensive effects. No interactions have been seen when Tamsulosin was given concomitantly with either atenolol, enalapril or nifedipine. Concomitant cimetidine brings about a rise and frusemide a fall in plasma levels of Tamsulosin, but as levels remain within the normal range posology need not be changed. No interactions at the level of hepatic metabolism have been seen during in vitro studies with liver microsomal fractions (representative of the cytochrome P450-linked drug-metabolizing enzyme system), involving amitriptyline, salbutamol, glibenclamide, and finasteride. Diclofenac and warfarin, however, may increase the elimination rate of Tamsulosin.

Use of Tamsulosin in pregnancy and lactation is not recommended.

No case of acute overdosage has been reported. However, acute hypotension is likely to occur after overdosage in which case cardiovascular support should be given. Blood pressure can be restored and the heart rate brought back to normal by lying the patient down. If this does not help then volume expanders, and when necessary, vasopressors could be employed. Renal function should be monitored and general supportive measures applied. Dialysis is unlikely to be of help as Tamsulosin is very highly bound to plasma proteins. Measures, such as emesis, can be taken to impede absorption. When large quantities are involved, gastric lavage can be applied and activated charcoal and an osmotic laxative, such as sodium sulphate, can be administered.

Store in a cool and dry place, below 30°C, protected from light.

Tamsulosin Hydrochloride & Dutasteride capsule is indicated in-

• Treatment of moderate to severe symptoms of benign prostatic hyperplasia (BPH).
• Reduction in the risk of acute urinary retention and surgery in patients with moderate to severe symptoms of BPH.

BPH/ Urinary retention/ Urinary incontinence

Tamsulosin & Dutasteride is a combination of two drugs with complementary mechanisms of action to improve symptoms in patients with Benign Prostatic Hyperplasia (BPH). Tamsulosin Hydrochloride, an antagonist of alpha_1A-adrenoreceptors and Dutasteride, a dual 5 alpha reductase inhibitor (5ARI). Treatment of BPH with alpha₁-adrenoreceptor blocking agents and 5ARIs results in an improvement in urine flow rate and a reduction in symptoms of BPH.

Tamsulosin: An alpha1-adrenoreceptor blocking agent that affects the dynamic component of BPH by inhibiting alpha₁-adrenoreceptors in the stromal prostatic smooth muscle and bladder neck. Blockade of these adrenoreceptors can cause smooth muscles in the bladder neck and prostate to relax. Specifically, Tamsulosin exhibits selectivity for both alpha _1A and alpha _1D receptors over the alpha_1B-adrenoreceptor subtype. These three adrenoreceptor subtypes have a distinct distribution pattern in human tissue. Whereas approximately 70% of the alpha₁-receptors in human prostate are of the alpha _1A subtype, the human bladder contains predominantly the alpha _1D subtype while blood vessels express predominantly alpha _1B subtype. It is further believed that blockade of the alpha _1D subtypes in the human obstructed bladder may be responsible for reducing detrusor overactivity and subsequent relief of storage symptoms.

Dutasteride: A synthetic 4-azasteriod compound is a competitive and specific inhibitor of both Type I and Type II 5 alpha-reductase isoenzymes that affects the static component of BPH by inhibiting the conversion of Testosterone to Dihydrotestosterone (DHT) by the enzyme 5 alpha-reductase. 5 alpha-reductase exists as 2 isoforms, Type I and Type II, both of which are present in the prostate. It has been observed that compared to normal tissue, the expression of both isoenzymes are increased in BPH tissue. Dissociation from this complex has been evaluated under in vitro and in vivo conditions and is extremely slow. Dutasteride lowers DHT levels and leads to a reduction in prostatic volume, thereby treating an underlying cause of BPH. Dutasteride does not bind to the human androgen receptor.

Adults (including elderly): The recommended dose is one capsule (Tamsulosin Hydrochloride 0.4 mg & Dutasteride 0.5 mg) taken orally approximately 30 minutes after the same meal each day. The capsules should be swallowed whole and not chewed or opened. Where appropriate, this capsule may be used to substitute concomitant Tamsulosin Hydrochloride and Dutasteride in existing dual therapy to simplify treatment. Where clinically appropriate, direct change from Tamsulosin Hydrochloride or Dutasteride monotherapy to this capsule may be considered.

Renal impairment: The effect of renal impairment on Tamsulosin-Dutasteride pharmacokinetics has not been studied. No adjustment in dosage is anticipated for patients with renal impairment.

Hepatic impairment: The effect of hepatic impairment on Tamsulosin-Dutasteride pharmacokinetics has not been studied so caution should be used in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the use of this capsule is contra-indicated.

The most common adverse reactions reported in subjects receiving combination therapy were impotence, decreased libido, breast disorders (including breast enlargement and tenderness), ejaculation disorders and dizziness. The percentages of subjects with ejaculation disorders, decreased libido and impotence were higher in the combination therapy group compared with either monotherapy groups.

Tamsulosin-Dutasteride combination is contra-indicated in women and children and adolescents, patients with hypersensitivity to Dutasteride, other 5-alpha reductase inhibitors, Tamsulosin (including Tamsulosin- induced angio-edema), soya, peanut or any of other the excipients, patients with a history of orthostatic hypotension and patients with severe hepatic impairment.

Combination therapy should be prescribed after careful benefit risk assessment due to the potential increased risk of adverse events (including cardiac failure) and after consideration of alternative treatment options including monotherapies.

Cardiac failure: In two 4-year clinical studies, the incidence of cardiac failure was higher among subjects taking the combination of Dutasteride and an alpha blocker, primarily Tamsulosin, than it was among subjects not taking the combination. In these two trials, the incidence of cardiac failure was low (1%) and variable between the studies.

Effects on prostate specific antigen (PSA) and prostate cancer detection: Digital rectal examination, as well as other evaluations for prostate cancer or other conditions which can cause the same symptoms as BPH, must be performed on patients prior to initiating therapy with Tamsulosin-Dutasteride combination and periodically thereafter. Serum prostate-specific antigen (PSA) concentration is an important component in the detection of prostate cancer. Tamsulosin-Dutasteride combination causes a decrease in mean serum PSA levels by approximately 50%, after 6 months of treatment. Patients receiving Tamsulosin-Dutasteride combination should have a new PSA baseline established after 6 months of treatment. It is recommended to monitor PSA values regularly thereafter. Any confirmed increase from lowest PSA level while on Tamsulosin-Dutasteride combination may signal the presence of prostate cancer or noncompliance to therapy with Tamsulosin-Dutasteride combination and should be carefully evaluated, even if those values are still within the normal range for men not taking a 5 alpha-reductase inhibitor. In the interpretation of a PSA value for a patient taking Tamsulosin-Dutasteride combination, previous PSA values while on Dutasteride treatment should be sought for comparison. Treatment with Tamsulosin-Dutasteride combination does not interfere with the use of PSA as a tool to assist in the diagnosis of prostate cancer after a new baseline has been established. Total serum PSA levels return to baseline within 6 months of discontinuing treatment. The ratio of free to total PSA remains constant even under the influence of Tamsulosin-Dutasteride combination. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men undergoing Tamsulosin-Dutasteride combination therapy, no adjustment to its value appears necessary.

Prostate cancer and high grade tumours: Results of one clinical study in men at increase risk of prostate cancer revealed a higher incidence of Gleason 8-10 prostate cancers in Dutasteride treated men compared to placebo. The relationship between Dutasteride and high grade prostate cancer is not clear. Men taking Tamsulosin-Dutasteride combination should be regularly evaluated for prostate cancer risk including PSA testing.

Renal impairment: The treatment of severely renally impaired patients (creatinine clearance of less than 10 ml/min) should be approached with caution as these patients have not been studied.

Hypotension: Orthostatic- As with other alpha-blockers, a reduction in blood pressure can occur during treatment with Tamsulosin, as a result of which, rarely, syncope can occur. Patients beginning treatment with Tamsulosin-Dutasteride combination should be cautioned to sit or lie down at the first signs of orthostatic hypotension (dizziness, weakness) until the symptoms have resolved. In order to minimize the potential for developing postural hypotension the patient should be haemodynamically stable on alpha-blocker therapy prior to initiating use of PDE5 inhibitors. Symptomatic: Caution is advised when alpha adrenergic blocking agents including Tamsulosin are coadministered with PDE5 inhibitors (e.g. sildenafil, tadalafil, vardenafil). Alpha adrenergic blockers and PDE5 inhibitors are both vasodilators that can lower blood pressure. Concomitant use of these two drug classes can potentially cause symptomatic hypotension.

Intraoperative Floppy Iris Syndrome: Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients on or previously treated with Tamsulosin. IFIS may lead to increased procedural complications during the operation. The initiation of therapy with Tamsulosin-Dutasteride combination in patients for whom cataract surgery is scheduled is therefore not recommended. Discontinuing Tamsulosin 1-2 weeks prior to cataract surgery is anecdotally considered helpful, but the benefit and duration of stopping therapy prior to cataract surgery has not yet been established. Leaking Capsule: Dutasteride is absorbed through the skin, therefore, women, children and adolescents must avoid contact with leaking capsules. If contact is made with leaking capsules, the contact area should be washed immediately with soap and water.

Hepatic impairment: Tamsulosin-Dutasteride combination has not been studied in patients with liver disease. Caution should be used in the administration of Tamsulosin-Dutasteride combination to patients with mild to moderate hepatic impairment.

Breast neoplasia: Breast cancer has been reported in men taking Dutasteride in clinical trials and during the post-marketing period. Physicians should instruct their patients to promptly report any changes in their breast tissue such as lumps or nipple discharge. Currently it is not clear if there is a causal relationship between the occurrence of male breast cancer and long term use of Dutasteride.

There have been no drug interaction studies for Dutasteride-Tamsulosin combination.

Effects of other drugs on the pharmacokinetics of Dutasteride: Use together with CYP3A4 and/or P-glycoprotein-inhibitors: Dutasteride is mainly eliminated via metabolism. In vitro studies indicate that this metabolism is catalysed by CYP3A4 and CYP3A5. No formal interaction studies have been performed with potent CYP3A4 inhibitors. However, in a population pharmacokinetic study, Dutasteride serum concentrations were on average 1.6 to 1.8 times greater, respectively, in a small number of patients treated concurrently with verapamil or diltiazem (moderate inhibitors of CYP3A4 and inhibitors of P-glycoprotein) than in other patients. Long-term combination of Dutasteride with drugs that are potent inhibitors of the enzyme CYP3A4 (e.g. ritonavir, indinavir, nefazodone, itraconazole, ketoconazole administered orally) may increase serum concentrations of Dutasteride. Further inhibition of 5-alpha reductase at increased Dutasteride exposure, is not likely. However, a reduction of the Dutasteride dosing frequency can be considered if side effects are noted. It should be noted that in the case of enzyme inhibition, the long half-life may be further prolonged and it can take more than 6 months of concurrent therapy before a new steady state is reached. Administration of 12 g cholestyramine one hour after a 5 mg single dose of Dutasteride did not affect the pharmacokinetics of Dutasteride.

Effects of Dutasteride on the pharmacokinetics of other drugs: In a small study (N=24) of two weeks duration in healthy men, Dutasteride (0.5 mg daily) had no effect on the pharmacokinetics of Tamsulosin or terazosin. There was also no indication of a pharmacodynamic interaction in this study. Dutasteride has no effect on the pharmacokinetics of warfarin or digoxin. This indicates that Dutasteride does not inhibit/induce CYP2C9 or the transporter P-glycoprotein. In vitro interaction studies indicate that Dutasteride does not inhibit the enzymes CYP1A2, CYP2D6, CYP2C9, CYP2C19 or CYP3A4. Tamsulosin: Concomitant administration of Tamsulosin Hydrochloride with drugs which can reduce blood pressure, including anaesthetic agents, PDE5 inhibitors and other alpha-1 adrenergic blockers could lead to enhanced hypotensive effects. Tamsulosin-Dutasteride should not be used in combination with other alpha-1 adrenergic blockers. Concomitant administration of Tamsulosin Hydrochloride (0.4 mg) and cimetidine (400 mg every six hours for six days) resulted in a decrease in the clearance (26%) and an increase in the AUC (44%) of Tamsulosin Hydrochloride. Caution should be used when Tamsulosin-Dutasteride is used in combination with cimetidine. A definitive drug-drug interaction study between Tamsulosin Hydrochloride and warfarin has not been conducted. Results from limited in vitro and in vivo studies are inconclusive. Caution should be exercised with concomitant administration of warfarin and Tamsulosin Hydrochloride. No interactions have been seen when Tamsulosin Hydrochloride was given concomitantly with either atenolol, enalapril, nifedipine or theophylline. Concomitant furosemide brings about a fall in plasma levels of Tamsulosin, but as levels remain within the normal range posology need not be adjusted. In vitro neither diazepam nor propranolol, trichlormethiazide, chlormadinon, amitryptyline, diclofenac, glibenclamide and simvastatin change the free fraction of Tamsulosin in human plasma. Neither does Tamsulosin change the free fractions of diazepam, propranolol, trichlormethiazide, and chlormadinon. No interactions at the level of hepatic metabolism have been seen during in vitro studies with liver microsomal fractions, involving amitriptyline, salbutamol and glibenclamide. Diclofenac however, may increase the elimination rate of Tamsulosin.

Tamsulosin-Dutasteride combination is contra-indicated for use by women. There have been no studies to investigate the effect of Tamsulosin-Dutasteride combination on pregnancy, lactation and fertility. The following statements reflect the information available from studies with the individual components. Fertility: Dutasteride has been reported to affect semen characteristics (reduction in sperm count, semen volume, and sperm motility) in healthy men. The possibility of reduced male fertility cannot be excluded. Effects of Tamsulosin Hydrochloride on sperm counts or sperm function have not been evaluated.

Pregnancy: As with other 5 alpha reductase inhibitors, Dutasteride inhibits the conversion of testosterone to dihydrotestosterone and may, if administered to a woman carrying a male foetus, inhibit the development of the external genitalia of the foetus. Small amounts of Dutasteride have been recovered from the semen in subjects receiving Dutasteride. It is not known whether a male foetus will be adversely affected if his mother is exposed to the semen of a patient being treated with Dutasteride. As with all 5 alpha reductase inhibitors, when the patient’s partner is or may potentially be pregnant it is recommended that the patient avoids exposure of his partner to semen by use of a condom. Administration of Tamsulosin Hydrochloride to pregnant female rats and rabbits showed no evidence of foetal harm.

Lactation: It is not known whether Tamsulosin or Dutasteride are excreted in human milk.

No data are available with regard to over dosage of Tamsulosin-Dutasteride combination. The following statements reflect the information available on the individual components.

Dutasteride: In volunteer studies, single daily doses of Dutasteride up to 40 mg/day (80 times the therapeutic dose) have been administered for 7 days without significant safety concerns. In clinical studies, doses of 5 mg daily have been administered to subjects for 6 months with no additional adverse effects to those seen at therapeutic doses of 0.5 mg. There is no specific antidote for Dutasteride, therefore, in suspected over dosage symptomatic and supportive treatment should be given as appropriate.

Tamsulosin: Acute overdose with 5 mg Tamsulosin Hydrochloride has been reported. Acute hypotension (systolic blood pressure 70 mm Hg), vomiting and diarrhoea were observed which were treated with fluid replacement and the patient could be discharged the same day. In case of acute hypotension occurring after over dosage cardiovascular support should be given. Blood pressure can be restored and heart rate brought back to normal by lying the patient down. If this does not help then volume expanders, and when necessary, vasopressors could be employed. Renal function should be monitored and general supportive measures applied. Dialysis is unlikely to be of help as Tamsulosin is very highly bound to plasma proteins. Measures, such as emesis, can be taken to impede absorption. When large quantities are involved, gastric lavage can be applied and activated charcoal and an osmotic laxative, such as sodium sulphate, can be administered.

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

Tamsulosin Hydrochloride is indicated for the treatment of functional symptoms of Benign Prostatic Hyperplasia (BPH).

BPH/ Urinary retention/ Urinary incontinence

Tamsulosin, a selective alpha1 adrenoceptor blocking agent, exhibits its selectivity for alpha1 A adrenoceptors in human prostate. Blockade of these adrenoceptors can cause smooth muscle in the bladder neck and prostate to relax, resulting in an improvement in urine flow rate and a reduction in symptoms of BPH. Absorption of Tamsulosin hydrochloride capsule 0.4mg is essentially complete (90%) following oral administration under fasting conditions. The time to maximum concentration (Tmax) is reached by four to five hours under fasting conditions and by six to seven hours when administered with food. Tamsulosin hydrochloride is extremely bound to human plasma protein (94% to 99%). Tamsulosin hydrochloride is extensively metabolized by cytochrome P 450 enzymes in the liver and less than 10% of the dose is excreted in urine as unchanged form. Following intravenous or oral administration of an immediate-release formulation the elimination half-life of Tamsulosin hydrochloride in plasma ranges from five to seven hours. Because of the absorption rate controlled pharmacokinetics with Prostam capsules, the apparent half-life of Tamsulosin hydrochloride is approximately 9 to 13 hours in healthy volunteers and 14 to 15 hours in the target population.

Tamsulosin Hydrochloride 0.4 mg (one capsule) daily, to be taken after meal at night. The dose may be increased after 2 to 4 weeks, if necessary, to Tamsulosin Hydrochloride 0.8 mg (two capsules) once daily. If Tamsulosin Hydrochloride administration is discontinued or interrupted for several days at either the 0.4 mg or 0.8 mg dose, therapy should be started again with the Tamsulosin Hydrochloride 0.4 mg (one capsule) once daily dose. The capsule should be swallowed whole with a glass of water (about 150 ml) in the standing or sitting position. The capsule should not be crunched or chewed, as this will interfere with the modified release of the active ingredient.

The following adverse reactions have been reported during the use of Tamsulosin: dizziness, abnormal ejaculation and; less frequently headache, asthenia, postural hypotension and palpitations.

Tamsulosin hydrochloride is contraindicated in patients with hypersensitivity to it; history of orthostatic hypotension; severe hepatic insufficiency.

As with other alpha1 blockers, a reduction in blood pressure can occur in individual cases during treatment with Tamsulosin, as a result of which, rarely, syncope can occur, at the first signs of orthostatic hypotension (dizziness, weakness) the patient should sit or lie down until the symptoms have disappeared. And they should be cautioned to avoid situations where injury could result (like driving, operating machinery or performing hazardous tasks).

Before therapy with Tamsulosin is initiated the patient should be examined in order to exclude the presence of other conditions which can cause the same symptoms as Benign Prostatic hyperplasia. Digital rectal examination and when the necessary determination of Prostate Specific Antigen (PSA) should be performed before treatment and at regular intervals afterwards.

Rarely, transient postural symptoms have occurred during orthostatic provocation testing after the first dose. Use in patients with micturition syncope is not advised.

Effects on ability to drive and use machines: No data is available on whether Tamsulosin adversely affects the ability to drive or operate machines. However, in this respect, patients should be aware of the fact that dizziness can occur.

Concurrent administration of other alfa1-adrenoceptor antagonists could lead to hypotensive effects. No interactions have been seen when Tamsulosin was given concomitantly with either atenolol, enalapril or nifedipine. Concomitant cimetidine brings about a rise and frusemide a fall in plasma levels of Tamsulosin, but as levels remain within the normal range posology need not be changed. No interactions at the level of hepatic metabolism have been seen during in vitro studies with liver microsomal fractions (representative of the cytochrome P450-linked drug-metabolizing enzyme system), involving amitriptyline, salbutamol, glibenclamide, and finasteride. Diclofenac and warfarin, however, may increase the elimination rate of Tamsulosin.

Use of Tamsulosin in pregnancy and lactation is not recommended.

No case of acute overdosage has been reported. However, acute hypotension is likely to occur after overdosage in which case cardiovascular support should be given. Blood pressure can be restored and the heart rate brought back to normal by lying the patient down. If this does not help then volume expanders, and when necessary, vasopressors could be employed. Renal function should be monitored and general supportive measures applied. Dialysis is unlikely to be of help as Tamsulosin is very highly bound to plasma proteins. Measures, such as emesis, can be taken to impede absorption. When large quantities are involved, gastric lavage can be applied and activated charcoal and an osmotic laxative, such as sodium sulphate, can be administered.

Store in a cool and dry place, below 30°C, protected from light.

This preparation is indicated in the following cases:

• To relieve discomfort in urinary tract infections
• To prevent kidney stone
• With uricosuric agent to prevent gout
• Acidosis caused by kidney diseases

Prevention of repeated kidney stone formation, Urinary Alkalinizing Agent

Potassium Citrate and Citric Acid oral solution is a stable and pleasant-tasting oral systemic alkalizer. Potassium Citrate is absorbed and metabolized to Potassium Bicarbonate, thus acting as a systemic alkalizer. This product alkalinizes the urine without producing a systemic alkalosis in recommended doses. It is highly palatable, pleasant tasting and tolerable, even when administered for long periods. Potassium Citrate does not neutralize the gastric juice or disturb digestion.

To relieve discomfort in UTI:

• Adults and children over 6 years: 10 ml 3 times daily, diluted with 1 glass of water.
• Children 1-6 years: 5 ml 3 times daily, diluted with ½ glass of water.

To prevent kidney stones, With a uricosuric agent to prevent gout, Acidosis caused by kidney diseases:

• Adults: 10-15 ml 4 times daily (or as directed by the physician) diluted with 1 glass of water.
• Pediatric: 5-10 ml 4 times daily (or as directed by the physician) diluted with ½ glass of water.

This solution is generally well tolerated without any unpleasant side effect when given in recommended doses to patients with normal renal function and urinary output. However, as with any alkalinizing agent, caution must be used in certain patients with abnormal renal mechanisms to avoid development of hyperkalemia or alkalosis. Potassium intoxication causes listlessness, weakness, mental confusion, tingling of extremities and other symptoms associated with a high concentration of Potassium in the serum.

The drug is contraindicated in severe renal impairment with oliguria or azotemia, untreated Addison's disease, acute dehydration, severe myocardial damage and hyperkalemia from any cause.

The solution should be used with caution in patients with low urinary output. It should be diluted adequately with water to minimize the possibility of gastrointestinal injury associated with the oral ingestion of concentrated Potassium salt preparations; and preferably, to take each dose after meals. Large doses may cause hyperkalemia and alkalosis, especially in the presence of renal disease.

Concurrent administration of potassium-containing medication, potassium-sparing diuretics, angiotensin-converting enzyme (ACE) inhibitors or cardiac glycosides may lead to toxicity.

No information is available regarding the use of this drug during pregnancy and lactation.

The administration of oral Potassium salts to persons with normal excretory mechanisms for potassium rarely causes serious hyperkalemia. However, if excretory mechanisms are impaired, hyperkalemia can result. Hyperkalemia, when detected, must be treated immediately because lethal levels can be reached in a few hours. If hyperkalemia occurs, treatment measures will include the followings: (1) Elimination of foods or medications containing potassium. (2) The intravenous administration of 300 to 500 ml/hr of dextrose solution (10 to 25%), containing 10 units of insulin/20 gm dextrose. (3) The use of exchange resins, hemodialysis or peritoneal dialysis.

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.

Nitrofurantoin is specifically indicated for the treatment & prophylaxis of urinary tract infections caused by susceptible strains of Escherichia coli, Enterococci, Staphylococcus aureus, Staphylococcus saprophyticus and certain susceptible strains of Klebsiella and Enterobacter species.

Systemic Urinary Anti- infective

Nitrofurantoin is an antibacterial agent specific for urinary tract infections. Nitrofurantoin is highly soluble in urine, to which it may impart a brown color. Nitrofurantoin inactivates or alters bacterial ribosomal proteins and other macromolecules. Nitrofurantoin has been shown to be active against the following bacteria: Gram-Positive Aerobes Staphylococcus saprophyticus, Coagulase-negative staphylococci (including Staphylococcus epidermidis), Enterococcus faecalis, Staphylococcus aureus, Streptococcus agalactiae, Group D streptococci, Viridans group streptococci. Gram-Negative Aerobes- Escherichia coli, Citrobacter amalonaticus, Citrobacter diversus, Citrobacter freundii, Klebsiella oxytoca, Klebsiella ozaenae.

Nitrofurantoin tablet (In adults):

• Uncomplicated urinary tract infections: 50-100 mg four times a day- the lower dosage level is recommended. Therapy should be continued for one week or for at least 3 days after sterility of the urine is obtained.
• For long-term suppressive therapy: In adults, a reduction of dosage to 50-100 mg at bedtime may be adequate.

Nitrofurantoin capsule (In adults):

• Acute Uncomplicated Urinary Tract Infections (UTIs): 50 mg four times daily for 7 days.
• Long term suppression: 50-100 mg once a day.
• Prophylaxis: 50 mg four times daily for the duration of procedure and for three days thereafter.

Nitrofurantoin SR capsule:

• Adults and Children over 12 years: One 100 mg capsule every 12 hours for seven days.
• Genito-urinary surgical prophylaxis: One capsule twice daily on day of procedure and for next 3 days.

Nitrofurantoin suspension: Children: 5-7 mg/kg/day in four divided doses (contraindicated under one month of age). The average dose of Nintoin suspension for pediatric patients are as follows-

• 7 to 11 kg: ½ (2.5 ml) teaspoonfuls 4 times daily.
• 12 to 21 kg: 1 (5 ml) teaspoonfuls 4 times daily.
• 22 to 30 kg: 1½ (7.5 ml) teaspoonfuls 4 times daily.
• 31 to 41 kg: 2 (10 ml) teaspoonfuls 4 times daily.

Therapy should be continued for one week or for at least 3 days after sterility of the urine is obtained. For long-term suppressive therapy in children, doses as low as 1 mg/kg per 24 hours, given in a single dose or in two divided doses, may be adequate.

Nitrofurantoin should be taken with food.

The most frequent clinical adverse events are nausea, headache, and flatulence. Other less occurred adverse events are diarrhea, dyspepsia, abdominal pain, constipation, emesis, dizziness and drowsiness.

Anuria, oliguria or significant impairment of renal function are contraindications. This drug is contraindicated in pregnant patients at 38-42 weeks, during labor and delivery. Nitrofurantoin is also contraindicated in those patients with known hypersensitivity to Nitrofurantoin.

If acute, sub-acute or chronic pulmonary reactions occur, Nitrofurantoin should be discontinued. Antacid preparations containing magnesium trisilicate should not be taken while taking Nitrofurantoin.

Antacids containing Magnesium Trisilicate, when administered concomitantly with Nitrofurantoin, reduce both the rate and extent of absorption of Uricosuric drugs, such as Probenecid and Sulfinpyrazone, can inhibit renal tubular secretion of Nitrofurantoin.

Pregnancy Category B. There are no adequate and well-controlled studies in pregnant women. This drug should be used during pregnancy only if clearly needed. Nitrofurantoin has been detected in human breast milk in trace amounts. Because of the potential for serious adverse reactions from Nitrofurantoin in nursing infants under one month of age, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Occasional incidents of acute overdosage of Nitrofurantoin have not resulted in any specific symptoms other than vomiting. Induction of emesis is recommended.

Do not store above 30°C. Keep away from light and out of the reach of children.

Nitrofurantoin is specifically indicated for the treatment & prophylaxis of urinary tract infections caused by susceptible strains of Escherichia coli, Enterococci, Staphylococcus aureus, Staphylococcus saprophyticus and certain susceptible strains of Klebsiella and Enterobacter species.

Systemic Urinary Anti- infective

Nitrofurantoin is an antibacterial agent specific for urinary tract infections. Nitrofurantoin is highly soluble in urine, to which it may impart a brown color. Nitrofurantoin inactivates or alters bacterial ribosomal proteins and other macromolecules. Nitrofurantoin has been shown to be active against the following bacteria: Gram-Positive Aerobes Staphylococcus saprophyticus, Coagulase-negative staphylococci (including Staphylococcus epidermidis), Enterococcus faecalis, Staphylococcus aureus, Streptococcus agalactiae, Group D streptococci, Viridans group streptococci. Gram-Negative Aerobes- Escherichia coli, Citrobacter amalonaticus, Citrobacter diversus, Citrobacter freundii, Klebsiella oxytoca, Klebsiella ozaenae.

Nitrofurantoin tablet (In adults):

• Uncomplicated urinary tract infections: 50-100 mg four times a day- the lower dosage level is recommended. Therapy should be continued for one week or for at least 3 days after sterility of the urine is obtained.
• For long-term suppressive therapy: In adults, a reduction of dosage to 50-100 mg at bedtime may be adequate.

Nitrofurantoin capsule (In adults):

• Acute Uncomplicated Urinary Tract Infections (UTIs): 50 mg four times daily for 7 days.
• Long term suppression: 50-100 mg once a day.
• Prophylaxis: 50 mg four times daily for the duration of procedure and for three days thereafter.

Nitrofurantoin SR capsule:

• Adults and Children over 12 years: One 100 mg capsule every 12 hours for seven days.
• Genito-urinary surgical prophylaxis: One capsule twice daily on day of procedure and for next 3 days.

Nitrofurantoin suspension: Children: 5-7 mg/kg/day in four divided doses (contraindicated under one month of age). The average dose of Nintoin suspension for pediatric patients are as follows-

• 7 to 11 kg: ½ (2.5 ml) teaspoonfuls 4 times daily.
• 12 to 21 kg: 1 (5 ml) teaspoonfuls 4 times daily.
• 22 to 30 kg: 1½ (7.5 ml) teaspoonfuls 4 times daily.
• 31 to 41 kg: 2 (10 ml) teaspoonfuls 4 times daily.

Therapy should be continued for one week or for at least 3 days after sterility of the urine is obtained. For long-term suppressive therapy in children, doses as low as 1 mg/kg per 24 hours, given in a single dose or in two divided doses, may be adequate.

Nitrofurantoin should be taken with food.

The most frequent clinical adverse events are nausea, headache, and flatulence. Other less occurred adverse events are diarrhea, dyspepsia, abdominal pain, constipation, emesis, dizziness and drowsiness.

Anuria, oliguria or significant impairment of renal function are contraindications. This drug is contraindicated in pregnant patients at 38-42 weeks, during labor and delivery. Nitrofurantoin is also contraindicated in those patients with known hypersensitivity to Nitrofurantoin.

If acute, sub-acute or chronic pulmonary reactions occur, Nitrofurantoin should be discontinued. Antacid preparations containing magnesium trisilicate should not be taken while taking Nitrofurantoin.

Antacids containing Magnesium Trisilicate, when administered concomitantly with Nitrofurantoin, reduce both the rate and extent of absorption of Uricosuric drugs, such as Probenecid and Sulfinpyrazone, can inhibit renal tubular secretion of Nitrofurantoin.

Pregnancy Category B. There are no adequate and well-controlled studies in pregnant women. This drug should be used during pregnancy only if clearly needed. Nitrofurantoin has been detected in human breast milk in trace amounts. Because of the potential for serious adverse reactions from Nitrofurantoin in nursing infants under one month of age, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Occasional incidents of acute overdosage of Nitrofurantoin have not resulted in any specific symptoms other than vomiting. Induction of emesis is recommended.

Do not store above 30°C. Keep away from light and out of the reach of children.

Dutasteride is indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to:

• Improve symptoms
• Reduce the risk of acute urinary retention
• Reduce the risk of the need for BPH-related surgery

BPH/ Urinary retention/ Urinary incontinence

Dutasteride is a dual inhibitor of 5α-reductase. It inhibits both type 1 and type 2, 5α-reductase isoenzymes, which are responsible for the conversion of testosterone to 5α-dihydrotestosterone (DHT). DHT is the androgen primarily responsible for hyperplasia of glandular prostatic tissue.

The recommended dose is Dutasteride 0.5 mg orally once daily. The capsules should be swallowed whole. Dutasteride may be administered with or without food.

Dutasteride is contra-indicated for use in women and children and for patients with known hypersensitivity to Dutasteride, and other 5 a-reductase inhibitors. Warnings: Exposure of women-risk to male fetus: Dutasteride is absorbed through the skin. Therefore, women who are pregnant or may be pregnant should not handle Dutasteride capsules because of the possibility of absorption of Dutasteride and the potential risk of a fetal anomaly to a male fetus. If contact is made with leaking capsules, the contact area should be washed immediately with soap and water.

Lower urinary tract symptoms of BPH can be indicative of other urological diseases, including prostate cancer. Patients should be assessed to rule out other urological diseases prior to treatment with Dutasteride. Patients with a large residual urinary volume and/or severely diminished urinary flow may not be good candidates for 5 a-reductase inhibitor therapy and should be carefully monitored for obstructive uropathy. Blood Donation: Men being treated with Dutasteride should not donate blood until at least 6 months have passed following their last dose. The purpose of this deferred period is to prevent administration of Dutasteride to a pregnant female transfusion recipient.

Care should be taken when administering Dutasteride to patients taking potent, chronic CYP3A4 inhibitors. Dutasteride does not inhibit the in vitro metabolism of model substrates for the major human cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at a concentration of 1,000 ng/ml, 25 times greater than steady-state serum concentrations in humans. In vitro studies demonstrate that Dutasteride does not displace Warfarin, Diazepam, or Phenytoin from plasma protein binding sites, nor do these model compounds displace Dutasteride.

Pregnancy Category X. Dutasteride is contraindicated for use in women.

Pediatric use: Dutasteride is not indicated for use in the pediatric population. Safety and effectiveness in the pediatric population have not been established.

Geriatric use: No overall differences in safety or efficacy were observed between elderly and adult subjects.

Elderly use: No dosage adjustment is necessary for subjects with renal impairment or for the elderly.

Hepatic impairment: Due to the absence of data in patients with hepatic impairment, no dosage recommendation can be made.

In volunteer studies, single doses of Dutasteride up to 40 mg (80 times the therapeutic dose) for 7 days have been administered without significant safety concerns. In a clinical study, daily doses of 5 mg (10 times the therapeutic dose) were administered to 60 subjects for 6 months with no additional adverse effects to those seen at therapeutic doses of 0.5 mg. There is no specific antidote for Dutasteride. Therefore, in cases of suspected overdosage symptomatic and supportive treatment should be given as appropriate, taking the long half-life of Dutasteride into consideration.

Store in a cool and dry place, protected from light

This preparation is indicated in the following cases:

• To relieve discomfort in urinary tract infections
• To prevent kidney stone
• With uricosuric agent to prevent gout
• Acidosis caused by kidney diseases

Prevention of repeated kidney stone formation, Urinary Alkalinizing Agent

Potassium Citrate and Citric Acid oral solution is a stable and pleasant-tasting oral systemic alkalizer. Potassium Citrate is absorbed and metabolized to Potassium Bicarbonate, thus acting as a systemic alkalizer. This product alkalinizes the urine without producing a systemic alkalosis in recommended doses. It is highly palatable, pleasant tasting and tolerable, even when administered for long periods. Potassium Citrate does not neutralize the gastric juice or disturb digestion.

To relieve discomfort in UTI:

• Adults and children over 6 years: 10 ml 3 times daily, diluted with 1 glass of water.
• Children 1-6 years: 5 ml 3 times daily, diluted with ½ glass of water.

To prevent kidney stones, With a uricosuric agent to prevent gout, Acidosis caused by kidney diseases:

• Adults: 10-15 ml 4 times daily (or as directed by the physician) diluted with 1 glass of water.
• Pediatric: 5-10 ml 4 times daily (or as directed by the physician) diluted with ½ glass of water.

This solution is generally well tolerated without any unpleasant side effect when given in recommended doses to patients with normal renal function and urinary output. However, as with any alkalinizing agent, caution must be used in certain patients with abnormal renal mechanisms to avoid development of hyperkalemia or alkalosis. Potassium intoxication causes listlessness, weakness, mental confusion, tingling of extremities and other symptoms associated with a high concentration of Potassium in the serum.

The drug is contraindicated in severe renal impairment with oliguria or azotemia, untreated Addison's disease, acute dehydration, severe myocardial damage and hyperkalemia from any cause.

The solution should be used with caution in patients with low urinary output. It should be diluted adequately with water to minimize the possibility of gastrointestinal injury associated with the oral ingestion of concentrated Potassium salt preparations; and preferably, to take each dose after meals. Large doses may cause hyperkalemia and alkalosis, especially in the presence of renal disease.

Concurrent administration of potassium-containing medication, potassium-sparing diuretics, angiotensin-converting enzyme (ACE) inhibitors or cardiac glycosides may lead to toxicity.

No information is available regarding the use of this drug during pregnancy and lactation.

The administration of oral Potassium salts to persons with normal excretory mechanisms for potassium rarely causes serious hyperkalemia. However, if excretory mechanisms are impaired, hyperkalemia can result. Hyperkalemia, when detected, must be treated immediately because lethal levels can be reached in a few hours. If hyperkalemia occurs, treatment measures will include the followings: (1) Elimination of foods or medications containing potassium. (2) The intravenous administration of 300 to 500 ml/hr of dextrose solution (10 to 25%), containing 10 units of insulin/20 gm dextrose. (3) The use of exchange resins, hemodialysis or peritoneal dialysis.

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.

Tamsulosin Hydrochloride is indicated for the treatment of functional symptoms of Benign Prostatic Hyperplasia (BPH).

BPH/ Urinary retention/ Urinary incontinence

Tamsulosin, a selective alpha1 adrenoceptor blocking agent, exhibits its selectivity for alpha1 A adrenoceptors in human prostate. Blockade of these adrenoceptors can cause smooth muscle in the bladder neck and prostate to relax, resulting in an improvement in urine flow rate and a reduction in symptoms of BPH. Absorption of Tamsulosin hydrochloride capsule 0.4mg is essentially complete (90%) following oral administration under fasting conditions. The time to maximum concentration (Tmax) is reached by four to five hours under fasting conditions and by six to seven hours when administered with food. Tamsulosin hydrochloride is extremely bound to human plasma protein (94% to 99%). Tamsulosin hydrochloride is extensively metabolized by cytochrome P 450 enzymes in the liver and less than 10% of the dose is excreted in urine as unchanged form. Following intravenous or oral administration of an immediate-release formulation the elimination half-life of Tamsulosin hydrochloride in plasma ranges from five to seven hours. Because of the absorption rate controlled pharmacokinetics with Prostam capsules, the apparent half-life of Tamsulosin hydrochloride is approximately 9 to 13 hours in healthy volunteers and 14 to 15 hours in the target population.

Tamsulosin Hydrochloride 0.4 mg (one capsule) daily, to be taken after meal at night. The dose may be increased after 2 to 4 weeks, if necessary, to Tamsulosin Hydrochloride 0.8 mg (two capsules) once daily. If Tamsulosin Hydrochloride administration is discontinued or interrupted for several days at either the 0.4 mg or 0.8 mg dose, therapy should be started again with the Tamsulosin Hydrochloride 0.4 mg (one capsule) once daily dose. The capsule should be swallowed whole with a glass of water (about 150 ml) in the standing or sitting position. The capsule should not be crunched or chewed, as this will interfere with the modified release of the active ingredient.

The following adverse reactions have been reported during the use of Tamsulosin: dizziness, abnormal ejaculation and; less frequently headache, asthenia, postural hypotension and palpitations.

Tamsulosin hydrochloride is contraindicated in patients with hypersensitivity to it; history of orthostatic hypotension; severe hepatic insufficiency.

As with other alpha1 blockers, a reduction in blood pressure can occur in individual cases during treatment with Tamsulosin, as a result of which, rarely, syncope can occur, at the first signs of orthostatic hypotension (dizziness, weakness) the patient should sit or lie down until the symptoms have disappeared. And they should be cautioned to avoid situations where injury could result (like driving, operating machinery or performing hazardous tasks).

Before therapy with Tamsulosin is initiated the patient should be examined in order to exclude the presence of other conditions which can cause the same symptoms as Benign Prostatic hyperplasia. Digital rectal examination and when the necessary determination of Prostate Specific Antigen (PSA) should be performed before treatment and at regular intervals afterwards.

Rarely, transient postural symptoms have occurred during orthostatic provocation testing after the first dose. Use in patients with micturition syncope is not advised.

Effects on ability to drive and use machines: No data is available on whether Tamsulosin adversely affects the ability to drive or operate machines. However, in this respect, patients should be aware of the fact that dizziness can occur.

Concurrent administration of other alfa1-adrenoceptor antagonists could lead to hypotensive effects. No interactions have been seen when Tamsulosin was given concomitantly with either atenolol, enalapril or nifedipine. Concomitant cimetidine brings about a rise and frusemide a fall in plasma levels of Tamsulosin, but as levels remain within the normal range posology need not be changed. No interactions at the level of hepatic metabolism have been seen during in vitro studies with liver microsomal fractions (representative of the cytochrome P450-linked drug-metabolizing enzyme system), involving amitriptyline, salbutamol, glibenclamide, and finasteride. Diclofenac and warfarin, however, may increase the elimination rate of Tamsulosin.

Use of Tamsulosin in pregnancy and lactation is not recommended.

No case of acute overdosage has been reported. However, acute hypotension is likely to occur after overdosage in which case cardiovascular support should be given. Blood pressure can be restored and the heart rate brought back to normal by lying the patient down. If this does not help then volume expanders, and when necessary, vasopressors could be employed. Renal function should be monitored and general supportive measures applied. Dialysis is unlikely to be of help as Tamsulosin is very highly bound to plasma proteins. Measures, such as emesis, can be taken to impede absorption. When large quantities are involved, gastric lavage can be applied and activated charcoal and an osmotic laxative, such as sodium sulphate, can be administered.

Store in a cool and dry place, below 30°C, protected from light.

Tamsulosin Hydrochloride & Dutasteride capsule is indicated in-

• Treatment of moderate to severe symptoms of benign prostatic hyperplasia (BPH).
• Reduction in the risk of acute urinary retention and surgery in patients with moderate to severe symptoms of BPH.

BPH/ Urinary retention/ Urinary incontinence

Tamsulosin & Dutasteride is a combination of two drugs with complementary mechanisms of action to improve symptoms in patients with Benign Prostatic Hyperplasia (BPH). Tamsulosin Hydrochloride, an antagonist of alpha_1A-adrenoreceptors and Dutasteride, a dual 5 alpha reductase inhibitor (5ARI). Treatment of BPH with alpha₁-adrenoreceptor blocking agents and 5ARIs results in an improvement in urine flow rate and a reduction in symptoms of BPH.

Tamsulosin: An alpha1-adrenoreceptor blocking agent that affects the dynamic component of BPH by inhibiting alpha₁-adrenoreceptors in the stromal prostatic smooth muscle and bladder neck. Blockade of these adrenoreceptors can cause smooth muscles in the bladder neck and prostate to relax. Specifically, Tamsulosin exhibits selectivity for both alpha _1A and alpha _1D receptors over the alpha_1B-adrenoreceptor subtype. These three adrenoreceptor subtypes have a distinct distribution pattern in human tissue. Whereas approximately 70% of the alpha₁-receptors in human prostate are of the alpha _1A subtype, the human bladder contains predominantly the alpha _1D subtype while blood vessels express predominantly alpha _1B subtype. It is further believed that blockade of the alpha _1D subtypes in the human obstructed bladder may be responsible for reducing detrusor overactivity and subsequent relief of storage symptoms.

Dutasteride: A synthetic 4-azasteriod compound is a competitive and specific inhibitor of both Type I and Type II 5 alpha-reductase isoenzymes that affects the static component of BPH by inhibiting the conversion of Testosterone to Dihydrotestosterone (DHT) by the enzyme 5 alpha-reductase. 5 alpha-reductase exists as 2 isoforms, Type I and Type II, both of which are present in the prostate. It has been observed that compared to normal tissue, the expression of both isoenzymes are increased in BPH tissue. Dissociation from this complex has been evaluated under in vitro and in vivo conditions and is extremely slow. Dutasteride lowers DHT levels and leads to a reduction in prostatic volume, thereby treating an underlying cause of BPH. Dutasteride does not bind to the human androgen receptor.

Adults (including elderly): The recommended dose is one capsule (Tamsulosin Hydrochloride 0.4 mg & Dutasteride 0.5 mg) taken orally approximately 30 minutes after the same meal each day. The capsules should be swallowed whole and not chewed or opened. Where appropriate, this capsule may be used to substitute concomitant Tamsulosin Hydrochloride and Dutasteride in existing dual therapy to simplify treatment. Where clinically appropriate, direct change from Tamsulosin Hydrochloride or Dutasteride monotherapy to this capsule may be considered.

Renal impairment: The effect of renal impairment on Tamsulosin-Dutasteride pharmacokinetics has not been studied. No adjustment in dosage is anticipated for patients with renal impairment.

Hepatic impairment: The effect of hepatic impairment on Tamsulosin-Dutasteride pharmacokinetics has not been studied so caution should be used in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the use of this capsule is contra-indicated.

The most common adverse reactions reported in subjects receiving combination therapy were impotence, decreased libido, breast disorders (including breast enlargement and tenderness), ejaculation disorders and dizziness. The percentages of subjects with ejaculation disorders, decreased libido and impotence were higher in the combination therapy group compared with either monotherapy groups.

Tamsulosin-Dutasteride combination is contra-indicated in women and children and adolescents, patients with hypersensitivity to Dutasteride, other 5-alpha reductase inhibitors, Tamsulosin (including Tamsulosin- induced angio-edema), soya, peanut or any of other the excipients, patients with a history of orthostatic hypotension and patients with severe hepatic impairment.

Combination therapy should be prescribed after careful benefit risk assessment due to the potential increased risk of adverse events (including cardiac failure) and after consideration of alternative treatment options including monotherapies.

Cardiac failure: In two 4-year clinical studies, the incidence of cardiac failure was higher among subjects taking the combination of Dutasteride and an alpha blocker, primarily Tamsulosin, than it was among subjects not taking the combination. In these two trials, the incidence of cardiac failure was low (1%) and variable between the studies.

Effects on prostate specific antigen (PSA) and prostate cancer detection: Digital rectal examination, as well as other evaluations for prostate cancer or other conditions which can cause the same symptoms as BPH, must be performed on patients prior to initiating therapy with Tamsulosin-Dutasteride combination and periodically thereafter. Serum prostate-specific antigen (PSA) concentration is an important component in the detection of prostate cancer. Tamsulosin-Dutasteride combination causes a decrease in mean serum PSA levels by approximately 50%, after 6 months of treatment. Patients receiving Tamsulosin-Dutasteride combination should have a new PSA baseline established after 6 months of treatment. It is recommended to monitor PSA values regularly thereafter. Any confirmed increase from lowest PSA level while on Tamsulosin-Dutasteride combination may signal the presence of prostate cancer or noncompliance to therapy with Tamsulosin-Dutasteride combination and should be carefully evaluated, even if those values are still within the normal range for men not taking a 5 alpha-reductase inhibitor. In the interpretation of a PSA value for a patient taking Tamsulosin-Dutasteride combination, previous PSA values while on Dutasteride treatment should be sought for comparison. Treatment with Tamsulosin-Dutasteride combination does not interfere with the use of PSA as a tool to assist in the diagnosis of prostate cancer after a new baseline has been established. Total serum PSA levels return to baseline within 6 months of discontinuing treatment. The ratio of free to total PSA remains constant even under the influence of Tamsulosin-Dutasteride combination. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men undergoing Tamsulosin-Dutasteride combination therapy, no adjustment to its value appears necessary.

Prostate cancer and high grade tumours: Results of one clinical study in men at increase risk of prostate cancer revealed a higher incidence of Gleason 8-10 prostate cancers in Dutasteride treated men compared to placebo. The relationship between Dutasteride and high grade prostate cancer is not clear. Men taking Tamsulosin-Dutasteride combination should be regularly evaluated for prostate cancer risk including PSA testing.

Renal impairment: The treatment of severely renally impaired patients (creatinine clearance of less than 10 ml/min) should be approached with caution as these patients have not been studied.

Hypotension: Orthostatic- As with other alpha-blockers, a reduction in blood pressure can occur during treatment with Tamsulosin, as a result of which, rarely, syncope can occur. Patients beginning treatment with Tamsulosin-Dutasteride combination should be cautioned to sit or lie down at the first signs of orthostatic hypotension (dizziness, weakness) until the symptoms have resolved. In order to minimize the potential for developing postural hypotension the patient should be haemodynamically stable on alpha-blocker therapy prior to initiating use of PDE5 inhibitors. Symptomatic: Caution is advised when alpha adrenergic blocking agents including Tamsulosin are coadministered with PDE5 inhibitors (e.g. sildenafil, tadalafil, vardenafil). Alpha adrenergic blockers and PDE5 inhibitors are both vasodilators that can lower blood pressure. Concomitant use of these two drug classes can potentially cause symptomatic hypotension.

Intraoperative Floppy Iris Syndrome: Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients on or previously treated with Tamsulosin. IFIS may lead to increased procedural complications during the operation. The initiation of therapy with Tamsulosin-Dutasteride combination in patients for whom cataract surgery is scheduled is therefore not recommended. Discontinuing Tamsulosin 1-2 weeks prior to cataract surgery is anecdotally considered helpful, but the benefit and duration of stopping therapy prior to cataract surgery has not yet been established. Leaking Capsule: Dutasteride is absorbed through the skin, therefore, women, children and adolescents must avoid contact with leaking capsules. If contact is made with leaking capsules, the contact area should be washed immediately with soap and water.

Hepatic impairment: Tamsulosin-Dutasteride combination has not been studied in patients with liver disease. Caution should be used in the administration of Tamsulosin-Dutasteride combination to patients with mild to moderate hepatic impairment.

Breast neoplasia: Breast cancer has been reported in men taking Dutasteride in clinical trials and during the post-marketing period. Physicians should instruct their patients to promptly report any changes in their breast tissue such as lumps or nipple discharge. Currently it is not clear if there is a causal relationship between the occurrence of male breast cancer and long term use of Dutasteride.

There have been no drug interaction studies for Dutasteride-Tamsulosin combination.

Effects of other drugs on the pharmacokinetics of Dutasteride: Use together with CYP3A4 and/or P-glycoprotein-inhibitors: Dutasteride is mainly eliminated via metabolism. In vitro studies indicate that this metabolism is catalysed by CYP3A4 and CYP3A5. No formal interaction studies have been performed with potent CYP3A4 inhibitors. However, in a population pharmacokinetic study, Dutasteride serum concentrations were on average 1.6 to 1.8 times greater, respectively, in a small number of patients treated concurrently with verapamil or diltiazem (moderate inhibitors of CYP3A4 and inhibitors of P-glycoprotein) than in other patients. Long-term combination of Dutasteride with drugs that are potent inhibitors of the enzyme CYP3A4 (e.g. ritonavir, indinavir, nefazodone, itraconazole, ketoconazole administered orally) may increase serum concentrations of Dutasteride. Further inhibition of 5-alpha reductase at increased Dutasteride exposure, is not likely. However, a reduction of the Dutasteride dosing frequency can be considered if side effects are noted. It should be noted that in the case of enzyme inhibition, the long half-life may be further prolonged and it can take more than 6 months of concurrent therapy before a new steady state is reached. Administration of 12 g cholestyramine one hour after a 5 mg single dose of Dutasteride did not affect the pharmacokinetics of Dutasteride.

Effects of Dutasteride on the pharmacokinetics of other drugs: In a small study (N=24) of two weeks duration in healthy men, Dutasteride (0.5 mg daily) had no effect on the pharmacokinetics of Tamsulosin or terazosin. There was also no indication of a pharmacodynamic interaction in this study. Dutasteride has no effect on the pharmacokinetics of warfarin or digoxin. This indicates that Dutasteride does not inhibit/induce CYP2C9 or the transporter P-glycoprotein. In vitro interaction studies indicate that Dutasteride does not inhibit the enzymes CYP1A2, CYP2D6, CYP2C9, CYP2C19 or CYP3A4. Tamsulosin: Concomitant administration of Tamsulosin Hydrochloride with drugs which can reduce blood pressure, including anaesthetic agents, PDE5 inhibitors and other alpha-1 adrenergic blockers could lead to enhanced hypotensive effects. Tamsulosin-Dutasteride should not be used in combination with other alpha-1 adrenergic blockers. Concomitant administration of Tamsulosin Hydrochloride (0.4 mg) and cimetidine (400 mg every six hours for six days) resulted in a decrease in the clearance (26%) and an increase in the AUC (44%) of Tamsulosin Hydrochloride. Caution should be used when Tamsulosin-Dutasteride is used in combination with cimetidine. A definitive drug-drug interaction study between Tamsulosin Hydrochloride and warfarin has not been conducted. Results from limited in vitro and in vivo studies are inconclusive. Caution should be exercised with concomitant administration of warfarin and Tamsulosin Hydrochloride. No interactions have been seen when Tamsulosin Hydrochloride was given concomitantly with either atenolol, enalapril, nifedipine or theophylline. Concomitant furosemide brings about a fall in plasma levels of Tamsulosin, but as levels remain within the normal range posology need not be adjusted. In vitro neither diazepam nor propranolol, trichlormethiazide, chlormadinon, amitryptyline, diclofenac, glibenclamide and simvastatin change the free fraction of Tamsulosin in human plasma. Neither does Tamsulosin change the free fractions of diazepam, propranolol, trichlormethiazide, and chlormadinon. No interactions at the level of hepatic metabolism have been seen during in vitro studies with liver microsomal fractions, involving amitriptyline, salbutamol and glibenclamide. Diclofenac however, may increase the elimination rate of Tamsulosin.

Tamsulosin-Dutasteride combination is contra-indicated for use by women. There have been no studies to investigate the effect of Tamsulosin-Dutasteride combination on pregnancy, lactation and fertility. The following statements reflect the information available from studies with the individual components. Fertility: Dutasteride has been reported to affect semen characteristics (reduction in sperm count, semen volume, and sperm motility) in healthy men. The possibility of reduced male fertility cannot be excluded. Effects of Tamsulosin Hydrochloride on sperm counts or sperm function have not been evaluated.

Pregnancy: As with other 5 alpha reductase inhibitors, Dutasteride inhibits the conversion of testosterone to dihydrotestosterone and may, if administered to a woman carrying a male foetus, inhibit the development of the external genitalia of the foetus. Small amounts of Dutasteride have been recovered from the semen in subjects receiving Dutasteride. It is not known whether a male foetus will be adversely affected if his mother is exposed to the semen of a patient being treated with Dutasteride. As with all 5 alpha reductase inhibitors, when the patient’s partner is or may potentially be pregnant it is recommended that the patient avoids exposure of his partner to semen by use of a condom. Administration of Tamsulosin Hydrochloride to pregnant female rats and rabbits showed no evidence of foetal harm.

Lactation: It is not known whether Tamsulosin or Dutasteride are excreted in human milk.

No data are available with regard to over dosage of Tamsulosin-Dutasteride combination. The following statements reflect the information available on the individual components.

Dutasteride: In volunteer studies, single daily doses of Dutasteride up to 40 mg/day (80 times the therapeutic dose) have been administered for 7 days without significant safety concerns. In clinical studies, doses of 5 mg daily have been administered to subjects for 6 months with no additional adverse effects to those seen at therapeutic doses of 0.5 mg. There is no specific antidote for Dutasteride, therefore, in suspected over dosage symptomatic and supportive treatment should be given as appropriate.

Tamsulosin: Acute overdose with 5 mg Tamsulosin Hydrochloride has been reported. Acute hypotension (systolic blood pressure 70 mm Hg), vomiting and diarrhoea were observed which were treated with fluid replacement and the patient could be discharged the same day. In case of acute hypotension occurring after over dosage cardiovascular support should be given. Blood pressure can be restored and heart rate brought back to normal by lying the patient down. If this does not help then volume expanders, and when necessary, vasopressors could be employed. Renal function should be monitored and general supportive measures applied. Dialysis is unlikely to be of help as Tamsulosin is very highly bound to plasma proteins. Measures, such as emesis, can be taken to impede absorption. When large quantities are involved, gastric lavage can be applied and activated charcoal and an osmotic laxative, such as sodium sulphate, can be administered.

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

Prevention of repeated kidney stone formation

When Potassium Citrate is given orally, the metabolism of absorbed citrate produces an alkaline load. The induced alkaline load in turn increases urinary pH and raises urinary citrate by augmenting citrate clearance without measurably altering ultrafilterable serum citrate. Thus, Potassium Citrate therapy appears to increase urinary citrate principally by modifying the renal handling of citrate, rather than by increasing the filtered load of citrate. The increased filtered load of citrate may play some role, however, as in small comparisons of oral citrate and oral bicarbonate, citrate had a greater effect on urinary citrate.

In addition to raising urinary pH and citrate, Potassium Citrate increases urinary potassium by approximately the amount contained in the medication. In some patients, Potassium Citrate causes a transient reduction in urinary calcium.

The changes induced by Potassium Citrate produce urine that is less conducive to the crystallization of stoneforming salts (calcium oxalate, calcium phosphate and uric acid). Increased citrate in the urine, by complexing with calcium, decreases calcium ion activity and thus the saturation of calcium oxalate. Citrate also inhibits the spontaneous nucleation of calcium oxalate and calcium phosphate (brushite).

The increase in urinary pH also decreases calcium ion activity by increasing calcium complexation to dissociated anions. The rise in urinary pH also increases the ionization of uric acid to the more soluble urate ion.

Potassium Citrate therapy does not alter the urinary saturation of calcium phosphate, since the effect of increased citrate complexation of calcium is opposed by the rise in pH-dependent dissociation of phosphate. Calcium phosphate stones are more stable in alkaline urine.

In the setting of normal renal function, the rise in urinary citrate following a single dose begins by the first hour and lasts for 12 hours. With multiple doses the rise in citrate excretion reaches its peak by the third day and averts the normally wide circadian fluctuation in urinary citrate, thus maintaining urinary citrate at a higher, more constant level throughout the day. When the treatment is withdrawn, urinary citrate begins to decline toward the pre-treatment level on the first day.

The rise in citrate excretion is directly dependent on the Potassium Citrate dosage. Following long-term treatment, Potassium Citrate at a dosage of 60 mEq/day raises urinary citrate by approximately 400 mg/day and increases urinary pH by approximately 0.7 units.

In patients with severe renal tubular acidosis or chronic diarrheal syndrome where urinary citrate may be very low (<100 mg/day), Potassium Citrate may be relatively ineffective in raising urinary citrate. A higher dose of Potassium Citrate may therefore be required to produce a satisfactory citraturic response. In patients with renal tubular acidosis in whom urinary pH may be high, Potassium Citrate produces a relatively small rise in urinary pH.

Dosing Instructions: Treatment with extended release potassium citrate should be added to a regimen that limits salt intake (avoidance of foods with high salt content and of added salt at the table) and encourages high fluid intake (urine volume should be at least two liters per day). The objective of treatment with Potassium Citrate is to provide Potassium Citrate in sufficient dosage to restore normal urinary citrate (greater than 320 mg/day and as close to the normal mean of 640 mg/day as possible), and to increase urinary pH to a level of 6.0 or 7.0.

Monitor serum electrolytes (sodium, potassium, chloride and carbon dioxide), serum creatinine and complete blood counts every four months and more frequently in patients with cardiac disease, renal disease or acidosis. Perform electrocardiograms periodically. Treatment should be discontinued if there is hyperkalemia, a significant rise in serum creatinine or a significant fall in blood hemocrit or hemoglobin.

Severe Hypocitraturia: In patients with severe hypocitraturia (urinary citrate <150 mg/day), therapy should be initiated at a dosage of 60 mEq/day (30 mEq two times/day or 20 mEq three times/day with meals or within 30 minutes after meals or bedtime snack). Twenty-four hour urinary citrate and/or urinary pH measurements should be used to determine the adequacy of the initial dosage and to evaluate the effectiveness of any dosage change. In addition, urinary citrate and/or pH should be measured every four months. Doses of Potassium Citrate greater than 100 mEq/day have not been studied and should be avoided.

Mild To Moderate Hypocitraturia: In patients with mild to moderate hypocitraturia (urinary citrate > 150 mg/day) therapy should be initiated at 30 mEq/day (15 mEq two times/day or 10 mEq three times/day within 30 minutes after meals or bedtime snack). Twenty-four hour urinary citrate and/or urinary pH measurements should be used to determine the adequacy of the initial dosage and to evaluate the effectiveness of any dosage change. Doses of Potassium Citrate greater than 100 mEq/day have not been studied and should be avoided.

Nausea, vomiting, diarrhea, and stomach pain may occur. Taking it after meals will help prevent these side effects. An empty tablet shell may appear in your stool. This is harmless because your body has already absorbed the medication.

This drug may cause serious stomach or intestinal problems (e.g., bleeding, blockage, puncture). This medication may cause high potassium levels in the blood (hyperkalemia). A very serious allergic reaction to this drug is rare.

Potassium Citrate is contraindicated:

• In patients with hyperkalemia (or who have conditions pre-disposing them to hyperkalemia), as a further rise in serum potassium concentration may produce cardiac arrest. Such conditions include: chronic renal failure, uncontrolled diabetes mellitus, acute dehydration, strenuous physical exercise in unconditioned individuals, adrenal insufficiency, extensive tissue breakdown or the administration of a potassium-sparing agent (such as triamterene, spironolactone or amiloride).
• In patients in whom there is cause for arrest or delay in tablet passage through the gastrointestinal tract, such as those suffering from delayed gastric emptying, esophageal compression, intestinal obstruction or stricture, or those taking anticholinergic medication.
• In patients with peptic ulcer disease because of its ulcerogenic potential.
• In patients with active urinary tract infection (with either urea-splitting or other organisms, in association with either calcium or struvite stones). The ability of Potassium Citrate to increase urinary citrate may be attenuated by bacterial enzymatic degradation of citrate. Moreover, the rise in urinary pH resulting from Potassium Citrate therapy might promote further bacterial growth.
• In patients with renal insufficiency (glomerular filtration rate of less than 0.7 ml/kg/min), because of the danger of soft tissue calcification and increased risk for the development of hyperkalemia.

This medication should not be used ifpatient have (Addison's disease), current bladder infection, uncontrolled diabetes, severe heart disease (e.g., recent heart attack, heart damage), certain stomach/intestinal problems (diabetic gastroparesis, conditions decreasing gut movement, peptic ulcer, blockage), severe kidney disease (e.g., inability to make urine), potassium-restricted diet, high potassium levels, severe loss of body water (dehydration).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: low calcium levels, severe diarrhea, heart problems (e.g., irregular heartbeat, heart failure), kidney disease, stomach/gut problems (e.g., irritable bowel), severe tissue damage (e.g., severe burns). Before having surgery, tell your doctor or dentist that you are taking this medication.

Pregnancy Category C. Animal reproduction studies have not been conducted. It is also not known whether Potassium Citrate can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Potassium Citrate should be given to a pregnant woman only if clearly needed.

Nursing Mothers: The normal potassium ion content of human milk is about 13 mEq/L. It is not known if Potassium Citrate has an effect on this content. Potassium Citrate should be given to a woman who is breast feeding only if clearly needed.

Pediatric Use: Safety and effectiveness in children have not been established.

Treatment Of Overdosage: The administration of potassium salts to persons without predisposing conditions for hyperkalemia rarely causes serious hyperkalemia at recommended dosages. It is important to recognize that hyperkalemia is usually asymptomatic and may be manifested only by an increased serum potassium concentration and characteristic electrocardiographic changes (peaking of T-wave, loss of P-wave, depression of S-T segment and prolongation of the QT interval). Late manifestations include muscle paralysis and cardiovascular collapse from cardiac arrest.

Treatment measures for hyperkalemia include the following:

• Patients should be closely monitored for arrhythmias and electrolyte changes.
• Elimination of medications containing potassium and of agents with potassium-sparing properties such as potassium-sparing diuretics, ARBs, ACE inhibitors, NSAIDs, certain nutritional supplements and many others.
• Elimination of foods containing high levels of potassium such as almonds, apricots, bananas, beans (lima, pinto, white), cantaloupe, carrot juice (canned), figs, grapefruit juice, halibut, milk, oat bran, potato (with skin), salmon, spinach, tuna and many others.
• Intravenous calcium gluconate if the patient is at no risk or low risk of developing digitalis toxicity.
• Intravenous administration of 300-500 mL/hr of 10% dextrose solution containing 10-20 units of crystalline insulin per 1,000 mL.
• Correction of acidosis, if present, with intravenous sodium bicarbonate.
• Hemodialysis or peritoneal dialysis.
• Exchange resins may be used. However, this measure alone is not sufficient for the acute treatment of hyperkalemia.

Lowering potassium levels too rapidly in patients taking digitalis can produce digitalis toxicity.

This preparation is indicated in the following cases:

• To relieve discomfort in urinary tract infections
• To prevent kidney stone
• With uricosuric agent to prevent gout
• Acidosis caused by kidney diseases

Prevention of repeated kidney stone formation, Urinary Alkalinizing Agent

Potassium Citrate and Citric Acid oral solution is a stable and pleasant-tasting oral systemic alkalizer. Potassium Citrate is absorbed and metabolized to Potassium Bicarbonate, thus acting as a systemic alkalizer. This product alkalinizes the urine without producing a systemic alkalosis in recommended doses. It is highly palatable, pleasant tasting and tolerable, even when administered for long periods. Potassium Citrate does not neutralize the gastric juice or disturb digestion.

To relieve discomfort in UTI:

• Adults and children over 6 years: 10 ml 3 times daily, diluted with 1 glass of water.
• Children 1-6 years: 5 ml 3 times daily, diluted with ½ glass of water.

To prevent kidney stones, With a uricosuric agent to prevent gout, Acidosis caused by kidney diseases:

• Adults: 10-15 ml 4 times daily (or as directed by the physician) diluted with 1 glass of water.
• Pediatric: 5-10 ml 4 times daily (or as directed by the physician) diluted with ½ glass of water.

This solution is generally well tolerated without any unpleasant side effect when given in recommended doses to patients with normal renal function and urinary output. However, as with any alkalinizing agent, caution must be used in certain patients with abnormal renal mechanisms to avoid development of hyperkalemia or alkalosis. Potassium intoxication causes listlessness, weakness, mental confusion, tingling of extremities and other symptoms associated with a high concentration of Potassium in the serum.

The drug is contraindicated in severe renal impairment with oliguria or azotemia, untreated Addison's disease, acute dehydration, severe myocardial damage and hyperkalemia from any cause.

The solution should be used with caution in patients with low urinary output. It should be diluted adequately with water to minimize the possibility of gastrointestinal injury associated with the oral ingestion of concentrated Potassium salt preparations; and preferably, to take each dose after meals. Large doses may cause hyperkalemia and alkalosis, especially in the presence of renal disease.

Concurrent administration of potassium-containing medication, potassium-sparing diuretics, angiotensin-converting enzyme (ACE) inhibitors or cardiac glycosides may lead to toxicity.

No information is available regarding the use of this drug during pregnancy and lactation.

The administration of oral Potassium salts to persons with normal excretory mechanisms for potassium rarely causes serious hyperkalemia. However, if excretory mechanisms are impaired, hyperkalemia can result. Hyperkalemia, when detected, must be treated immediately because lethal levels can be reached in a few hours. If hyperkalemia occurs, treatment measures will include the followings: (1) Elimination of foods or medications containing potassium. (2) The intravenous administration of 300 to 500 ml/hr of dextrose solution (10 to 25%), containing 10 units of insulin/20 gm dextrose. (3) The use of exchange resins, hemodialysis or peritoneal dialysis.

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.

This preparation is indicated in the following cases:

• To relieve discomfort in urinary tract infections
• To prevent kidney stone
• With uricosuric agent to prevent gout
• Acidosis caused by kidney diseases

Prevention of repeated kidney stone formation, Urinary Alkalinizing Agent

Potassium Citrate and Citric Acid oral solution is a stable and pleasant-tasting oral systemic alkalizer. Potassium Citrate is absorbed and metabolized to Potassium Bicarbonate, thus acting as a systemic alkalizer. This product alkalinizes the urine without producing a systemic alkalosis in recommended doses. It is highly palatable, pleasant tasting and tolerable, even when administered for long periods. Potassium Citrate does not neutralize the gastric juice or disturb digestion.

To relieve discomfort in UTI:

• Adults and children over 6 years: 10 ml 3 times daily, diluted with 1 glass of water.
• Children 1-6 years: 5 ml 3 times daily, diluted with ½ glass of water.

To prevent kidney stones, With a uricosuric agent to prevent gout, Acidosis caused by kidney diseases:

• Adults: 10-15 ml 4 times daily (or as directed by the physician) diluted with 1 glass of water.
• Pediatric: 5-10 ml 4 times daily (or as directed by the physician) diluted with ½ glass of water.

This solution is generally well tolerated without any unpleasant side effect when given in recommended doses to patients with normal renal function and urinary output. However, as with any alkalinizing agent, caution must be used in certain patients with abnormal renal mechanisms to avoid development of hyperkalemia or alkalosis. Potassium intoxication causes listlessness, weakness, mental confusion, tingling of extremities and other symptoms associated with a high concentration of Potassium in the serum.

The drug is contraindicated in severe renal impairment with oliguria or azotemia, untreated Addison's disease, acute dehydration, severe myocardial damage and hyperkalemia from any cause.

The solution should be used with caution in patients with low urinary output. It should be diluted adequately with water to minimize the possibility of gastrointestinal injury associated with the oral ingestion of concentrated Potassium salt preparations; and preferably, to take each dose after meals. Large doses may cause hyperkalemia and alkalosis, especially in the presence of renal disease.

Concurrent administration of potassium-containing medication, potassium-sparing diuretics, angiotensin-converting enzyme (ACE) inhibitors or cardiac glycosides may lead to toxicity.

No information is available regarding the use of this drug during pregnancy and lactation.

The administration of oral Potassium salts to persons with normal excretory mechanisms for potassium rarely causes serious hyperkalemia. However, if excretory mechanisms are impaired, hyperkalemia can result. Hyperkalemia, when detected, must be treated immediately because lethal levels can be reached in a few hours. If hyperkalemia occurs, treatment measures will include the followings: (1) Elimination of foods or medications containing potassium. (2) The intravenous administration of 300 to 500 ml/hr of dextrose solution (10 to 25%), containing 10 units of insulin/20 gm dextrose. (3) The use of exchange resins, hemodialysis or peritoneal dialysis.

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.

Tamsulosin Hydrochloride is indicated for the treatment of functional symptoms of Benign Prostatic Hyperplasia (BPH).

BPH/ Urinary retention/ Urinary incontinence

Tamsulosin, a selective alpha1 adrenoceptor blocking agent, exhibits its selectivity for alpha1 A adrenoceptors in human prostate. Blockade of these adrenoceptors can cause smooth muscle in the bladder neck and prostate to relax, resulting in an improvement in urine flow rate and a reduction in symptoms of BPH. Absorption of Tamsulosin hydrochloride capsule 0.4mg is essentially complete (90%) following oral administration under fasting conditions. The time to maximum concentration (Tmax) is reached by four to five hours under fasting conditions and by six to seven hours when administered with food. Tamsulosin hydrochloride is extremely bound to human plasma protein (94% to 99%). Tamsulosin hydrochloride is extensively metabolized by cytochrome P 450 enzymes in the liver and less than 10% of the dose is excreted in urine as unchanged form. Following intravenous or oral administration of an immediate-release formulation the elimination half-life of Tamsulosin hydrochloride in plasma ranges from five to seven hours. Because of the absorption rate controlled pharmacokinetics with Prostam capsules, the apparent half-life of Tamsulosin hydrochloride is approximately 9 to 13 hours in healthy volunteers and 14 to 15 hours in the target population.

Tamsulosin Hydrochloride 0.4 mg (one capsule) daily, to be taken after meal at night. The dose may be increased after 2 to 4 weeks, if necessary, to Tamsulosin Hydrochloride 0.8 mg (two capsules) once daily. If Tamsulosin Hydrochloride administration is discontinued or interrupted for several days at either the 0.4 mg or 0.8 mg dose, therapy should be started again with the Tamsulosin Hydrochloride 0.4 mg (one capsule) once daily dose. The capsule should be swallowed whole with a glass of water (about 150 ml) in the standing or sitting position. The capsule should not be crunched or chewed, as this will interfere with the modified release of the active ingredient.

The following adverse reactions have been reported during the use of Tamsulosin: dizziness, abnormal ejaculation and; less frequently headache, asthenia, postural hypotension and palpitations.

Tamsulosin hydrochloride is contraindicated in patients with hypersensitivity to it; history of orthostatic hypotension; severe hepatic insufficiency.

As with other alpha1 blockers, a reduction in blood pressure can occur in individual cases during treatment with Tamsulosin, as a result of which, rarely, syncope can occur, at the first signs of orthostatic hypotension (dizziness, weakness) the patient should sit or lie down until the symptoms have disappeared. And they should be cautioned to avoid situations where injury could result (like driving, operating machinery or performing hazardous tasks).

Before therapy with Tamsulosin is initiated the patient should be examined in order to exclude the presence of other conditions which can cause the same symptoms as Benign Prostatic hyperplasia. Digital rectal examination and when the necessary determination of Prostate Specific Antigen (PSA) should be performed before treatment and at regular intervals afterwards.

Rarely, transient postural symptoms have occurred during orthostatic provocation testing after the first dose. Use in patients with micturition syncope is not advised.

Effects on ability to drive and use machines: No data is available on whether Tamsulosin adversely affects the ability to drive or operate machines. However, in this respect, patients should be aware of the fact that dizziness can occur.

Concurrent administration of other alfa1-adrenoceptor antagonists could lead to hypotensive effects. No interactions have been seen when Tamsulosin was given concomitantly with either atenolol, enalapril or nifedipine. Concomitant cimetidine brings about a rise and frusemide a fall in plasma levels of Tamsulosin, but as levels remain within the normal range posology need not be changed. No interactions at the level of hepatic metabolism have been seen during in vitro studies with liver microsomal fractions (representative of the cytochrome P450-linked drug-metabolizing enzyme system), involving amitriptyline, salbutamol, glibenclamide, and finasteride. Diclofenac and warfarin, however, may increase the elimination rate of Tamsulosin.

Use of Tamsulosin in pregnancy and lactation is not recommended.

No case of acute overdosage has been reported. However, acute hypotension is likely to occur after overdosage in which case cardiovascular support should be given. Blood pressure can be restored and the heart rate brought back to normal by lying the patient down. If this does not help then volume expanders, and when necessary, vasopressors could be employed. Renal function should be monitored and general supportive measures applied. Dialysis is unlikely to be of help as Tamsulosin is very highly bound to plasma proteins. Measures, such as emesis, can be taken to impede absorption. When large quantities are involved, gastric lavage can be applied and activated charcoal and an osmotic laxative, such as sodium sulphate, can be administered.

Store in a cool and dry place, below 30°C, protected from light.