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Anti-coagulants, Anti-platelet drugs, Fibrinolytics (Thrombolytics)

Dabigatran and its acyl glucuronides are competitive, direct thrombin inhibitors. Because thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of a thrombus. Both free and clot-bound thrombin, and thrombin-induced platelet aggregation are inhibited by the active moieties.

At recommended therapeutic doses, dabigatran etexilate prolongs the coagulation markers such as aPTT, ECT, and TT. INR is relatively insensitive to the exposure to dabigatran and cannot be interpreted the same way as used for warfarin monitoring. The aPTT test provides an approximation of Dabigatran Etexilate’s anticoagulant effect. The average time course for effects on aPTT, following approved dosing regimens in patients with various degrees of renal impairment is shown in Figure 2. The curves represent mean levels without confidence intervals; variations should be expected when measuring aPTT. While advice cannot be provided on the level of recovery of aPTT needed in any particular clinical setting, the curves can be used to estimate the time to get to a particular level of recovery, even when the time since the last dose of Dabigatran Etexilate is not precisely known. In the RE-LY trial, the median (10 th to 90 th percentile) trough aPTT in patients receiving the 150 mg dose was 52 (40 to 76) seconds.

Reduction in Risk of Stroke and Systemic Embolism in Non-valvular AF-

• CrCl >30 mL/min: 150 mg twice daily
• CrCl 15 to 30 mL/min: 75 mg twice daily
• CrCl <15 mL/min or on dialysis: Dosing recommendations cannot be provided
• CrCl 30 to 50 mL/min with concomitant use of P-gp inhibitors: Reduce dose to 75 mg twice daily if given with P-gp inhibitors dronedarone or systemic ketoconazole.
• CrCl <30 mL/min with concomitant use of P-gp inhibitors: Avoid co-administration

Treatment of DVT and PE, Reduction in the Risk of Recurrence of DVT and PE-

• CrCl >30 mL/min: 150 mg twice daily
• CrCl ≤30 mL/min or on dialysis: Dosing recommendations cannot be provided
• CrCl <50 mL/min with concomitant use of P-gp inhibitors: Avoid co-administration

Prophylaxis of DVT and PE Following Hip Replacement Surgery-

• CrCl >30 mL/min: 110 mg for first day, then 220 mg once daily
• CrCl ≤30 mL/min or on dialysis: Dosing recommendations cannot be provided
• CrCl <50 mL/min with concomitant use of P-gp inhibitors: Avoid co-administration.

Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation: For patients with creatinine clearance (CrCl) >30 mL/min, the recommended dose of Dabigatran Etexilate is 150 mg taken orally, twice daily. For patients with severe renal impairment (CrCl 15-30 mL/min), the recommended dose of Dabigatran Etexilate is 75 mg twice daily. Dosing recommendations for patients with a CrCl <15 mL/min or on dialysis cannot be provided.

Treatment of Deep Venous Thrombosis and Pulmonary Embolism: For patients with CrCl >30 mL/min, the recommended dose of Dabigatran Etexilate is 150 mg taken orally, twice daily, after 5-10 days of parenteral anticoagulation. Dosing recommendations for patients with a CrCl ≤30 mL/min or on dialysis cannot be provided.

Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: For patients with CrCl >30 mL/min, the recommended dose of Dabigatran Etexilate is 150 mg taken orally, twice daily after previous treatment. Dosing recommendations for patients with a CrCl ≤30 mL/min or on dialysis cannot be provided.

Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism Following Hip Replacement Surgery: For patients with CrCl >30 mL/min, the recommended dose of Dabigatran Etexilate is 110 mg taken orally 1-4 hours after surgery and after hemostasis has been achieved, then 220 mg taken once daily for 28-35 days. If Dabigatran Etexilate is not started on the day of surgery, after hemostasis has been achieved initiate treatment with 220 mg once daily. Dosing recommendations for patients with a CrCl ≤30 mL/min or on dialysis cannot be provided

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Increased Risk of Thrombotic Events after Premature Discontinuation
• Risk of Bleeding
• Spinal/Epidural Anesthesia or Puncture
• Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves
• Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome

Dabigatran Etexilate is contraindicated in patients with:

• Active pathological bleeding.
• History of a serious hypersensitivity reaction to Dabigatran Etexilate (e.g., anaphylactic reaction or anaphylactic shock).
• Mechanical prosthetic heart valve.

Bleeding: Dabigatran Etexilate can cause serious and fatal bleeding

Bioprosthetic heart valves: Dabigatran Etexilate use not recommended

Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome: Dabigatran Etexilate use not recommended

Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation: The concomitant use of Dabigatran Etexilate with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided. P-gp inhibition and impaired renal function are the major independent factors that result in increased exposure to dabigatran. Concomitant use of P-gp inhibitors in patients with renal impairment is expected to produce increased exposure of dabigatran compared to that seen with either factor alone. In patients with moderate renal impairment (CrCl 30-50 mL/min), reduce the dose of Dabigatran Etexilate to 75 mg twice daily when administered concomitantly with the P-gp inhibitors dronedarone or systemic ketoconazole. The use of the P-gp inhibitors verapamil, amiodarone, quinidine, clarithromycin, and ticagrelor does not require a dose adjustment of Dabigatran Etexilate. These results should not be extrapolated to other P-gp inhibitors. The concomitant use of Dabigatran Etexilate and P-gp inhibitors in patients with severe renal impairment (CrCl 15-30 mL/min) should be avoided.

Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: Avoid use of Dabigatran Etexilate and P-gp inhibitors in patients with CrCl <50 mL/min.

Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism Following Hip Replacement Surgery: In patients with CrCl ≥50 mL/min who have concomitant administration of P-gp inhibitors such as dronedarone or systemic ketoconazole, it may be helpful to separate the timing of administration of dabigatran and the P-gp inhibitor by several hours. The concomitant use of Dabigatran Etexilate and P-gp inhibitors in patients with CrCl <50 mL/min should be avoided.

Pregnancy: The limited available data on Dabigatran Etexilate use in pregnant women are insufficient to determine drug-associated risks for adverse developmental outcomes. There are risks to the mother associated with untreated venous thromboembolism in pregnancy and a risk of hemorrhage in the mother and fetus associated with the use of anticoagulant

Lactation: There are no data on the presence of dabigatran in human milk, the effects on the breastfed child, or on milk production. Dabigatran and/or its metabolites were present in rat milk. Breastfeeding is not recommended during treatment with Dabigatran Etexilate.

Pediatric Use: The safety and effectiveness of Dabigatran Etexilate in pediatric patients have not been established.

Geriatric Use: Of the total number of patients in the RE-LY study, 82% were 65 and over, while 40% were 75 and over. The risk of stroke and bleeding increases with age, but the risk-benefit profile is favorable in all age groups.

Accidental overdose may lead to hemorrhagic complications. In the event of hemorrhagic complications, initiate appropriate clinical support, discontinue treatment with Dabigatran Etexilate, and investigate the source of bleeding. A specific reversal agent (idarucizumab) is available. Dabigatran is primarily eliminated by the kidneys with a low plasma protein binding of approximately 35%. Hemodialysis can remove dabigatran; however, data supporting this approach are limited. Using a high-flux dialyzer, blood flow rate of 200 mL/min, and dialysate flow rate of 700 mL/min, approximately 49% of total dabigatran can be cleared from plasma over 4 hours. At the same dialysate flow rate, approximately 57% can be cleared using a dialyzer blood flow rate of 300 mL/min, with no appreciable increase in clearance observed at higher blood flow rates. Upon cessation of hemodialysis, a redistribution effect of approximately 7% to 15% is seen. The effect of dialysis on dabigatran’s plasma concentration would be expected to vary based on patient specific characteristics. Measurement of aPTT or ECT may help guide therapy

Store Dabigatran Etexilate at room temperature 20°C to 25°C. After opening the bottle, use Dabigatran Etexilate within 4 months. Safely throw away any unused Dabigatran Etexilate after 4 months. Keep Dabigatran Etexilate in the original bottle or blister package to keep it dry (protect the capsules from moisture). Do not put Dabigatran Etexilate in pill boxes or pill organizers. Tightly close your bottle of Dabigatran Etexilate right away after you take your dose. Keep Dabigatran Etexilate and all medicines out of the reach of children.

Anti-coagulants, Anti-platelet drugs, Fibrinolytics (Thrombolytics)

Dabigatran and its acyl glucuronides are competitive, direct thrombin inhibitors. Because thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of a thrombus. Both free and clot-bound thrombin, and thrombin-induced platelet aggregation are inhibited by the active moieties.

At recommended therapeutic doses, dabigatran etexilate prolongs the coagulation markers such as aPTT, ECT, and TT. INR is relatively insensitive to the exposure to dabigatran and cannot be interpreted the same way as used for warfarin monitoring. The aPTT test provides an approximation of Dabigatran Etexilate’s anticoagulant effect. The average time course for effects on aPTT, following approved dosing regimens in patients with various degrees of renal impairment is shown in Figure 2. The curves represent mean levels without confidence intervals; variations should be expected when measuring aPTT. While advice cannot be provided on the level of recovery of aPTT needed in any particular clinical setting, the curves can be used to estimate the time to get to a particular level of recovery, even when the time since the last dose of Dabigatran Etexilate is not precisely known. In the RE-LY trial, the median (10 th to 90 th percentile) trough aPTT in patients receiving the 150 mg dose was 52 (40 to 76) seconds.

Reduction in Risk of Stroke and Systemic Embolism in Non-valvular AF-

• CrCl >30 mL/min: 150 mg twice daily
• CrCl 15 to 30 mL/min: 75 mg twice daily
• CrCl <15 mL/min or on dialysis: Dosing recommendations cannot be provided
• CrCl 30 to 50 mL/min with concomitant use of P-gp inhibitors: Reduce dose to 75 mg twice daily if given with P-gp inhibitors dronedarone or systemic ketoconazole.
• CrCl <30 mL/min with concomitant use of P-gp inhibitors: Avoid co-administration

Treatment of DVT and PE, Reduction in the Risk of Recurrence of DVT and PE-

• CrCl >30 mL/min: 150 mg twice daily
• CrCl ≤30 mL/min or on dialysis: Dosing recommendations cannot be provided
• CrCl <50 mL/min with concomitant use of P-gp inhibitors: Avoid co-administration

Prophylaxis of DVT and PE Following Hip Replacement Surgery-

• CrCl >30 mL/min: 110 mg for first day, then 220 mg once daily
• CrCl ≤30 mL/min or on dialysis: Dosing recommendations cannot be provided
• CrCl <50 mL/min with concomitant use of P-gp inhibitors: Avoid co-administration.

Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation: For patients with creatinine clearance (CrCl) >30 mL/min, the recommended dose of Dabigatran Etexilate is 150 mg taken orally, twice daily. For patients with severe renal impairment (CrCl 15-30 mL/min), the recommended dose of Dabigatran Etexilate is 75 mg twice daily. Dosing recommendations for patients with a CrCl <15 mL/min or on dialysis cannot be provided.

Treatment of Deep Venous Thrombosis and Pulmonary Embolism: For patients with CrCl >30 mL/min, the recommended dose of Dabigatran Etexilate is 150 mg taken orally, twice daily, after 5-10 days of parenteral anticoagulation. Dosing recommendations for patients with a CrCl ≤30 mL/min or on dialysis cannot be provided.

Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: For patients with CrCl >30 mL/min, the recommended dose of Dabigatran Etexilate is 150 mg taken orally, twice daily after previous treatment. Dosing recommendations for patients with a CrCl ≤30 mL/min or on dialysis cannot be provided.

Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism Following Hip Replacement Surgery: For patients with CrCl >30 mL/min, the recommended dose of Dabigatran Etexilate is 110 mg taken orally 1-4 hours after surgery and after hemostasis has been achieved, then 220 mg taken once daily for 28-35 days. If Dabigatran Etexilate is not started on the day of surgery, after hemostasis has been achieved initiate treatment with 220 mg once daily. Dosing recommendations for patients with a CrCl ≤30 mL/min or on dialysis cannot be provided

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Increased Risk of Thrombotic Events after Premature Discontinuation
• Risk of Bleeding
• Spinal/Epidural Anesthesia or Puncture
• Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves
• Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome

Dabigatran Etexilate is contraindicated in patients with:

• Active pathological bleeding.
• History of a serious hypersensitivity reaction to Dabigatran Etexilate (e.g., anaphylactic reaction or anaphylactic shock).
• Mechanical prosthetic heart valve.

Bleeding: Dabigatran Etexilate can cause serious and fatal bleeding

Bioprosthetic heart valves: Dabigatran Etexilate use not recommended

Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome: Dabigatran Etexilate use not recommended

Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation: The concomitant use of Dabigatran Etexilate with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided. P-gp inhibition and impaired renal function are the major independent factors that result in increased exposure to dabigatran. Concomitant use of P-gp inhibitors in patients with renal impairment is expected to produce increased exposure of dabigatran compared to that seen with either factor alone. In patients with moderate renal impairment (CrCl 30-50 mL/min), reduce the dose of Dabigatran Etexilate to 75 mg twice daily when administered concomitantly with the P-gp inhibitors dronedarone or systemic ketoconazole. The use of the P-gp inhibitors verapamil, amiodarone, quinidine, clarithromycin, and ticagrelor does not require a dose adjustment of Dabigatran Etexilate. These results should not be extrapolated to other P-gp inhibitors. The concomitant use of Dabigatran Etexilate and P-gp inhibitors in patients with severe renal impairment (CrCl 15-30 mL/min) should be avoided.

Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: Avoid use of Dabigatran Etexilate and P-gp inhibitors in patients with CrCl <50 mL/min.

Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism Following Hip Replacement Surgery: In patients with CrCl ≥50 mL/min who have concomitant administration of P-gp inhibitors such as dronedarone or systemic ketoconazole, it may be helpful to separate the timing of administration of dabigatran and the P-gp inhibitor by several hours. The concomitant use of Dabigatran Etexilate and P-gp inhibitors in patients with CrCl <50 mL/min should be avoided.

Pregnancy: The limited available data on Dabigatran Etexilate use in pregnant women are insufficient to determine drug-associated risks for adverse developmental outcomes. There are risks to the mother associated with untreated venous thromboembolism in pregnancy and a risk of hemorrhage in the mother and fetus associated with the use of anticoagulant

Lactation: There are no data on the presence of dabigatran in human milk, the effects on the breastfed child, or on milk production. Dabigatran and/or its metabolites were present in rat milk. Breastfeeding is not recommended during treatment with Dabigatran Etexilate.

Pediatric Use: The safety and effectiveness of Dabigatran Etexilate in pediatric patients have not been established.

Geriatric Use: Of the total number of patients in the RE-LY study, 82% were 65 and over, while 40% were 75 and over. The risk of stroke and bleeding increases with age, but the risk-benefit profile is favorable in all age groups.

Accidental overdose may lead to hemorrhagic complications. In the event of hemorrhagic complications, initiate appropriate clinical support, discontinue treatment with Dabigatran Etexilate, and investigate the source of bleeding. A specific reversal agent (idarucizumab) is available. Dabigatran is primarily eliminated by the kidneys with a low plasma protein binding of approximately 35%. Hemodialysis can remove dabigatran; however, data supporting this approach are limited. Using a high-flux dialyzer, blood flow rate of 200 mL/min, and dialysate flow rate of 700 mL/min, approximately 49% of total dabigatran can be cleared from plasma over 4 hours. At the same dialysate flow rate, approximately 57% can be cleared using a dialyzer blood flow rate of 300 mL/min, with no appreciable increase in clearance observed at higher blood flow rates. Upon cessation of hemodialysis, a redistribution effect of approximately 7% to 15% is seen. The effect of dialysis on dabigatran’s plasma concentration would be expected to vary based on patient specific characteristics. Measurement of aPTT or ECT may help guide therapy

Store Dabigatran Etexilate at room temperature 20°C to 25°C. After opening the bottle, use Dabigatran Etexilate within 4 months. Safely throw away any unused Dabigatran Etexilate after 4 months. Keep Dabigatran Etexilate in the original bottle or blister package to keep it dry (protect the capsules from moisture). Do not put Dabigatran Etexilate in pill boxes or pill organizers. Tightly close your bottle of Dabigatran Etexilate right away after you take your dose. Keep Dabigatran Etexilate and all medicines out of the reach of children.

Anti-coagulants, Anti-platelet drugs, Fibrinolytics (Thrombolytics)

Dabigatran and its acyl glucuronides are competitive, direct thrombin inhibitors. Because thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of a thrombus. Both free and clot-bound thrombin, and thrombin-induced platelet aggregation are inhibited by the active moieties.

At recommended therapeutic doses, dabigatran etexilate prolongs the coagulation markers such as aPTT, ECT, and TT. INR is relatively insensitive to the exposure to dabigatran and cannot be interpreted the same way as used for warfarin monitoring. The aPTT test provides an approximation of Dabigatran Etexilate’s anticoagulant effect. The average time course for effects on aPTT, following approved dosing regimens in patients with various degrees of renal impairment is shown in Figure 2. The curves represent mean levels without confidence intervals; variations should be expected when measuring aPTT. While advice cannot be provided on the level of recovery of aPTT needed in any particular clinical setting, the curves can be used to estimate the time to get to a particular level of recovery, even when the time since the last dose of Dabigatran Etexilate is not precisely known. In the RE-LY trial, the median (10 th to 90 th percentile) trough aPTT in patients receiving the 150 mg dose was 52 (40 to 76) seconds.

Reduction in Risk of Stroke and Systemic Embolism in Non-valvular AF-

• CrCl >30 mL/min: 150 mg twice daily
• CrCl 15 to 30 mL/min: 75 mg twice daily
• CrCl <15 mL/min or on dialysis: Dosing recommendations cannot be provided
• CrCl 30 to 50 mL/min with concomitant use of P-gp inhibitors: Reduce dose to 75 mg twice daily if given with P-gp inhibitors dronedarone or systemic ketoconazole.
• CrCl <30 mL/min with concomitant use of P-gp inhibitors: Avoid co-administration

Treatment of DVT and PE, Reduction in the Risk of Recurrence of DVT and PE-

• CrCl >30 mL/min: 150 mg twice daily
• CrCl ≤30 mL/min or on dialysis: Dosing recommendations cannot be provided
• CrCl <50 mL/min with concomitant use of P-gp inhibitors: Avoid co-administration

Prophylaxis of DVT and PE Following Hip Replacement Surgery-

• CrCl >30 mL/min: 110 mg for first day, then 220 mg once daily
• CrCl ≤30 mL/min or on dialysis: Dosing recommendations cannot be provided
• CrCl <50 mL/min with concomitant use of P-gp inhibitors: Avoid co-administration.

Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation: For patients with creatinine clearance (CrCl) >30 mL/min, the recommended dose of Dabigatran Etexilate is 150 mg taken orally, twice daily. For patients with severe renal impairment (CrCl 15-30 mL/min), the recommended dose of Dabigatran Etexilate is 75 mg twice daily. Dosing recommendations for patients with a CrCl <15 mL/min or on dialysis cannot be provided.

Treatment of Deep Venous Thrombosis and Pulmonary Embolism: For patients with CrCl >30 mL/min, the recommended dose of Dabigatran Etexilate is 150 mg taken orally, twice daily, after 5-10 days of parenteral anticoagulation. Dosing recommendations for patients with a CrCl ≤30 mL/min or on dialysis cannot be provided.

Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: For patients with CrCl >30 mL/min, the recommended dose of Dabigatran Etexilate is 150 mg taken orally, twice daily after previous treatment. Dosing recommendations for patients with a CrCl ≤30 mL/min or on dialysis cannot be provided.

Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism Following Hip Replacement Surgery: For patients with CrCl >30 mL/min, the recommended dose of Dabigatran Etexilate is 110 mg taken orally 1-4 hours after surgery and after hemostasis has been achieved, then 220 mg taken once daily for 28-35 days. If Dabigatran Etexilate is not started on the day of surgery, after hemostasis has been achieved initiate treatment with 220 mg once daily. Dosing recommendations for patients with a CrCl ≤30 mL/min or on dialysis cannot be provided

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Increased Risk of Thrombotic Events after Premature Discontinuation
• Risk of Bleeding
• Spinal/Epidural Anesthesia or Puncture
• Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves
• Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome

Dabigatran Etexilate is contraindicated in patients with:

• Active pathological bleeding.
• History of a serious hypersensitivity reaction to Dabigatran Etexilate (e.g., anaphylactic reaction or anaphylactic shock).
• Mechanical prosthetic heart valve.

Bleeding: Dabigatran Etexilate can cause serious and fatal bleeding

Bioprosthetic heart valves: Dabigatran Etexilate use not recommended

Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome: Dabigatran Etexilate use not recommended

Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation: The concomitant use of Dabigatran Etexilate with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided. P-gp inhibition and impaired renal function are the major independent factors that result in increased exposure to dabigatran. Concomitant use of P-gp inhibitors in patients with renal impairment is expected to produce increased exposure of dabigatran compared to that seen with either factor alone. In patients with moderate renal impairment (CrCl 30-50 mL/min), reduce the dose of Dabigatran Etexilate to 75 mg twice daily when administered concomitantly with the P-gp inhibitors dronedarone or systemic ketoconazole. The use of the P-gp inhibitors verapamil, amiodarone, quinidine, clarithromycin, and ticagrelor does not require a dose adjustment of Dabigatran Etexilate. These results should not be extrapolated to other P-gp inhibitors. The concomitant use of Dabigatran Etexilate and P-gp inhibitors in patients with severe renal impairment (CrCl 15-30 mL/min) should be avoided.

Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: Avoid use of Dabigatran Etexilate and P-gp inhibitors in patients with CrCl <50 mL/min.

Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism Following Hip Replacement Surgery: In patients with CrCl ≥50 mL/min who have concomitant administration of P-gp inhibitors such as dronedarone or systemic ketoconazole, it may be helpful to separate the timing of administration of dabigatran and the P-gp inhibitor by several hours. The concomitant use of Dabigatran Etexilate and P-gp inhibitors in patients with CrCl <50 mL/min should be avoided.

Pregnancy: The limited available data on Dabigatran Etexilate use in pregnant women are insufficient to determine drug-associated risks for adverse developmental outcomes. There are risks to the mother associated with untreated venous thromboembolism in pregnancy and a risk of hemorrhage in the mother and fetus associated with the use of anticoagulant

Lactation: There are no data on the presence of dabigatran in human milk, the effects on the breastfed child, or on milk production. Dabigatran and/or its metabolites were present in rat milk. Breastfeeding is not recommended during treatment with Dabigatran Etexilate.

Pediatric Use: The safety and effectiveness of Dabigatran Etexilate in pediatric patients have not been established.

Geriatric Use: Of the total number of patients in the RE-LY study, 82% were 65 and over, while 40% were 75 and over. The risk of stroke and bleeding increases with age, but the risk-benefit profile is favorable in all age groups.

Accidental overdose may lead to hemorrhagic complications. In the event of hemorrhagic complications, initiate appropriate clinical support, discontinue treatment with Dabigatran Etexilate, and investigate the source of bleeding. A specific reversal agent (idarucizumab) is available. Dabigatran is primarily eliminated by the kidneys with a low plasma protein binding of approximately 35%. Hemodialysis can remove dabigatran; however, data supporting this approach are limited. Using a high-flux dialyzer, blood flow rate of 200 mL/min, and dialysate flow rate of 700 mL/min, approximately 49% of total dabigatran can be cleared from plasma over 4 hours. At the same dialysate flow rate, approximately 57% can be cleared using a dialyzer blood flow rate of 300 mL/min, with no appreciable increase in clearance observed at higher blood flow rates. Upon cessation of hemodialysis, a redistribution effect of approximately 7% to 15% is seen. The effect of dialysis on dabigatran’s plasma concentration would be expected to vary based on patient specific characteristics. Measurement of aPTT or ECT may help guide therapy

Store Dabigatran Etexilate at room temperature 20°C to 25°C. After opening the bottle, use Dabigatran Etexilate within 4 months. Safely throw away any unused Dabigatran Etexilate after 4 months. Keep Dabigatran Etexilate in the original bottle or blister package to keep it dry (protect the capsules from moisture). Do not put Dabigatran Etexilate in pill boxes or pill organizers. Tightly close your bottle of Dabigatran Etexilate right away after you take your dose. Keep Dabigatran Etexilate and all medicines out of the reach of children.

Anti-coagulants, Anti-platelet drugs, Fibrinolytics (Thrombolytics)

Dabigatran and its acyl glucuronides are competitive, direct thrombin inhibitors. Because thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of a thrombus. Both free and clot-bound thrombin, and thrombin-induced platelet aggregation are inhibited by the active moieties.

At recommended therapeutic doses, dabigatran etexilate prolongs the coagulation markers such as aPTT, ECT, and TT. INR is relatively insensitive to the exposure to dabigatran and cannot be interpreted the same way as used for warfarin monitoring. The aPTT test provides an approximation of Dabigatran Etexilate’s anticoagulant effect. The average time course for effects on aPTT, following approved dosing regimens in patients with various degrees of renal impairment is shown in Figure 2. The curves represent mean levels without confidence intervals; variations should be expected when measuring aPTT. While advice cannot be provided on the level of recovery of aPTT needed in any particular clinical setting, the curves can be used to estimate the time to get to a particular level of recovery, even when the time since the last dose of Dabigatran Etexilate is not precisely known. In the RE-LY trial, the median (10 th to 90 th percentile) trough aPTT in patients receiving the 150 mg dose was 52 (40 to 76) seconds.

Reduction in Risk of Stroke and Systemic Embolism in Non-valvular AF-

• CrCl >30 mL/min: 150 mg twice daily
• CrCl 15 to 30 mL/min: 75 mg twice daily
• CrCl <15 mL/min or on dialysis: Dosing recommendations cannot be provided
• CrCl 30 to 50 mL/min with concomitant use of P-gp inhibitors: Reduce dose to 75 mg twice daily if given with P-gp inhibitors dronedarone or systemic ketoconazole.
• CrCl <30 mL/min with concomitant use of P-gp inhibitors: Avoid co-administration

Treatment of DVT and PE, Reduction in the Risk of Recurrence of DVT and PE-

• CrCl >30 mL/min: 150 mg twice daily
• CrCl ≤30 mL/min or on dialysis: Dosing recommendations cannot be provided
• CrCl <50 mL/min with concomitant use of P-gp inhibitors: Avoid co-administration

Prophylaxis of DVT and PE Following Hip Replacement Surgery-

• CrCl >30 mL/min: 110 mg for first day, then 220 mg once daily
• CrCl ≤30 mL/min or on dialysis: Dosing recommendations cannot be provided
• CrCl <50 mL/min with concomitant use of P-gp inhibitors: Avoid co-administration.

Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation: For patients with creatinine clearance (CrCl) >30 mL/min, the recommended dose of Dabigatran Etexilate is 150 mg taken orally, twice daily. For patients with severe renal impairment (CrCl 15-30 mL/min), the recommended dose of Dabigatran Etexilate is 75 mg twice daily. Dosing recommendations for patients with a CrCl <15 mL/min or on dialysis cannot be provided.

Treatment of Deep Venous Thrombosis and Pulmonary Embolism: For patients with CrCl >30 mL/min, the recommended dose of Dabigatran Etexilate is 150 mg taken orally, twice daily, after 5-10 days of parenteral anticoagulation. Dosing recommendations for patients with a CrCl ≤30 mL/min or on dialysis cannot be provided.

Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: For patients with CrCl >30 mL/min, the recommended dose of Dabigatran Etexilate is 150 mg taken orally, twice daily after previous treatment. Dosing recommendations for patients with a CrCl ≤30 mL/min or on dialysis cannot be provided.

Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism Following Hip Replacement Surgery: For patients with CrCl >30 mL/min, the recommended dose of Dabigatran Etexilate is 110 mg taken orally 1-4 hours after surgery and after hemostasis has been achieved, then 220 mg taken once daily for 28-35 days. If Dabigatran Etexilate is not started on the day of surgery, after hemostasis has been achieved initiate treatment with 220 mg once daily. Dosing recommendations for patients with a CrCl ≤30 mL/min or on dialysis cannot be provided

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Increased Risk of Thrombotic Events after Premature Discontinuation
• Risk of Bleeding
• Spinal/Epidural Anesthesia or Puncture
• Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves
• Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome

Dabigatran Etexilate is contraindicated in patients with:

• Active pathological bleeding.
• History of a serious hypersensitivity reaction to Dabigatran Etexilate (e.g., anaphylactic reaction or anaphylactic shock).
• Mechanical prosthetic heart valve.

Bleeding: Dabigatran Etexilate can cause serious and fatal bleeding

Bioprosthetic heart valves: Dabigatran Etexilate use not recommended

Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome: Dabigatran Etexilate use not recommended

Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation: The concomitant use of Dabigatran Etexilate with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided. P-gp inhibition and impaired renal function are the major independent factors that result in increased exposure to dabigatran. Concomitant use of P-gp inhibitors in patients with renal impairment is expected to produce increased exposure of dabigatran compared to that seen with either factor alone. In patients with moderate renal impairment (CrCl 30-50 mL/min), reduce the dose of Dabigatran Etexilate to 75 mg twice daily when administered concomitantly with the P-gp inhibitors dronedarone or systemic ketoconazole. The use of the P-gp inhibitors verapamil, amiodarone, quinidine, clarithromycin, and ticagrelor does not require a dose adjustment of Dabigatran Etexilate. These results should not be extrapolated to other P-gp inhibitors. The concomitant use of Dabigatran Etexilate and P-gp inhibitors in patients with severe renal impairment (CrCl 15-30 mL/min) should be avoided.

Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: Avoid use of Dabigatran Etexilate and P-gp inhibitors in patients with CrCl <50 mL/min.

Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism Following Hip Replacement Surgery: In patients with CrCl ≥50 mL/min who have concomitant administration of P-gp inhibitors such as dronedarone or systemic ketoconazole, it may be helpful to separate the timing of administration of dabigatran and the P-gp inhibitor by several hours. The concomitant use of Dabigatran Etexilate and P-gp inhibitors in patients with CrCl <50 mL/min should be avoided.

Pregnancy: The limited available data on Dabigatran Etexilate use in pregnant women are insufficient to determine drug-associated risks for adverse developmental outcomes. There are risks to the mother associated with untreated venous thromboembolism in pregnancy and a risk of hemorrhage in the mother and fetus associated with the use of anticoagulant

Lactation: There are no data on the presence of dabigatran in human milk, the effects on the breastfed child, or on milk production. Dabigatran and/or its metabolites were present in rat milk. Breastfeeding is not recommended during treatment with Dabigatran Etexilate.

Pediatric Use: The safety and effectiveness of Dabigatran Etexilate in pediatric patients have not been established.

Geriatric Use: Of the total number of patients in the RE-LY study, 82% were 65 and over, while 40% were 75 and over. The risk of stroke and bleeding increases with age, but the risk-benefit profile is favorable in all age groups.

Accidental overdose may lead to hemorrhagic complications. In the event of hemorrhagic complications, initiate appropriate clinical support, discontinue treatment with Dabigatran Etexilate, and investigate the source of bleeding. A specific reversal agent (idarucizumab) is available. Dabigatran is primarily eliminated by the kidneys with a low plasma protein binding of approximately 35%. Hemodialysis can remove dabigatran; however, data supporting this approach are limited. Using a high-flux dialyzer, blood flow rate of 200 mL/min, and dialysate flow rate of 700 mL/min, approximately 49% of total dabigatran can be cleared from plasma over 4 hours. At the same dialysate flow rate, approximately 57% can be cleared using a dialyzer blood flow rate of 300 mL/min, with no appreciable increase in clearance observed at higher blood flow rates. Upon cessation of hemodialysis, a redistribution effect of approximately 7% to 15% is seen. The effect of dialysis on dabigatran’s plasma concentration would be expected to vary based on patient specific characteristics. Measurement of aPTT or ECT may help guide therapy

Store Dabigatran Etexilate at room temperature 20°C to 25°C. After opening the bottle, use Dabigatran Etexilate within 4 months. Safely throw away any unused Dabigatran Etexilate after 4 months. Keep Dabigatran Etexilate in the original bottle or blister package to keep it dry (protect the capsules from moisture). Do not put Dabigatran Etexilate in pill boxes or pill organizers. Tightly close your bottle of Dabigatran Etexilate right away after you take your dose. Keep Dabigatran Etexilate and all medicines out of the reach of children.

Anti-coagulants, Anti-platelet drugs, Fibrinolytics (Thrombolytics)

Dabigatran and its acyl glucuronides are competitive, direct thrombin inhibitors. Because thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of a thrombus. Both free and clot-bound thrombin, and thrombin-induced platelet aggregation are inhibited by the active moieties.

At recommended therapeutic doses, dabigatran etexilate prolongs the coagulation markers such as aPTT, ECT, and TT. INR is relatively insensitive to the exposure to dabigatran and cannot be interpreted the same way as used for warfarin monitoring. The aPTT test provides an approximation of Dabigatran Etexilate’s anticoagulant effect. The average time course for effects on aPTT, following approved dosing regimens in patients with various degrees of renal impairment is shown in Figure 2. The curves represent mean levels without confidence intervals; variations should be expected when measuring aPTT. While advice cannot be provided on the level of recovery of aPTT needed in any particular clinical setting, the curves can be used to estimate the time to get to a particular level of recovery, even when the time since the last dose of Dabigatran Etexilate is not precisely known. In the RE-LY trial, the median (10 th to 90 th percentile) trough aPTT in patients receiving the 150 mg dose was 52 (40 to 76) seconds.

Reduction in Risk of Stroke and Systemic Embolism in Non-valvular AF-

• CrCl >30 mL/min: 150 mg twice daily
• CrCl 15 to 30 mL/min: 75 mg twice daily
• CrCl <15 mL/min or on dialysis: Dosing recommendations cannot be provided
• CrCl 30 to 50 mL/min with concomitant use of P-gp inhibitors: Reduce dose to 75 mg twice daily if given with P-gp inhibitors dronedarone or systemic ketoconazole.
• CrCl <30 mL/min with concomitant use of P-gp inhibitors: Avoid co-administration

Treatment of DVT and PE, Reduction in the Risk of Recurrence of DVT and PE-

• CrCl >30 mL/min: 150 mg twice daily
• CrCl ≤30 mL/min or on dialysis: Dosing recommendations cannot be provided
• CrCl <50 mL/min with concomitant use of P-gp inhibitors: Avoid co-administration

Prophylaxis of DVT and PE Following Hip Replacement Surgery-

• CrCl >30 mL/min: 110 mg for first day, then 220 mg once daily
• CrCl ≤30 mL/min or on dialysis: Dosing recommendations cannot be provided
• CrCl <50 mL/min with concomitant use of P-gp inhibitors: Avoid co-administration.

Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation: For patients with creatinine clearance (CrCl) >30 mL/min, the recommended dose of Dabigatran Etexilate is 150 mg taken orally, twice daily. For patients with severe renal impairment (CrCl 15-30 mL/min), the recommended dose of Dabigatran Etexilate is 75 mg twice daily. Dosing recommendations for patients with a CrCl <15 mL/min or on dialysis cannot be provided.

Treatment of Deep Venous Thrombosis and Pulmonary Embolism: For patients with CrCl >30 mL/min, the recommended dose of Dabigatran Etexilate is 150 mg taken orally, twice daily, after 5-10 days of parenteral anticoagulation. Dosing recommendations for patients with a CrCl ≤30 mL/min or on dialysis cannot be provided.

Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: For patients with CrCl >30 mL/min, the recommended dose of Dabigatran Etexilate is 150 mg taken orally, twice daily after previous treatment. Dosing recommendations for patients with a CrCl ≤30 mL/min or on dialysis cannot be provided.

Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism Following Hip Replacement Surgery: For patients with CrCl >30 mL/min, the recommended dose of Dabigatran Etexilate is 110 mg taken orally 1-4 hours after surgery and after hemostasis has been achieved, then 220 mg taken once daily for 28-35 days. If Dabigatran Etexilate is not started on the day of surgery, after hemostasis has been achieved initiate treatment with 220 mg once daily. Dosing recommendations for patients with a CrCl ≤30 mL/min or on dialysis cannot be provided

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Increased Risk of Thrombotic Events after Premature Discontinuation
• Risk of Bleeding
• Spinal/Epidural Anesthesia or Puncture
• Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves
• Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome

Dabigatran Etexilate is contraindicated in patients with:

• Active pathological bleeding.
• History of a serious hypersensitivity reaction to Dabigatran Etexilate (e.g., anaphylactic reaction or anaphylactic shock).
• Mechanical prosthetic heart valve.

Bleeding: Dabigatran Etexilate can cause serious and fatal bleeding

Bioprosthetic heart valves: Dabigatran Etexilate use not recommended

Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome: Dabigatran Etexilate use not recommended

Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation: The concomitant use of Dabigatran Etexilate with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided. P-gp inhibition and impaired renal function are the major independent factors that result in increased exposure to dabigatran. Concomitant use of P-gp inhibitors in patients with renal impairment is expected to produce increased exposure of dabigatran compared to that seen with either factor alone. In patients with moderate renal impairment (CrCl 30-50 mL/min), reduce the dose of Dabigatran Etexilate to 75 mg twice daily when administered concomitantly with the P-gp inhibitors dronedarone or systemic ketoconazole. The use of the P-gp inhibitors verapamil, amiodarone, quinidine, clarithromycin, and ticagrelor does not require a dose adjustment of Dabigatran Etexilate. These results should not be extrapolated to other P-gp inhibitors. The concomitant use of Dabigatran Etexilate and P-gp inhibitors in patients with severe renal impairment (CrCl 15-30 mL/min) should be avoided.

Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: Avoid use of Dabigatran Etexilate and P-gp inhibitors in patients with CrCl <50 mL/min.

Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism Following Hip Replacement Surgery: In patients with CrCl ≥50 mL/min who have concomitant administration of P-gp inhibitors such as dronedarone or systemic ketoconazole, it may be helpful to separate the timing of administration of dabigatran and the P-gp inhibitor by several hours. The concomitant use of Dabigatran Etexilate and P-gp inhibitors in patients with CrCl <50 mL/min should be avoided.

Pregnancy: The limited available data on Dabigatran Etexilate use in pregnant women are insufficient to determine drug-associated risks for adverse developmental outcomes. There are risks to the mother associated with untreated venous thromboembolism in pregnancy and a risk of hemorrhage in the mother and fetus associated with the use of anticoagulant

Lactation: There are no data on the presence of dabigatran in human milk, the effects on the breastfed child, or on milk production. Dabigatran and/or its metabolites were present in rat milk. Breastfeeding is not recommended during treatment with Dabigatran Etexilate.

Pediatric Use: The safety and effectiveness of Dabigatran Etexilate in pediatric patients have not been established.

Geriatric Use: Of the total number of patients in the RE-LY study, 82% were 65 and over, while 40% were 75 and over. The risk of stroke and bleeding increases with age, but the risk-benefit profile is favorable in all age groups.

Accidental overdose may lead to hemorrhagic complications. In the event of hemorrhagic complications, initiate appropriate clinical support, discontinue treatment with Dabigatran Etexilate, and investigate the source of bleeding. A specific reversal agent (idarucizumab) is available. Dabigatran is primarily eliminated by the kidneys with a low plasma protein binding of approximately 35%. Hemodialysis can remove dabigatran; however, data supporting this approach are limited. Using a high-flux dialyzer, blood flow rate of 200 mL/min, and dialysate flow rate of 700 mL/min, approximately 49% of total dabigatran can be cleared from plasma over 4 hours. At the same dialysate flow rate, approximately 57% can be cleared using a dialyzer blood flow rate of 300 mL/min, with no appreciable increase in clearance observed at higher blood flow rates. Upon cessation of hemodialysis, a redistribution effect of approximately 7% to 15% is seen. The effect of dialysis on dabigatran’s plasma concentration would be expected to vary based on patient specific characteristics. Measurement of aPTT or ECT may help guide therapy

Store Dabigatran Etexilate at room temperature 20°C to 25°C. After opening the bottle, use Dabigatran Etexilate within 4 months. Safely throw away any unused Dabigatran Etexilate after 4 months. Keep Dabigatran Etexilate in the original bottle or blister package to keep it dry (protect the capsules from moisture). Do not put Dabigatran Etexilate in pill boxes or pill organizers. Tightly close your bottle of Dabigatran Etexilate right away after you take your dose. Keep Dabigatran Etexilate and all medicines out of the reach of children.

Anti-coagulants, Anti-platelet drugs, Fibrinolytics (Thrombolytics)

Dabigatran and its acyl glucuronides are competitive, direct thrombin inhibitors. Because thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of a thrombus. Both free and clot-bound thrombin, and thrombin-induced platelet aggregation are inhibited by the active moieties.

At recommended therapeutic doses, dabigatran etexilate prolongs the coagulation markers such as aPTT, ECT, and TT. INR is relatively insensitive to the exposure to dabigatran and cannot be interpreted the same way as used for warfarin monitoring. The aPTT test provides an approximation of Dabigatran Etexilate’s anticoagulant effect. The average time course for effects on aPTT, following approved dosing regimens in patients with various degrees of renal impairment is shown in Figure 2. The curves represent mean levels without confidence intervals; variations should be expected when measuring aPTT. While advice cannot be provided on the level of recovery of aPTT needed in any particular clinical setting, the curves can be used to estimate the time to get to a particular level of recovery, even when the time since the last dose of Dabigatran Etexilate is not precisely known. In the RE-LY trial, the median (10 th to 90 th percentile) trough aPTT in patients receiving the 150 mg dose was 52 (40 to 76) seconds.

Reduction in Risk of Stroke and Systemic Embolism in Non-valvular AF-

• CrCl >30 mL/min: 150 mg twice daily
• CrCl 15 to 30 mL/min: 75 mg twice daily
• CrCl <15 mL/min or on dialysis: Dosing recommendations cannot be provided
• CrCl 30 to 50 mL/min with concomitant use of P-gp inhibitors: Reduce dose to 75 mg twice daily if given with P-gp inhibitors dronedarone or systemic ketoconazole.
• CrCl <30 mL/min with concomitant use of P-gp inhibitors: Avoid co-administration

Treatment of DVT and PE, Reduction in the Risk of Recurrence of DVT and PE-

• CrCl >30 mL/min: 150 mg twice daily
• CrCl ≤30 mL/min or on dialysis: Dosing recommendations cannot be provided
• CrCl <50 mL/min with concomitant use of P-gp inhibitors: Avoid co-administration

Prophylaxis of DVT and PE Following Hip Replacement Surgery-

• CrCl >30 mL/min: 110 mg for first day, then 220 mg once daily
• CrCl ≤30 mL/min or on dialysis: Dosing recommendations cannot be provided
• CrCl <50 mL/min with concomitant use of P-gp inhibitors: Avoid co-administration.

Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation: For patients with creatinine clearance (CrCl) >30 mL/min, the recommended dose of Dabigatran Etexilate is 150 mg taken orally, twice daily. For patients with severe renal impairment (CrCl 15-30 mL/min), the recommended dose of Dabigatran Etexilate is 75 mg twice daily. Dosing recommendations for patients with a CrCl <15 mL/min or on dialysis cannot be provided.

Treatment of Deep Venous Thrombosis and Pulmonary Embolism: For patients with CrCl >30 mL/min, the recommended dose of Dabigatran Etexilate is 150 mg taken orally, twice daily, after 5-10 days of parenteral anticoagulation. Dosing recommendations for patients with a CrCl ≤30 mL/min or on dialysis cannot be provided.

Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: For patients with CrCl >30 mL/min, the recommended dose of Dabigatran Etexilate is 150 mg taken orally, twice daily after previous treatment. Dosing recommendations for patients with a CrCl ≤30 mL/min or on dialysis cannot be provided.

Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism Following Hip Replacement Surgery: For patients with CrCl >30 mL/min, the recommended dose of Dabigatran Etexilate is 110 mg taken orally 1-4 hours after surgery and after hemostasis has been achieved, then 220 mg taken once daily for 28-35 days. If Dabigatran Etexilate is not started on the day of surgery, after hemostasis has been achieved initiate treatment with 220 mg once daily. Dosing recommendations for patients with a CrCl ≤30 mL/min or on dialysis cannot be provided

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Increased Risk of Thrombotic Events after Premature Discontinuation
• Risk of Bleeding
• Spinal/Epidural Anesthesia or Puncture
• Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves
• Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome

Dabigatran Etexilate is contraindicated in patients with:

• Active pathological bleeding.
• History of a serious hypersensitivity reaction to Dabigatran Etexilate (e.g., anaphylactic reaction or anaphylactic shock).
• Mechanical prosthetic heart valve.

Bleeding: Dabigatran Etexilate can cause serious and fatal bleeding

Bioprosthetic heart valves: Dabigatran Etexilate use not recommended

Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome: Dabigatran Etexilate use not recommended

Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation: The concomitant use of Dabigatran Etexilate with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided. P-gp inhibition and impaired renal function are the major independent factors that result in increased exposure to dabigatran. Concomitant use of P-gp inhibitors in patients with renal impairment is expected to produce increased exposure of dabigatran compared to that seen with either factor alone. In patients with moderate renal impairment (CrCl 30-50 mL/min), reduce the dose of Dabigatran Etexilate to 75 mg twice daily when administered concomitantly with the P-gp inhibitors dronedarone or systemic ketoconazole. The use of the P-gp inhibitors verapamil, amiodarone, quinidine, clarithromycin, and ticagrelor does not require a dose adjustment of Dabigatran Etexilate. These results should not be extrapolated to other P-gp inhibitors. The concomitant use of Dabigatran Etexilate and P-gp inhibitors in patients with severe renal impairment (CrCl 15-30 mL/min) should be avoided.

Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: Avoid use of Dabigatran Etexilate and P-gp inhibitors in patients with CrCl <50 mL/min.

Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism Following Hip Replacement Surgery: In patients with CrCl ≥50 mL/min who have concomitant administration of P-gp inhibitors such as dronedarone or systemic ketoconazole, it may be helpful to separate the timing of administration of dabigatran and the P-gp inhibitor by several hours. The concomitant use of Dabigatran Etexilate and P-gp inhibitors in patients with CrCl <50 mL/min should be avoided.

Pregnancy: The limited available data on Dabigatran Etexilate use in pregnant women are insufficient to determine drug-associated risks for adverse developmental outcomes. There are risks to the mother associated with untreated venous thromboembolism in pregnancy and a risk of hemorrhage in the mother and fetus associated with the use of anticoagulant

Lactation: There are no data on the presence of dabigatran in human milk, the effects on the breastfed child, or on milk production. Dabigatran and/or its metabolites were present in rat milk. Breastfeeding is not recommended during treatment with Dabigatran Etexilate.

Pediatric Use: The safety and effectiveness of Dabigatran Etexilate in pediatric patients have not been established.

Geriatric Use: Of the total number of patients in the RE-LY study, 82% were 65 and over, while 40% were 75 and over. The risk of stroke and bleeding increases with age, but the risk-benefit profile is favorable in all age groups.

Accidental overdose may lead to hemorrhagic complications. In the event of hemorrhagic complications, initiate appropriate clinical support, discontinue treatment with Dabigatran Etexilate, and investigate the source of bleeding. A specific reversal agent (idarucizumab) is available. Dabigatran is primarily eliminated by the kidneys with a low plasma protein binding of approximately 35%. Hemodialysis can remove dabigatran; however, data supporting this approach are limited. Using a high-flux dialyzer, blood flow rate of 200 mL/min, and dialysate flow rate of 700 mL/min, approximately 49% of total dabigatran can be cleared from plasma over 4 hours. At the same dialysate flow rate, approximately 57% can be cleared using a dialyzer blood flow rate of 300 mL/min, with no appreciable increase in clearance observed at higher blood flow rates. Upon cessation of hemodialysis, a redistribution effect of approximately 7% to 15% is seen. The effect of dialysis on dabigatran’s plasma concentration would be expected to vary based on patient specific characteristics. Measurement of aPTT or ECT may help guide therapy

Store Dabigatran Etexilate at room temperature 20°C to 25°C. After opening the bottle, use Dabigatran Etexilate within 4 months. Safely throw away any unused Dabigatran Etexilate after 4 months. Keep Dabigatran Etexilate in the original bottle or blister package to keep it dry (protect the capsules from moisture). Do not put Dabigatran Etexilate in pill boxes or pill organizers. Tightly close your bottle of Dabigatran Etexilate right away after you take your dose. Keep Dabigatran Etexilate and all medicines out of the reach of children.

Anti-coagulants, Anti-platelet drugs, Fibrinolytics (Thrombolytics)

Dabigatran and its acyl glucuronides are competitive, direct thrombin inhibitors. Because thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of a thrombus. Both free and clot-bound thrombin, and thrombin-induced platelet aggregation are inhibited by the active moieties.

At recommended therapeutic doses, dabigatran etexilate prolongs the coagulation markers such as aPTT, ECT, and TT. INR is relatively insensitive to the exposure to dabigatran and cannot be interpreted the same way as used for warfarin monitoring. The aPTT test provides an approximation of Dabigatran Etexilate’s anticoagulant effect. The average time course for effects on aPTT, following approved dosing regimens in patients with various degrees of renal impairment is shown in Figure 2. The curves represent mean levels without confidence intervals; variations should be expected when measuring aPTT. While advice cannot be provided on the level of recovery of aPTT needed in any particular clinical setting, the curves can be used to estimate the time to get to a particular level of recovery, even when the time since the last dose of Dabigatran Etexilate is not precisely known. In the RE-LY trial, the median (10 th to 90 th percentile) trough aPTT in patients receiving the 150 mg dose was 52 (40 to 76) seconds.

Reduction in Risk of Stroke and Systemic Embolism in Non-valvular AF-

• CrCl >30 mL/min: 150 mg twice daily
• CrCl 15 to 30 mL/min: 75 mg twice daily
• CrCl <15 mL/min or on dialysis: Dosing recommendations cannot be provided
• CrCl 30 to 50 mL/min with concomitant use of P-gp inhibitors: Reduce dose to 75 mg twice daily if given with P-gp inhibitors dronedarone or systemic ketoconazole.
• CrCl <30 mL/min with concomitant use of P-gp inhibitors: Avoid co-administration

Treatment of DVT and PE, Reduction in the Risk of Recurrence of DVT and PE-

• CrCl >30 mL/min: 150 mg twice daily
• CrCl ≤30 mL/min or on dialysis: Dosing recommendations cannot be provided
• CrCl <50 mL/min with concomitant use of P-gp inhibitors: Avoid co-administration

Prophylaxis of DVT and PE Following Hip Replacement Surgery-

• CrCl >30 mL/min: 110 mg for first day, then 220 mg once daily
• CrCl ≤30 mL/min or on dialysis: Dosing recommendations cannot be provided
• CrCl <50 mL/min with concomitant use of P-gp inhibitors: Avoid co-administration.

Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation: For patients with creatinine clearance (CrCl) >30 mL/min, the recommended dose of Dabigatran Etexilate is 150 mg taken orally, twice daily. For patients with severe renal impairment (CrCl 15-30 mL/min), the recommended dose of Dabigatran Etexilate is 75 mg twice daily. Dosing recommendations for patients with a CrCl <15 mL/min or on dialysis cannot be provided.

Treatment of Deep Venous Thrombosis and Pulmonary Embolism: For patients with CrCl >30 mL/min, the recommended dose of Dabigatran Etexilate is 150 mg taken orally, twice daily, after 5-10 days of parenteral anticoagulation. Dosing recommendations for patients with a CrCl ≤30 mL/min or on dialysis cannot be provided.

Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: For patients with CrCl >30 mL/min, the recommended dose of Dabigatran Etexilate is 150 mg taken orally, twice daily after previous treatment. Dosing recommendations for patients with a CrCl ≤30 mL/min or on dialysis cannot be provided.

Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism Following Hip Replacement Surgery: For patients with CrCl >30 mL/min, the recommended dose of Dabigatran Etexilate is 110 mg taken orally 1-4 hours after surgery and after hemostasis has been achieved, then 220 mg taken once daily for 28-35 days. If Dabigatran Etexilate is not started on the day of surgery, after hemostasis has been achieved initiate treatment with 220 mg once daily. Dosing recommendations for patients with a CrCl ≤30 mL/min or on dialysis cannot be provided

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Increased Risk of Thrombotic Events after Premature Discontinuation
• Risk of Bleeding
• Spinal/Epidural Anesthesia or Puncture
• Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves
• Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome

Dabigatran Etexilate is contraindicated in patients with:

• Active pathological bleeding.
• History of a serious hypersensitivity reaction to Dabigatran Etexilate (e.g., anaphylactic reaction or anaphylactic shock).
• Mechanical prosthetic heart valve.

Bleeding: Dabigatran Etexilate can cause serious and fatal bleeding

Bioprosthetic heart valves: Dabigatran Etexilate use not recommended

Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome: Dabigatran Etexilate use not recommended

Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation: The concomitant use of Dabigatran Etexilate with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided. P-gp inhibition and impaired renal function are the major independent factors that result in increased exposure to dabigatran. Concomitant use of P-gp inhibitors in patients with renal impairment is expected to produce increased exposure of dabigatran compared to that seen with either factor alone. In patients with moderate renal impairment (CrCl 30-50 mL/min), reduce the dose of Dabigatran Etexilate to 75 mg twice daily when administered concomitantly with the P-gp inhibitors dronedarone or systemic ketoconazole. The use of the P-gp inhibitors verapamil, amiodarone, quinidine, clarithromycin, and ticagrelor does not require a dose adjustment of Dabigatran Etexilate. These results should not be extrapolated to other P-gp inhibitors. The concomitant use of Dabigatran Etexilate and P-gp inhibitors in patients with severe renal impairment (CrCl 15-30 mL/min) should be avoided.

Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism: Avoid use of Dabigatran Etexilate and P-gp inhibitors in patients with CrCl <50 mL/min.

Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism Following Hip Replacement Surgery: In patients with CrCl ≥50 mL/min who have concomitant administration of P-gp inhibitors such as dronedarone or systemic ketoconazole, it may be helpful to separate the timing of administration of dabigatran and the P-gp inhibitor by several hours. The concomitant use of Dabigatran Etexilate and P-gp inhibitors in patients with CrCl <50 mL/min should be avoided.

Pregnancy: The limited available data on Dabigatran Etexilate use in pregnant women are insufficient to determine drug-associated risks for adverse developmental outcomes. There are risks to the mother associated with untreated venous thromboembolism in pregnancy and a risk of hemorrhage in the mother and fetus associated with the use of anticoagulant

Lactation: There are no data on the presence of dabigatran in human milk, the effects on the breastfed child, or on milk production. Dabigatran and/or its metabolites were present in rat milk. Breastfeeding is not recommended during treatment with Dabigatran Etexilate.

Pediatric Use: The safety and effectiveness of Dabigatran Etexilate in pediatric patients have not been established.

Geriatric Use: Of the total number of patients in the RE-LY study, 82% were 65 and over, while 40% were 75 and over. The risk of stroke and bleeding increases with age, but the risk-benefit profile is favorable in all age groups.

Accidental overdose may lead to hemorrhagic complications. In the event of hemorrhagic complications, initiate appropriate clinical support, discontinue treatment with Dabigatran Etexilate, and investigate the source of bleeding. A specific reversal agent (idarucizumab) is available. Dabigatran is primarily eliminated by the kidneys with a low plasma protein binding of approximately 35%. Hemodialysis can remove dabigatran; however, data supporting this approach are limited. Using a high-flux dialyzer, blood flow rate of 200 mL/min, and dialysate flow rate of 700 mL/min, approximately 49% of total dabigatran can be cleared from plasma over 4 hours. At the same dialysate flow rate, approximately 57% can be cleared using a dialyzer blood flow rate of 300 mL/min, with no appreciable increase in clearance observed at higher blood flow rates. Upon cessation of hemodialysis, a redistribution effect of approximately 7% to 15% is seen. The effect of dialysis on dabigatran’s plasma concentration would be expected to vary based on patient specific characteristics. Measurement of aPTT or ECT may help guide therapy

Store Dabigatran Etexilate at room temperature 20°C to 25°C. After opening the bottle, use Dabigatran Etexilate within 4 months. Safely throw away any unused Dabigatran Etexilate after 4 months. Keep Dabigatran Etexilate in the original bottle or blister package to keep it dry (protect the capsules from moisture). Do not put Dabigatran Etexilate in pill boxes or pill organizers. Tightly close your bottle of Dabigatran Etexilate right away after you take your dose. Keep Dabigatran Etexilate and all medicines out of the reach of children.

Herbal and Nutraceuticals

Adults: 1-2 teaspoonful(s) twice daily.

Children: 1/2 teaspoon twice daily or as prescribed by the physician.

No significant side effect has been observed in proper dosage.

There is no known contraindication.

Keep out of reach of the children.

Store at cool and dry place, protect from light.

Dacarbazine is indicated in the treatment of metastatic malignant melanoma. In addition, Dacarbazine is also indicated for Hodgkin’s disease as a second-line therapy when used in combination with other effective agents

Cytotoxic Chemotherapy

Dacarbazine is a non-cell cycle specific antineoplastic agent. The exact mechanism of action by which it exerts cytotoxic effects is still unclear. However, three possible mechanisms have been postulated, including inhibition of DNA synthesis by acting as a purine analog, action as an alkylating agent, and interaction with sulfydryl group in the inhibition of bacterial cell growth.

Malignant Melanoma: The recommended dosage is 2 to 4.5 mg/kg/day for 10 days. Treatment may be repeated at 4 week intervals. An alternate recommended dosage is 250 mg/m²/day IV for 5 days. Treatment may be repeated every 3 weeks.

Hodgkin’s Disease: The recommended dosage of Dacarbazine in the treatment of Hodgkin’s disease is 150 mg/m²/day for 5 days, in combination with other effective drugs. Treatment may be repeated every 4 weeks. An alternative recommended dosage is 375 mg/m² on day 1, in combination with other effective drugs, to be repeated every 15 days.

Symptoms of anorexia, nausea and vomiting are the most frequently noted of all toxic reactions. Over 90% of patients are affected with the initial few doses. The vomiting lasts 1 to 12 hours and is incompletely and unpredictably palliated with phenobarbital and/or prochlorperazine. Rarely, intractable nausea and vomiting have necessitated discontinuance of therapy with Dacarbazine for Injection. Rarely, Dacarbazine for Injection has caused diarrhea. Some helpful suggestions include restricting the patient’s oral intake of food for 4 to 6 hours prior to treatment. The rapid toleration of these symptoms suggests that a central nervous system mechanism may be involved, and usually these symptoms subside after the first 1 or 2 days.

Dacarbazine is contraindicated in patients who  have demonstrated a hypersensitivity to it in the past.

Hospitalization is not always necessary but adequate laboratory study capability must be available. Extravasation of the drug subcutaneously during intravenous administration may result in tissue damage and severe pain. Local pain, burning sensation and irritation at the site of injection may be relieved by locally applied hot packs. Carcinogenicity of dacarbazine was studied in rats and mice. Proliferative endocardial lesions, including fibrosarcomas and sarcomas were induced by dacarbazine in rats. In mice, administration of dacarbazine resulted in the induction of angiosarcomas of the spleen.

Increased metabolism when used with enzyme inducers (e.g. barbiturates, rifampicin, phenytoin). May potentiate the effect of mercaptopurine, azathioprine, allopurinol. May impair immune response to vaccines. May enhance the effects of methoxsalen due to photosensitisation.

Pregnancy Category C. Dacarbazine for Injection has been shown to be teratogenic in rats when given in doses 20 times the human daily dose on day 12 of gestation. Dacarbazine when administered in 10 times the human daily dose to male rats (twice weekly for 9 weeks) did not affect the male libido, although female rats mated to male rats had higher incidence of resorptions than controls. In rabbits, dacarbazine daily dose 7 times the human daily dose given on Days 6 to 15 of gestation resulted in fetal skeletal anomalies. There are no adequate and well controlled studies in pregnant women. Dacarbazine for Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for Dacarbazine for Injection in animal studies, 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.

Give supportive treatment and monitor blood cell counts.

Dacarbazine 200 mg/vial is reconstituted with 19.7 mL of Sterile Water for Injection. The resulting solution contains 10 mg/mL of dacarbazine having a pH of 3.0 to 4.0. The calculated dose of the resulting solution is drawn into a syringe and administered only intravenously. The reconstituted solution may be further diluted with 5% dextrose injection or sodium chloride injection and administered as an intravenous infusion. After reconstitution and prior to use, the solution in the vial may be stored at 4°C for up to 72 hours or at normal room conditions (temperature and light) for up to 8 hours. If the reconstituted solution is further diluted in 5% dextrose injection or sodium chloride injection, the resulting solution may be stored at 4°C for up to 24 hours or at normal room conditions for up to 8 hours. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. There is no general agreement that all the procedures recommended in the guidelines are necessary or appropriate.

Store in a refrigerator 2°C to 8°C

Daclatasvir is indicated in combination with Sofosbuvir for the treatment of chronic hepatitis C virus (HCV) infection in adults.

Hepatic viral infections (Hepatitis C)

Daclatasvir is a direct acting antiviral agent (DAA) against the Hepatitis C Virus (HCV). Daclatasvir is an inhibitor of NS5A, a nonstructural protein encoded by HCV. Daclatasvir binds to the N-terminus of NS5A and inhibits both viral RNA replication and virion assembly. Characterization of Daclatasvir-resistant viruses, biochemical studies, and computer modeling data indicate that Daclatasvir interacts with the N-terminus within Domain 1 of the protein, which may cause structural distortions that interfere with NS5A functions.

Recommended Dosage: The recommended dose of Daclatasvir is 60 mg once daily, to be taken orally with or without meals.

Daclatasvir must be administered in combination with other medicinal products. The Summary of Product Characteristics for the other medicinal products in the regimen should also be consulted before initiation of therapy with Daclatasvir. Recommended regimens and treatment duration are provided in table below:

For the regimen of Daclatasvir+Sofosbuvir, data for 12-week treatment duration are available only for treatment-naïve patients with genotype 1 infection. For Daclatasvir+Sofosbuvir with or without Ribavirin, data are available for patients with advanced liver disease (≥F3) without cirrhosis. The recommended use of Daclatasvir+Sofosbuvir in genotype 4 is based on extrapolation from genotype 1. For the regimen of Daclatasvir+Peginterferon alfa + Ribavirin, data are available for treatment-naïve patients.

• The dose of Ribavirin, when combined with Daclatasvir, is weight-based (1,000 or 1,200 mg in patients <75 kg or ≥75 kg, respectively).
• Dose modification, interruption and discontinuation: Dose modification of Daclatasvir to manage adverse reactions is not recommended. If treatment interruption of components in the regimen is necessary because of adverse reactions, Daclatasvir must not be given as monotherapy.
• There are no virologic treatment stopping rules that apply to the combination of Daclatasvir with Sofosbuvir.
• Treatment discontinuation in patients with inadequate on-treatment virologic response during treatment with Daclatasvir, Peginterferon alfa and Ribavirin.

Dose recommendation for concomitant medicines:

• Strong inhibitors of cytochrome P450 enzyme 3A4 (CYP3A4): The dose of Daclatasvir should be reduced to 30 mg once daily when coadministered with strong inhibitors of CYP3A4.
• Moderate inducers of CYP3A4: The dose of Daclatasvir should be increased to 90 mg once daily when coadministered with moderate inducers of CYP3A4.
• Missed doses: Patients should be instructed that, if they miss a dose of Daclatasvir, the dose should be taken as soon as possible if remembered within 20 hours of the scheduled dose time. However, if the missed dose is remembered more than 20 hours after the scheduled dose, the dose should be skipped and the next dose taken at the appropriate time.

The following serious adverse reactions are described below and elsewhere in the labeling: Serious Symptomatic Bradycardia When Coadministered with Sofosbuvir and Amiodarone. One can get any of the following symptoms: Fainting or near-fainting, dizziness or lightheadedness, not feeling well, weakness, tiredness, shortness of breath, chest pain, confusion, memory problems.

Daclatasvir is contraindicated in combination with drugs that strongly induce CYP3A and, thus, may lead to lower exposure and loss of efficacy of Daclatasvir. Contraindicated drugs include, but are not limited to, Anticonvulsants (phenytoin, carbamazepine), Antimycobacterial agents (rifampin), Herbal Products st.Jhon’s wort (Hypericum perforatum).

Risk of adverse reactions or loss of virologic response due to drug interactions. The concomitant use of Daclatasvir and other drugs may result in known or potentially significant drug interactions, some of which may lead to:

• loss of therapeutic effect of Daclatasvir and possible development of resistance
• dosage adjustments of concomitant medications or Daclatasvir
• possible clinically significant adverse reactions from greater exposures of concomitant drugs or Daclatasvir

Serious Symptomatic Bradycardia When Coadministered with Sofosbuvir and Amiodarone and patients counseling: Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when Amiodarone is coadministered with Sofosbuvir in combination with another HCV direct-acting antiviral, including Daclatasvir. Patients who are taking Sofosbuvir in combination with Daclatasvir who need to start Amiodarone therapy due to no other alternative treatment options should undergo cardiac monitoring.

Potential for Other Drugs to Affect Daclatasvir: Daclatasvir is a substrate of CYP3A. Therefore, moderate or strong inducers of CYP3A may decrease the plasma levels and therapeutic effect of Daclatasvir. Strong inhibitors of CYP3A (eg, clarithromycin, itraconazole, ketoconazole, ritonavir) may increase the plasma levels of Daclatasvir.

Potential for Daclatasvir to Affect Other Drugs: Daclatasvir is an inhibitor of P-glycoprotein transporter (P-gp), organic anion transporting polypeptide (OATP) 1B1 and 1B3, and breast cancer resistance protein (BCRP). Administration of Daclatasvir may increase systemic exposure to medicinal products that are substrates of P-gp, OATP 1B1 or 1B3, or BCRP, which could increase or prolong their therapeutic effect or adverse reaction.

No data with Daclatasvir in pregnant women are available to inform a drug-associated risk. No information regarding the presence of Daclatasvir in human milk, the effects on the breastfed infant, or the effects on milk production is available.

Elderly: No dose adjustment of Daclatasvir is required for patients aged ≥65 years.

Renal impairment: No dose adjustment of Daclatasvir is required for patients with any degree of renal impairment.

Hepatic impairment: No dose adjustment of Daclatasvir is required for patients with mild (Child-Pugh A, score 5-6), moderate (Child-Pugh B, score 7-9) or severe (Child-Pugh C, score ≥10) hepatic impairment.

Paediatric population: The safety and efficacy of Daclatasvir in children and adolescents aged below 18 years have not yet been established. No data are available.

There is no known antidote for overdose of Daclatasvir. Treatment of overdose with Daclatasvir should consist of general supportive measures, including monitoring of vital signs and observation of the patient’s clinical status. Because Daclatasvir is highly protein bound (>99%), dialysis is unlikely to significantly reduce plasma concentrations of the drug.

Store at room temperature below 30°C, protect from light. keep out of the reach of children.

Daclatasvir is indicated in combination with Sofosbuvir for the treatment of chronic hepatitis C virus (HCV) infection in adults.

Hepatic viral infections (Hepatitis C)

Daclatasvir is a direct acting antiviral agent (DAA) against the Hepatitis C Virus (HCV). Daclatasvir is an inhibitor of NS5A, a nonstructural protein encoded by HCV. Daclatasvir binds to the N-terminus of NS5A and inhibits both viral RNA replication and virion assembly. Characterization of Daclatasvir-resistant viruses, biochemical studies, and computer modeling data indicate that Daclatasvir interacts with the N-terminus within Domain 1 of the protein, which may cause structural distortions that interfere with NS5A functions.

Recommended Dosage: The recommended dose of Daclatasvir is 60 mg once daily, to be taken orally with or without meals.

Daclatasvir must be administered in combination with other medicinal products. The Summary of Product Characteristics for the other medicinal products in the regimen should also be consulted before initiation of therapy with Daclatasvir. Recommended regimens and treatment duration are provided in table below:

For the regimen of Daclatasvir+Sofosbuvir, data for 12-week treatment duration are available only for treatment-naïve patients with genotype 1 infection. For Daclatasvir+Sofosbuvir with or without Ribavirin, data are available for patients with advanced liver disease (≥F3) without cirrhosis. The recommended use of Daclatasvir+Sofosbuvir in genotype 4 is based on extrapolation from genotype 1. For the regimen of Daclatasvir+Peginterferon alfa + Ribavirin, data are available for treatment-naïve patients.

• The dose of Ribavirin, when combined with Daclatasvir, is weight-based (1,000 or 1,200 mg in patients <75 kg or ≥75 kg, respectively).
• Dose modification, interruption and discontinuation: Dose modification of Daclatasvir to manage adverse reactions is not recommended. If treatment interruption of components in the regimen is necessary because of adverse reactions, Daclatasvir must not be given as monotherapy.
• There are no virologic treatment stopping rules that apply to the combination of Daclatasvir with Sofosbuvir.
• Treatment discontinuation in patients with inadequate on-treatment virologic response during treatment with Daclatasvir, Peginterferon alfa and Ribavirin.

Dose recommendation for concomitant medicines:

• Strong inhibitors of cytochrome P450 enzyme 3A4 (CYP3A4): The dose of Daclatasvir should be reduced to 30 mg once daily when coadministered with strong inhibitors of CYP3A4.
• Moderate inducers of CYP3A4: The dose of Daclatasvir should be increased to 90 mg once daily when coadministered with moderate inducers of CYP3A4.
• Missed doses: Patients should be instructed that, if they miss a dose of Daclatasvir, the dose should be taken as soon as possible if remembered within 20 hours of the scheduled dose time. However, if the missed dose is remembered more than 20 hours after the scheduled dose, the dose should be skipped and the next dose taken at the appropriate time.

The following serious adverse reactions are described below and elsewhere in the labeling: Serious Symptomatic Bradycardia When Coadministered with Sofosbuvir and Amiodarone. One can get any of the following symptoms: Fainting or near-fainting, dizziness or lightheadedness, not feeling well, weakness, tiredness, shortness of breath, chest pain, confusion, memory problems.

Daclatasvir is contraindicated in combination with drugs that strongly induce CYP3A and, thus, may lead to lower exposure and loss of efficacy of Daclatasvir. Contraindicated drugs include, but are not limited to, Anticonvulsants (phenytoin, carbamazepine), Antimycobacterial agents (rifampin), Herbal Products st.Jhon’s wort (Hypericum perforatum).

Risk of adverse reactions or loss of virologic response due to drug interactions. The concomitant use of Daclatasvir and other drugs may result in known or potentially significant drug interactions, some of which may lead to:

• loss of therapeutic effect of Daclatasvir and possible development of resistance
• dosage adjustments of concomitant medications or Daclatasvir
• possible clinically significant adverse reactions from greater exposures of concomitant drugs or Daclatasvir

Serious Symptomatic Bradycardia When Coadministered with Sofosbuvir and Amiodarone and patients counseling: Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when Amiodarone is coadministered with Sofosbuvir in combination with another HCV direct-acting antiviral, including Daclatasvir. Patients who are taking Sofosbuvir in combination with Daclatasvir who need to start Amiodarone therapy due to no other alternative treatment options should undergo cardiac monitoring.

Potential for Other Drugs to Affect Daclatasvir: Daclatasvir is a substrate of CYP3A. Therefore, moderate or strong inducers of CYP3A may decrease the plasma levels and therapeutic effect of Daclatasvir. Strong inhibitors of CYP3A (eg, clarithromycin, itraconazole, ketoconazole, ritonavir) may increase the plasma levels of Daclatasvir.

Potential for Daclatasvir to Affect Other Drugs: Daclatasvir is an inhibitor of P-glycoprotein transporter (P-gp), organic anion transporting polypeptide (OATP) 1B1 and 1B3, and breast cancer resistance protein (BCRP). Administration of Daclatasvir may increase systemic exposure to medicinal products that are substrates of P-gp, OATP 1B1 or 1B3, or BCRP, which could increase or prolong their therapeutic effect or adverse reaction.

No data with Daclatasvir in pregnant women are available to inform a drug-associated risk. No information regarding the presence of Daclatasvir in human milk, the effects on the breastfed infant, or the effects on milk production is available.

Elderly: No dose adjustment of Daclatasvir is required for patients aged ≥65 years.

Renal impairment: No dose adjustment of Daclatasvir is required for patients with any degree of renal impairment.

Hepatic impairment: No dose adjustment of Daclatasvir is required for patients with mild (Child-Pugh A, score 5-6), moderate (Child-Pugh B, score 7-9) or severe (Child-Pugh C, score ≥10) hepatic impairment.

Paediatric population: The safety and efficacy of Daclatasvir in children and adolescents aged below 18 years have not yet been established. No data are available.

There is no known antidote for overdose of Daclatasvir. Treatment of overdose with Daclatasvir should consist of general supportive measures, including monitoring of vital signs and observation of the patient’s clinical status. Because Daclatasvir is highly protein bound (>99%), dialysis is unlikely to significantly reduce plasma concentrations of the drug.

Store at room temperature below 30°C, protect from light. keep out of the reach of children.

Daclatasvir is indicated in combination with Sofosbuvir for the treatment of chronic hepatitis C virus (HCV) infection in adults.

Hepatic viral infections (Hepatitis C)

Daclatasvir is a direct acting antiviral agent (DAA) against the Hepatitis C Virus (HCV). Daclatasvir is an inhibitor of NS5A, a nonstructural protein encoded by HCV. Daclatasvir binds to the N-terminus of NS5A and inhibits both viral RNA replication and virion assembly. Characterization of Daclatasvir-resistant viruses, biochemical studies, and computer modeling data indicate that Daclatasvir interacts with the N-terminus within Domain 1 of the protein, which may cause structural distortions that interfere with NS5A functions.

Recommended Dosage: The recommended dose of Daclatasvir is 60 mg once daily, to be taken orally with or without meals.

Daclatasvir must be administered in combination with other medicinal products. The Summary of Product Characteristics for the other medicinal products in the regimen should also be consulted before initiation of therapy with Daclatasvir. Recommended regimens and treatment duration are provided in table below:

For the regimen of Daclatasvir+Sofosbuvir, data for 12-week treatment duration are available only for treatment-naïve patients with genotype 1 infection. For Daclatasvir+Sofosbuvir with or without Ribavirin, data are available for patients with advanced liver disease (≥F3) without cirrhosis. The recommended use of Daclatasvir+Sofosbuvir in genotype 4 is based on extrapolation from genotype 1. For the regimen of Daclatasvir+Peginterferon alfa + Ribavirin, data are available for treatment-naïve patients.

• The dose of Ribavirin, when combined with Daclatasvir, is weight-based (1,000 or 1,200 mg in patients <75 kg or ≥75 kg, respectively).
• Dose modification, interruption and discontinuation: Dose modification of Daclatasvir to manage adverse reactions is not recommended. If treatment interruption of components in the regimen is necessary because of adverse reactions, Daclatasvir must not be given as monotherapy.
• There are no virologic treatment stopping rules that apply to the combination of Daclatasvir with Sofosbuvir.
• Treatment discontinuation in patients with inadequate on-treatment virologic response during treatment with Daclatasvir, Peginterferon alfa and Ribavirin.

Dose recommendation for concomitant medicines:

• Strong inhibitors of cytochrome P450 enzyme 3A4 (CYP3A4): The dose of Daclatasvir should be reduced to 30 mg once daily when coadministered with strong inhibitors of CYP3A4.
• Moderate inducers of CYP3A4: The dose of Daclatasvir should be increased to 90 mg once daily when coadministered with moderate inducers of CYP3A4.
• Missed doses: Patients should be instructed that, if they miss a dose of Daclatasvir, the dose should be taken as soon as possible if remembered within 20 hours of the scheduled dose time. However, if the missed dose is remembered more than 20 hours after the scheduled dose, the dose should be skipped and the next dose taken at the appropriate time.

The following serious adverse reactions are described below and elsewhere in the labeling: Serious Symptomatic Bradycardia When Coadministered with Sofosbuvir and Amiodarone. One can get any of the following symptoms: Fainting or near-fainting, dizziness or lightheadedness, not feeling well, weakness, tiredness, shortness of breath, chest pain, confusion, memory problems.

Daclatasvir is contraindicated in combination with drugs that strongly induce CYP3A and, thus, may lead to lower exposure and loss of efficacy of Daclatasvir. Contraindicated drugs include, but are not limited to, Anticonvulsants (phenytoin, carbamazepine), Antimycobacterial agents (rifampin), Herbal Products st.Jhon’s wort (Hypericum perforatum).

Risk of adverse reactions or loss of virologic response due to drug interactions. The concomitant use of Daclatasvir and other drugs may result in known or potentially significant drug interactions, some of which may lead to:

• loss of therapeutic effect of Daclatasvir and possible development of resistance
• dosage adjustments of concomitant medications or Daclatasvir
• possible clinically significant adverse reactions from greater exposures of concomitant drugs or Daclatasvir

Serious Symptomatic Bradycardia When Coadministered with Sofosbuvir and Amiodarone and patients counseling: Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when Amiodarone is coadministered with Sofosbuvir in combination with another HCV direct-acting antiviral, including Daclatasvir. Patients who are taking Sofosbuvir in combination with Daclatasvir who need to start Amiodarone therapy due to no other alternative treatment options should undergo cardiac monitoring.

Potential for Other Drugs to Affect Daclatasvir: Daclatasvir is a substrate of CYP3A. Therefore, moderate or strong inducers of CYP3A may decrease the plasma levels and therapeutic effect of Daclatasvir. Strong inhibitors of CYP3A (eg, clarithromycin, itraconazole, ketoconazole, ritonavir) may increase the plasma levels of Daclatasvir.

Potential for Daclatasvir to Affect Other Drugs: Daclatasvir is an inhibitor of P-glycoprotein transporter (P-gp), organic anion transporting polypeptide (OATP) 1B1 and 1B3, and breast cancer resistance protein (BCRP). Administration of Daclatasvir may increase systemic exposure to medicinal products that are substrates of P-gp, OATP 1B1 or 1B3, or BCRP, which could increase or prolong their therapeutic effect or adverse reaction.

No data with Daclatasvir in pregnant women are available to inform a drug-associated risk. No information regarding the presence of Daclatasvir in human milk, the effects on the breastfed infant, or the effects on milk production is available.

Elderly: No dose adjustment of Daclatasvir is required for patients aged ≥65 years.

Renal impairment: No dose adjustment of Daclatasvir is required for patients with any degree of renal impairment.

Hepatic impairment: No dose adjustment of Daclatasvir is required for patients with mild (Child-Pugh A, score 5-6), moderate (Child-Pugh B, score 7-9) or severe (Child-Pugh C, score ≥10) hepatic impairment.

Paediatric population: The safety and efficacy of Daclatasvir in children and adolescents aged below 18 years have not yet been established. No data are available.

There is no known antidote for overdose of Daclatasvir. Treatment of overdose with Daclatasvir should consist of general supportive measures, including monitoring of vital signs and observation of the patient’s clinical status. Because Daclatasvir is highly protein bound (>99%), dialysis is unlikely to significantly reduce plasma concentrations of the drug.

Store at room temperature below 30°C, protect from light. keep out of the reach of children.

Clindamycin lotion is indicated in the treatment of acne vulgaris. Other uses of topical Clindamycin lotion are:

• Skin infections such as erythrasma caused by Corynebacterium minutissimum; rosacea, periorificial dermatitis, folliculitis, stasis, chronic lymphaedema and familial pemphigus.
• Dermal ulcers.

Macrolides

Clindamycin is a lincosamide antibiotic used in the treatment of infections caused by susceptible microorganisms. Clindamycin is a semisynthetic antibiotic derived from lincomycin. It has antiacne and antibacterial activity. It binds with the 50s subunit of the bacterial ribosome and inhibits the early stage of protein synthesis. It is highly potent against gram positive and anaerobic bacteria.

Microbiology: Aerobic gram-positive cocci, including: Staphylococcus aureus, Staphylococcus epidermidis (penicillinase and non-penicillinase producing strains), Streptococci, Pneumococci. Anaerobic gram-negative bacilli, including: Bacteroides species, Fusobacterium species. Anaerobic gram-positive non-spore forming bacilli, including: Propionibacterium species, Eubacterium species, Actinomyces species. Anaerobic and microaerophilic gram-positive cocci, including: Peptococcus species, Peptostreptococcus species, Microaerophilic streptococci, C. perfringes

At first, wash the face or affected area gently with warm water or soap. When the skin is completely dried (about 30 minutes later) apply a thin film of Clindamycin lotion to the entire affected area twice daily. The Applied area should not be washed within 3 hours. Noticeable improvement is usually seen after about 6 weeks. However, 8 to 12 weeks of treatment may be required for maximum benefit. Eye, lip or nose contact should be avoided while applying Clindamycin lotion.

Side effects are usually rare. Possible side-effects may includes skin rash, itching, oily skin, dryness, erythema, burning, change in skin color, diarrhea, colitis, GI disturbance etc.

Clindamycin lotion is not for oral, ophthalmic, or Intravaginal use. Avoid exposure to sunlight and sunlamps. Wear sunscreen daily.

Clindamycin enhances the action of other neuromuscular blocking agents. Therefore, it should be used with caution in patients receiving such agents. Antagonism has been demonstrated between clindamycin and erythromycin in vitro. Because of possible clinical significance, these two drugs should not be administered concurrently.

There is no adequate data for safe use in pregnancy. Animal studies showed no adverse effects on the fetus. It is not known that whether Clindamycin is excreted through breast milk following topical administration. However, Clindamycin lotion can be used during lactation with caution.

Intravaginal overdose is not possible. Accidental ingestion of the product could be accompanied by effects related to therapeutic levels of oral clindamycin.

Store the tube below 25 °C, away from light & moisture. Keep out of the reach of children.

Macrolides

Dosage of Clindamycin Capsule:

• Serious Infections: 150 mg-300 mg every six hours.
• More severe infections: 300 mg-450 mg every six hours.

To avoid the possibility of oesophageal irritation, Clindacin capsules should be taken with a full glass of water.

Several researches has found that Clindamycin 300 mg capsule provides plasma concentration over MIC₉₀ for more than 12 hours. This finding supports the twice-daily dosing of Clindacin 300 mg capsule, particularly in SSTIs & RTIs. However, in case of bone & joint infections, diabetic foot infections dose of Clindamycin should be 300 mg capsule 3-4 times daily.

Dosage of Clindamycin Powder for oral solution:

• Serious infections: 8-12 mg/kg/day divided into 3 or 4 equal doses.
• Severe infections: 13-16 mg/kg/day divided into 3 or 4 equal doses.
• More severe infections: 17-25 mg/kg/day divided into 3 or 4 equal doses.

In pediatric patients weighing 10 kg or less, 1/2 teaspoon (37.5 mg) three times a day should be considered the minimum recommended dose.

Dosage of Clindamycin IV/IM Injection:
Adults-

• Serious infections due to aerobic gram-positive cocci and the more susceptible anaerobes: 600-1200 mg/day in 2- 4 equal doses.
• More severe infections: 1200-2700 mg/day in 2-4 equal doses.
• For more serious infections: these doses may have to be increased. In life-threatening situations due to either aerobes or anaerobes, these doses may be increased.
• Doses of as much as 4800 mg daily have been given intravenously to adults. Single intramuscular injections of greater than 600 mg are not recommended.

Neonates (less than 1 month): 15 to 20 mg/kg/day in 3 to 4 equal doses. The lower effective dosage may be adequate for small prematures.

Pediatric patients (1 month of age to 16 years):

• 20 to 40 mg/kg/day in 3 or 4 equal doses. The higher doses would be used for more severe infections.
• Parenteral therapy may be changed to Capsules (clindamycin hydrochloride) when the condition warrants and at the discretion of the physician.
• In cases of (3-hemolytic streptococcal infections, treatment should be continued for at least 10 days.

The adverse effects have been reported with the use of clindamycin are- abdominal pain, oesophagitis and oesophagial ulcer, nausea, vomiting and diarrhoea, pruritus, skin rashes, urticaria.

Clindamycin is contraindicated in patients previously found to be sensitive to clindamycin or any of the ingredients of this medicine.

Clindamycin should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.

Clindamycin enhances the action of other neuromuscular blocking agents. Therefore, it should be used with caution in patients receiving such agents. Antagonism has been demonstrated between clindamycin and erythromycin in vitro. Because of possible clinical significance, these two drugs should not be administered concurrently.

Pregnancy Category B. Clindamycin crosses the placenta in humans. After multiple doses, amniotic fluid concentrations were approximately 30% of maternal concentrations. Clindamycin should be used in pregnancy only if clearly needed. Clindamycin has been reported to appear in breast milk. Therefore, it is not recommended for nursing mothers if not clearly needed.

Use in newborns and infants: When Clindamycin is administered to newborns and infants (birth to 16 years), appropriate monitoring of organ system functions is desirable.

Geriatric use: Dose adjustment of Clindamycin is not necessary.

Overdosage with orally administered clindamycin has been rare. Adverse reactions similar to those seen with normal doses can be expected, however, unexpected reactions could occur. Haemodialysis and peritoneal dialysis are not effective in removing clindamycin from the serum. Overdosage should be treated with simple gastric lavage. No specific antidote is known.

Direction for reconstitution (powder for oral solution): Shake the bottle well to loosen the powder. Add 80 ml of boiled and cooled water to the dry mixture in the bottle. For ease of preparation, add water to the bottle in two proportions. Shake well after each addition until all the powder is in solution. Keep the bottle tightly closed. The reconstituted solution should be used within 2 weeks if kept at room temperature.

Dilution of Clindamycin injection for intravenous use: Clindamycin phosphate must be diluted prior to IV administration. The concentration of clindamycin in diluent for infusion should not exceed 18 mg per ml. Infusion rates should not exceed 30 mg per minute.

• Administration of more than 1200 mg in a single 1 hour infusion is not recommended.
• Single IM injections of greater than 600 mg are not recommended. Dilution is not required for intramuscular administration.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Dilution and Compatibility: Physical and biological compatibility studies monitored for 24 hours at room temperature have demonstrated no inactivation or incompatibility with the use of Clindamycin phosphate Sterile Solution (clindamycin phosphate) in IV solutions containing sodium chloride, glucose, calcium or potassium, and solutions containing vitamin B complex in concentrations usually used clinically. No incompatibility has been demonstrated with the antibiotics cephalothin, kanamycin, gentamicin, penicillin or carbenicillin.

Physico-Chemical Stability of diluted solutions of Clindacin Injection-

• Room temperature: 16 days at 25°C.
• Refrigeration: 32 days at 4°C.

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

Macrolides

Dosage of Clindamycin Capsule:

• Serious Infections: 150 mg-300 mg every six hours.
• More severe infections: 300 mg-450 mg every six hours.

To avoid the possibility of oesophageal irritation, Clindacin capsules should be taken with a full glass of water.

Several researches has found that Clindamycin 300 mg capsule provides plasma concentration over MIC₉₀ for more than 12 hours. This finding supports the twice-daily dosing of Clindacin 300 mg capsule, particularly in SSTIs & RTIs. However, in case of bone & joint infections, diabetic foot infections dose of Clindamycin should be 300 mg capsule 3-4 times daily.

Dosage of Clindamycin Powder for oral solution:

• Serious infections: 8-12 mg/kg/day divided into 3 or 4 equal doses.
• Severe infections: 13-16 mg/kg/day divided into 3 or 4 equal doses.
• More severe infections: 17-25 mg/kg/day divided into 3 or 4 equal doses.

In pediatric patients weighing 10 kg or less, 1/2 teaspoon (37.5 mg) three times a day should be considered the minimum recommended dose.

Dosage of Clindamycin IV/IM Injection:
Adults-

• Serious infections due to aerobic gram-positive cocci and the more susceptible anaerobes: 600-1200 mg/day in 2- 4 equal doses.
• More severe infections: 1200-2700 mg/day in 2-4 equal doses.
• For more serious infections: these doses may have to be increased. In life-threatening situations due to either aerobes or anaerobes, these doses may be increased.
• Doses of as much as 4800 mg daily have been given intravenously to adults. Single intramuscular injections of greater than 600 mg are not recommended.

Neonates (less than 1 month): 15 to 20 mg/kg/day in 3 to 4 equal doses. The lower effective dosage may be adequate for small prematures.

Pediatric patients (1 month of age to 16 years):

• 20 to 40 mg/kg/day in 3 or 4 equal doses. The higher doses would be used for more severe infections.
• Parenteral therapy may be changed to Capsules (clindamycin hydrochloride) when the condition warrants and at the discretion of the physician.
• In cases of (3-hemolytic streptococcal infections, treatment should be continued for at least 10 days.

The adverse effects have been reported with the use of clindamycin are- abdominal pain, oesophagitis and oesophagial ulcer, nausea, vomiting and diarrhoea, pruritus, skin rashes, urticaria.

Clindamycin is contraindicated in patients previously found to be sensitive to clindamycin or any of the ingredients of this medicine.

Clindamycin should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.

Clindamycin enhances the action of other neuromuscular blocking agents. Therefore, it should be used with caution in patients receiving such agents. Antagonism has been demonstrated between clindamycin and erythromycin in vitro. Because of possible clinical significance, these two drugs should not be administered concurrently.

Pregnancy Category B. Clindamycin crosses the placenta in humans. After multiple doses, amniotic fluid concentrations were approximately 30% of maternal concentrations. Clindamycin should be used in pregnancy only if clearly needed. Clindamycin has been reported to appear in breast milk. Therefore, it is not recommended for nursing mothers if not clearly needed.

Use in newborns and infants: When Clindamycin is administered to newborns and infants (birth to 16 years), appropriate monitoring of organ system functions is desirable.

Geriatric use: Dose adjustment of Clindamycin is not necessary.

Overdosage with orally administered clindamycin has been rare. Adverse reactions similar to those seen with normal doses can be expected, however, unexpected reactions could occur. Haemodialysis and peritoneal dialysis are not effective in removing clindamycin from the serum. Overdosage should be treated with simple gastric lavage. No specific antidote is known.

Direction for reconstitution (powder for oral solution): Shake the bottle well to loosen the powder. Add 80 ml of boiled and cooled water to the dry mixture in the bottle. For ease of preparation, add water to the bottle in two proportions. Shake well after each addition until all the powder is in solution. Keep the bottle tightly closed. The reconstituted solution should be used within 2 weeks if kept at room temperature.

Dilution of Clindamycin injection for intravenous use: Clindamycin phosphate must be diluted prior to IV administration. The concentration of clindamycin in diluent for infusion should not exceed 18 mg per ml. Infusion rates should not exceed 30 mg per minute.

• Administration of more than 1200 mg in a single 1 hour infusion is not recommended.
• Single IM injections of greater than 600 mg are not recommended. Dilution is not required for intramuscular administration.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Dilution and Compatibility: Physical and biological compatibility studies monitored for 24 hours at room temperature have demonstrated no inactivation or incompatibility with the use of Clindamycin phosphate Sterile Solution (clindamycin phosphate) in IV solutions containing sodium chloride, glucose, calcium or potassium, and solutions containing vitamin B complex in concentrations usually used clinically. No incompatibility has been demonstrated with the antibiotics cephalothin, kanamycin, gentamicin, penicillin or carbenicillin.

Physico-Chemical Stability of diluted solutions of Clindacin Injection-

• Room temperature: 16 days at 25°C.
• Refrigeration: 32 days at 4°C.

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

Dacomitinib is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA-approved test.

Cytotoxic Chemotherapy

Dacomitinib is an irreversible inhibitor of the kinase activity of the human EGFR family (EGFR/HER1, HER2, and HER4) and certain EGFR activating mutations (exon 19 deletion or the exon 21 L858R substitution mutation). In vitro dacomitinib also inhibited the activity of DDR1, EPHA6, LCK, DDR2, and MNK1 at clinically relevant concentrations. Dacomitinib demonstrated dose-dependent inhibition of EGFR and HER2 autophosphorylation and tumor growth in mice bearing subcutaneously implanted human tumor xenografts driven by HER family targets including mutated EGFR. Dacomitinib also exhibited antitumor activity in orally-dosed mice bearing intracranial human tumor xenografts driven by EGFR amplifications.

The recommended dosage of Dacomitinib is 45 mg taken orally once daily, until disease progression or unacceptable toxicity occurs. Dacomitinib can be taken with or without food. Take Dacomitinib the same time each day. If the patient vomits or misses a dose, do not take an additional dose or make up a missed dose but continue with the next scheduled dose. First dose reduction Dose Level-30 mg Dose (Once Daily) Second dose reduction Dose Level-15 mg Dose.

Most common adverse reactions (incidence >20%) are diarrhea, rash, paronychia, stomatitis, decreased appetite, dry skin, decreased weight, alopecia, cough, and pruritus.

Interstitial Lung Disease (ILD): Permanently discontinue Dacomitinib if ILD is confirmed
Diarrhea: Withhold and reduce the dose of DACOMITINIB based on the severity
Dermatologic Adverse Reactions: Withhold and reduce the dose of DACOMITINIB based on the severity
Embryo-Fetal Toxicity: Dacomitinib can cause fetal harm. Advise females of reproductive potential to use effective contraception.

Proton Pump Inhibitors (PPIs): Avoid use with DACOMITINIB; use locally-acting antacids or H2-receptor antagonist; administer DACOMITINIB at least 6 hours before or 10 hours after H2-receptor antagonist

CYP2D6 Substrates: Avoid concomitant use with DACOMITINIB where minimal increases in concentration of the CYP2D6 substrate may lead to serious or life-threatening toxicities

Dacomitinib can cause fetal harm when administered to a pregnant woman. There is no information regarding the presence of dacomitinib or its metabolites in human milk or their effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants from Dacomitinib, advise women not to breastfeed during treatment with Dacomitinib and for at least 17 days after the last dose.

Pediatric Use: The safety and effectiveness of Dacomitinib in pediatrics have not been established.

Renal Impairment: No dosage modification is recommended for patients with mild or moderate renal impairment (ClCr 30 to 89 mL/min estimated by Cockcroft-Gault). The recommended dose of Dacomitinib has not been established for patients with severe renal impairment (ClCr<30 mL/min)

Do not store above 30⁰C. Keep away from light and out of the reach of children.

Sulfonylureas

Glimepiride is a sulfonylurea antidiabetic agent which decreases blood glucose concentration. The primary mechanism of action of Glimepiride appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells. Glimepiride acts in concert with glucose by improving the sensitivity of beta cells to physiological glucose stimulus, resulting in insulin secretion. In addition, extrapancreatic effects like reduction of basal hepatic glucose production, increased peripheral tissue sensitivity to insulin and glucose uptake may also play role in the activity of Glimepiride. In non-fasting diabetic patients, the hypoglycaemic action of a single dose of Glimepiride persists for 24 hours.

In principle, the dosage of Glimepiride is governed by the desired blood sugar level. The dosage of Glimepiride must be the lowest which is sufficient to achieve the desired metabolic control. The initial and the maintenance doses are set based on the results of regular check of glucose in blood and urine. Monitoring of glucose levels in blood and urine also serves to detect either primary or secondary failure of therapy.

Initial dose and dose titration: the usual initial dose is 1 mg once daily, if necessary, the daily dose can be increased. Any increase can be based on regular blood sugar monitoring, and should be gradual, i.e., at intervals of 1 to 2 weeks, and carried out stepwise, as follows: 1 mg -> 2 mg -> 3 mg -> 4 mg -> 6 mg.

Dose in patients with well controlled diabetes: the usual dose range in patients with well controlled diabetes is 1 to 4 mg daily.

Distribution of doses: Timing and distribution of doses are decided by the physician, in consideration of the patient's current life-style. Normally, a single daily dose is sufficient. This should be taken immediately before a substantial breakfast or if none is taken immediately before the first main meal. It is very important not to skip meals after taking the drug.

Secondary dosage adjustment: As control of diabetes improves, sensitivity to insuiin increases; therefore, Glimepiride requirement may fall as treatment proceeds. To avoid hypoglycaemia, timely dose reduction or cessation of Glimepiride therapy must be considered. A dose adjustment must also be considered whenever the patient's weight or life-styie changes, or other factors arise which cause an increased susceptibility to hypo or hyperglycaemia.

Changeover from other oral antidiabetics to Glimepiride: There is no exact dosage relationship between Glimepiride and other oral blood sugar lowering agents. When substituting Glimepiride for other such agents, the initial daily dose is 1 mg; this applies even in changeover from maximum dose of other oral blood sugar lowering agents. Any dose increase should be in accordance with guideline given above in 'initial dose and dose titration'. Consideration must be given to the potency and duration of action of the previous blood sugar lowering agent. It may be necessary to interrupt treatment to avoid additive effects which would increase the risk of hypoglycaemia.

Glimepiride tablet must be swallowed with sufficient amount of liquid.

Hypoglycaemia, temporary visual impairment, nausea, vomiting, diarrhoea, abdominal pain, urticaria, fall in blood pressure.

Glimepiride is not suitable for the treatment of insulin dependent (type I) diabetes mellitus, or for the treatment of diabetic ketoacidosis, nor for the treatment of diabetic coma. Glimepiride must not be used in patients hypersensitive to Glimepiride, other sulfonylureas, other sulfonamides, severe hepatic dysfunction, severe impairment of renal function and dialysis patients.

in the initial weeks of treatment, the risk of hypoglycaemia may be increased and necessitates careful monitoring. If such risk present it may be necessary to adjust the dosage of Glimepiride, Hypoglycaemia can almost be promptly controlled by immediate intake of carbohydrates (glucose or sugar).

Based on experience with Glimepiride and known interactions for other sulfonylureas, the following interactions must be considered.

In addition to insulin and other oral antidiabetic agents, drugs which may potentiate the hypoglycaemic action of Glimepiride include: ACE inhibitors, aminosalicylic acid, anabolic steroids and male sex hormones, azapropazone, chloramphenicol, ciofibrate, coumarin derivatives, cyclophosphamide, disopyramide, fenfluramine, fenyramidol, fibrates, fluconazole, fluoxetine, guanethidine, ifosfamide, MAO-inhibitors, miconazole, oxpentifylline (high dose parenteral), oxyphenbutazone, para-aminosalicylic acid, phenylbutazone, probenecid, quinolones, salicylates, sulphinpyrazone, sulfonamide antibiotics, tetracyclines, tritoqualine, trofosfamide.

Drugs which may attenuate the hypoglycaemic action of Glimepiride include:

• Acetazoiamide, barbiturates, calcium channel blockers, corticosteroids, diazoxide, diuretics, glucagon, isoniazid, laxatives, nicotinic acid (high doses), oestrogens, phenothiazines, phenytoin, progestagens, rifampicin, sympathomimetic agents, thyroid hormones.
• H2 receptor antagonists, beta-blockers, clonidine and reserpine may lead to either potentiation or weakening of the blood-glucose-lowering effect.
• Concomitant treatment with a beta-receptor blocker, clonidine, guanethidine or reserpine may mask the warning symptoms of a hypoglycaemic attack.
• Acute and chronic aicohol intake may either potentiate or attenuate the activity of Glimepiride in an unpredictable fashion.

Glimepiride must not be taken during pregnancy; a changeover to insulin is necessary. Patients planning a pregnancy must inform their physician, and should change over to insulin. Ingestion of Glimepiride with breast milk feeding may harm the child. Therefore, Glimepiride must not be taken by breastfeeding women. Either a changeover or complete discontinuation of breastfeeding is necessary.

Overdosage of sulfonylureas, including Glimepiride, can produce hypoglycaemia. Mild hypoglycaemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in drug dosage or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycaemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medicai emergencies requiring immediate hospitalization. If hypoglycaemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of  concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dl. Patients should be closely monitored for a minimum of 24 to 48 hours, because hypoglycaemia may recur after apparent clinical recovery.

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

Sulfonylureas

Glimepiride is a sulfonylurea antidiabetic agent which decreases blood glucose concentration. The primary mechanism of action of Glimepiride appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells. Glimepiride acts in concert with glucose by improving the sensitivity of beta cells to physiological glucose stimulus, resulting in insulin secretion. In addition, extrapancreatic effects like reduction of basal hepatic glucose production, increased peripheral tissue sensitivity to insulin and glucose uptake may also play role in the activity of Glimepiride. In non-fasting diabetic patients, the hypoglycaemic action of a single dose of Glimepiride persists for 24 hours.

In principle, the dosage of Glimepiride is governed by the desired blood sugar level. The dosage of Glimepiride must be the lowest which is sufficient to achieve the desired metabolic control. The initial and the maintenance doses are set based on the results of regular check of glucose in blood and urine. Monitoring of glucose levels in blood and urine also serves to detect either primary or secondary failure of therapy.

Initial dose and dose titration: the usual initial dose is 1 mg once daily, if necessary, the daily dose can be increased. Any increase can be based on regular blood sugar monitoring, and should be gradual, i.e., at intervals of 1 to 2 weeks, and carried out stepwise, as follows: 1 mg -> 2 mg -> 3 mg -> 4 mg -> 6 mg.

Dose in patients with well controlled diabetes: the usual dose range in patients with well controlled diabetes is 1 to 4 mg daily.

Distribution of doses: Timing and distribution of doses are decided by the physician, in consideration of the patient's current life-style. Normally, a single daily dose is sufficient. This should be taken immediately before a substantial breakfast or if none is taken immediately before the first main meal. It is very important not to skip meals after taking the drug.

Secondary dosage adjustment: As control of diabetes improves, sensitivity to insuiin increases; therefore, Glimepiride requirement may fall as treatment proceeds. To avoid hypoglycaemia, timely dose reduction or cessation of Glimepiride therapy must be considered. A dose adjustment must also be considered whenever the patient's weight or life-styie changes, or other factors arise which cause an increased susceptibility to hypo or hyperglycaemia.

Changeover from other oral antidiabetics to Glimepiride: There is no exact dosage relationship between Glimepiride and other oral blood sugar lowering agents. When substituting Glimepiride for other such agents, the initial daily dose is 1 mg; this applies even in changeover from maximum dose of other oral blood sugar lowering agents. Any dose increase should be in accordance with guideline given above in 'initial dose and dose titration'. Consideration must be given to the potency and duration of action of the previous blood sugar lowering agent. It may be necessary to interrupt treatment to avoid additive effects which would increase the risk of hypoglycaemia.

Glimepiride tablet must be swallowed with sufficient amount of liquid.

Hypoglycaemia, temporary visual impairment, nausea, vomiting, diarrhoea, abdominal pain, urticaria, fall in blood pressure.

Glimepiride is not suitable for the treatment of insulin dependent (type I) diabetes mellitus, or for the treatment of diabetic ketoacidosis, nor for the treatment of diabetic coma. Glimepiride must not be used in patients hypersensitive to Glimepiride, other sulfonylureas, other sulfonamides, severe hepatic dysfunction, severe impairment of renal function and dialysis patients.

in the initial weeks of treatment, the risk of hypoglycaemia may be increased and necessitates careful monitoring. If such risk present it may be necessary to adjust the dosage of Glimepiride, Hypoglycaemia can almost be promptly controlled by immediate intake of carbohydrates (glucose or sugar).

Based on experience with Glimepiride and known interactions for other sulfonylureas, the following interactions must be considered.

In addition to insulin and other oral antidiabetic agents, drugs which may potentiate the hypoglycaemic action of Glimepiride include: ACE inhibitors, aminosalicylic acid, anabolic steroids and male sex hormones, azapropazone, chloramphenicol, ciofibrate, coumarin derivatives, cyclophosphamide, disopyramide, fenfluramine, fenyramidol, fibrates, fluconazole, fluoxetine, guanethidine, ifosfamide, MAO-inhibitors, miconazole, oxpentifylline (high dose parenteral), oxyphenbutazone, para-aminosalicylic acid, phenylbutazone, probenecid, quinolones, salicylates, sulphinpyrazone, sulfonamide antibiotics, tetracyclines, tritoqualine, trofosfamide.

Drugs which may attenuate the hypoglycaemic action of Glimepiride include:

• Acetazoiamide, barbiturates, calcium channel blockers, corticosteroids, diazoxide, diuretics, glucagon, isoniazid, laxatives, nicotinic acid (high doses), oestrogens, phenothiazines, phenytoin, progestagens, rifampicin, sympathomimetic agents, thyroid hormones.
• H2 receptor antagonists, beta-blockers, clonidine and reserpine may lead to either potentiation or weakening of the blood-glucose-lowering effect.
• Concomitant treatment with a beta-receptor blocker, clonidine, guanethidine or reserpine may mask the warning symptoms of a hypoglycaemic attack.
• Acute and chronic aicohol intake may either potentiate or attenuate the activity of Glimepiride in an unpredictable fashion.

Glimepiride must not be taken during pregnancy; a changeover to insulin is necessary. Patients planning a pregnancy must inform their physician, and should change over to insulin. Ingestion of Glimepiride with breast milk feeding may harm the child. Therefore, Glimepiride must not be taken by breastfeeding women. Either a changeover or complete discontinuation of breastfeeding is necessary.

Overdosage of sulfonylureas, including Glimepiride, can produce hypoglycaemia. Mild hypoglycaemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in drug dosage or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycaemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medicai emergencies requiring immediate hospitalization. If hypoglycaemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of  concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dl. Patients should be closely monitored for a minimum of 24 to 48 hours, because hypoglycaemia may recur after apparent clinical recovery.

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

Sulfonylureas

Glimepiride is a sulfonylurea antidiabetic agent which decreases blood glucose concentration. The primary mechanism of action of Glimepiride appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells. Glimepiride acts in concert with glucose by improving the sensitivity of beta cells to physiological glucose stimulus, resulting in insulin secretion. In addition, extrapancreatic effects like reduction of basal hepatic glucose production, increased peripheral tissue sensitivity to insulin and glucose uptake may also play role in the activity of Glimepiride. In non-fasting diabetic patients, the hypoglycaemic action of a single dose of Glimepiride persists for 24 hours.

In principle, the dosage of Glimepiride is governed by the desired blood sugar level. The dosage of Glimepiride must be the lowest which is sufficient to achieve the desired metabolic control. The initial and the maintenance doses are set based on the results of regular check of glucose in blood and urine. Monitoring of glucose levels in blood and urine also serves to detect either primary or secondary failure of therapy.

Initial dose and dose titration: the usual initial dose is 1 mg once daily, if necessary, the daily dose can be increased. Any increase can be based on regular blood sugar monitoring, and should be gradual, i.e., at intervals of 1 to 2 weeks, and carried out stepwise, as follows: 1 mg -> 2 mg -> 3 mg -> 4 mg -> 6 mg.

Dose in patients with well controlled diabetes: the usual dose range in patients with well controlled diabetes is 1 to 4 mg daily.

Distribution of doses: Timing and distribution of doses are decided by the physician, in consideration of the patient's current life-style. Normally, a single daily dose is sufficient. This should be taken immediately before a substantial breakfast or if none is taken immediately before the first main meal. It is very important not to skip meals after taking the drug.

Secondary dosage adjustment: As control of diabetes improves, sensitivity to insuiin increases; therefore, Glimepiride requirement may fall as treatment proceeds. To avoid hypoglycaemia, timely dose reduction or cessation of Glimepiride therapy must be considered. A dose adjustment must also be considered whenever the patient's weight or life-styie changes, or other factors arise which cause an increased susceptibility to hypo or hyperglycaemia.

Changeover from other oral antidiabetics to Glimepiride: There is no exact dosage relationship between Glimepiride and other oral blood sugar lowering agents. When substituting Glimepiride for other such agents, the initial daily dose is 1 mg; this applies even in changeover from maximum dose of other oral blood sugar lowering agents. Any dose increase should be in accordance with guideline given above in 'initial dose and dose titration'. Consideration must be given to the potency and duration of action of the previous blood sugar lowering agent. It may be necessary to interrupt treatment to avoid additive effects which would increase the risk of hypoglycaemia.

Glimepiride tablet must be swallowed with sufficient amount of liquid.

Hypoglycaemia, temporary visual impairment, nausea, vomiting, diarrhoea, abdominal pain, urticaria, fall in blood pressure.

Glimepiride is not suitable for the treatment of insulin dependent (type I) diabetes mellitus, or for the treatment of diabetic ketoacidosis, nor for the treatment of diabetic coma. Glimepiride must not be used in patients hypersensitive to Glimepiride, other sulfonylureas, other sulfonamides, severe hepatic dysfunction, severe impairment of renal function and dialysis patients.

in the initial weeks of treatment, the risk of hypoglycaemia may be increased and necessitates careful monitoring. If such risk present it may be necessary to adjust the dosage of Glimepiride, Hypoglycaemia can almost be promptly controlled by immediate intake of carbohydrates (glucose or sugar).

Based on experience with Glimepiride and known interactions for other sulfonylureas, the following interactions must be considered.

In addition to insulin and other oral antidiabetic agents, drugs which may potentiate the hypoglycaemic action of Glimepiride include: ACE inhibitors, aminosalicylic acid, anabolic steroids and male sex hormones, azapropazone, chloramphenicol, ciofibrate, coumarin derivatives, cyclophosphamide, disopyramide, fenfluramine, fenyramidol, fibrates, fluconazole, fluoxetine, guanethidine, ifosfamide, MAO-inhibitors, miconazole, oxpentifylline (high dose parenteral), oxyphenbutazone, para-aminosalicylic acid, phenylbutazone, probenecid, quinolones, salicylates, sulphinpyrazone, sulfonamide antibiotics, tetracyclines, tritoqualine, trofosfamide.

Drugs which may attenuate the hypoglycaemic action of Glimepiride include:

• Acetazoiamide, barbiturates, calcium channel blockers, corticosteroids, diazoxide, diuretics, glucagon, isoniazid, laxatives, nicotinic acid (high doses), oestrogens, phenothiazines, phenytoin, progestagens, rifampicin, sympathomimetic agents, thyroid hormones.
• H2 receptor antagonists, beta-blockers, clonidine and reserpine may lead to either potentiation or weakening of the blood-glucose-lowering effect.
• Concomitant treatment with a beta-receptor blocker, clonidine, guanethidine or reserpine may mask the warning symptoms of a hypoglycaemic attack.
• Acute and chronic aicohol intake may either potentiate or attenuate the activity of Glimepiride in an unpredictable fashion.

Glimepiride must not be taken during pregnancy; a changeover to insulin is necessary. Patients planning a pregnancy must inform their physician, and should change over to insulin. Ingestion of Glimepiride with breast milk feeding may harm the child. Therefore, Glimepiride must not be taken by breastfeeding women. Either a changeover or complete discontinuation of breastfeeding is necessary.

Overdosage of sulfonylureas, including Glimepiride, can produce hypoglycaemia. Mild hypoglycaemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in drug dosage or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycaemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medicai emergencies requiring immediate hospitalization. If hypoglycaemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of  concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dl. Patients should be closely monitored for a minimum of 24 to 48 hours, because hypoglycaemia may recur after apparent clinical recovery.

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

It is indicated in the treatment of-

• Acute hemorrhoidal attacks.
• Chronic hemorrhoidal disease.
• Organic and functional chronic venous insufficiency of the lower limbs with the following symptoms: heavy legs, pain, nocturnal cramps.

Phlebotonic & Vascular protecting preparation

Diosmin and Hesperidin is a phlebotonic drug and a vascular protecting agent. It reinforces venous tone by prolonging the activity of parietal noradrenaline. Thus Diosmin and Hesperidin decreases venous capacitance, venous distensibility, and venous emptying time.

Diosmin and Hesperidin protects the microcirculation by fighting the microcirculation damaging process; It combats venous inflammation by decreasing leukocyte activation, and as a consequence, by inhibiting the release of inflammatory mediators, principally free radicals and prostaglandin. Thus Diosmin and Hesperidin normalizes capillary permeability and strengthens capillary resistance.

Diosmin and Hesperidin acts on the lymphatic system, It improves lymphatic drainage by increasing lymph flow and lymph oncotic pressure.

Diosmin 450 mg & Hesperidin 50 mg-

• Acute hemorrhoidal attacks: 3 tablets twice daily for the first 4 days, then 2 tablets twice daily for three days and if required 1 tablet twice daily as a maintenance dosage.
• Chronic hemorrhoids: 1 tablet twice daily.
• Chronic venous insufficiency: 1 tablet twice daily initially for seven days. Duration may be increased depending on severity.

Diosmin 900 mg & Hesperidin 100 mg-

• Acute Hemorrhoid: 1 tablet thrice daily for first 4 days, followed by 1 tablet twice daily for 3 days & then 1 tablet once daily as maintenance dose.
• Relapse of Internal Hemorrhoid & Chronic Hemorrhoid: 1 tablet once daily for 3 months.
• Chronic venous insufficiency: 1 tablet once daily for 2-6 months.
• Leg Wounds: 1 tablet once daily for 2 months.

Tablet should be taken at meal times.

Some cases of routine gastric disorders and neurovegetative disorders (feeling of discomfort) have been reported. In this cases discontinuation of treatment is not required.

Chronic venous insufficiency and its complications should be diagnosed and management monitored by a physician. It is contraindicated for anyone having a hypersensitivity to any ingredient in the product.

If the hemorrhoidal symptoms do not disappear within 15 days, patient should ask doctor for advice. Diosmin (up to 900 mg/day) has been administered to a small number of breast cancer patients who were experiencing lymphedema following surgical and nodal irradiation treatment with resultant reduction of arm edema but no effect on the cancer. Animal studies and more than 20 years of clinical use in Europe have not found any evidence of carcinogenicity or mutagenicity when the components of Diosmin & Hesperidin are used as recommended. As a precaution, Diosmin & Hesperidin is not recommended for patients with a history of cancer since no specific studies have been performed in this population.

No evidence of drug incompatibility (drug interaction) has been reported in clinical trials.

Experimental studies have not shown any teratogenic effect in animals. In human beings, no harmful effect has so far been reported. In the absence of data concerning excretion into breast milk, breast feeding is not recommended during treatment.

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