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Antiparkinson drugs

Cabergoline is a long-acting dopamine receptor agonist with a high affinity for D2 receptors. It works by reducing the amount of prolactin that is released from pituitary gland. Results of in vitro studies demonstrate that Cabergoline exerts a direct inhibitory effect on the secretion of prolactin.

The recommended dosage of Cabergoline Tablet for initiation of therapy is 0.25 mg twice a week. Dosage may be increased by 0.25 mg twice weekly up to a dosage of 1 mg twice a week according to the patient’s serum prolactin level. Before initiating treatment, cardiovascular evaluation should be performed and echocardiography should be considered to assess for valvular disease.

Dosage increases should not occur more rapidly than every 4 weeks. If the patient does not respond adequately, and no additional benefit is observed with higher doses, the lowest dose that achieved maximal response should be used and other therapeutic approaches considered. Patients receiving long term treatment with Cabergoline should undergo periodic assessment of their cardiac status and echocardiography should be considered.

After a normal serum prolactin level has been maintained for 6 months, Cabergoline may be discontinued, with periodic monitoring of the serum prolactin level to determine whether or when treatment with Cabergoline should be reinstituted.

To prevent milk production (lactation): 1 mg (two 0.5 mg tablets) on the first day after delivery.

To stop lactation once after start of breastfeeding: 0.25 mg (one half of Cabergoline 0.5 mg table) every 12 hours for two days. To reduce prolactin levels in other conditions: Initially, 0.25 mg twice a week. Dose may be increased up to maximum dose of 4.5 mg or until have responded fully to treatment.

Pathological gambling, increased libido, and hypersexuality have been reported in patients treated with dopamine agonists including cabergoline. This has been generally reversible upon reduction of the dose or treatment discontinuation.

Cabergoline tablet is contraindicated in patients with:

• Uncontrolled hypertension or known hypersensitivity
• History of cardiac valvular disorders demonstration of valve leaflet thickening
• High blood pressure in pregnancy associated with swelling and protein in urine
• History of pulmonary, pericardial, or retroperitoneal fibrotic disorders & serious mental disease.

Initial doses higher than 1.0 mg may produce orthostatic hypotension. Care should be exercised when administering Cabergoline with other medications known to lower blood pressure, hypersensitivity, severe liver disease & mental illness.

Cabergoline should not be administered concurrently with D2-antagonists, such as Phenothiazines, Butyrophenones, Thioxanthenes, or Metoclopramide, Chlorpromazine, Domperidone, and medicines to lower blood pressure.

Pregnancy category B. It is not known whether this drug is excreted in human milk.

Pediatric Use: Safety and effectiveness of Cabergoline in pediatric patients have not been established.

Geriatric Use: In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Use in patients with hepatic impairment: Since cabergoline is extensively metabolized by the liver, caution should be used, and careful monitoring exercised, when administering Cabergoline to patients with hepatic impairment.

Over dosage might be expected to produce nasal congestion, syncope, or hallucinations. Measures to support blood pressure should be taken if necessary.

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

Minerals in bone formation, Specific mineral preparations

Calcium carbonate reacts with gastric acid to produce a salt and water. For calcium carbonate the postulated chemical reaction is: CaCO₃+2HCl = CaCl₂+H₂O+CO₂. Two grams of calcium carbonate will readily bring 100 ml of hydrochloric acid to a pH above 6. The increase in gastric pH diminishes the activity of pepsin in the gastric secretion. Up to 30% of the oral calcium load may be absorbed.

250 mg or 500 mg tablet: Calcium Carbonate is always used orally and when used as an antacid the recommended doses for adults are equivalent to 540-2000 mg Calcium Carbonate per day, doses for children being half of those for adults. As a dietary supplement, such as for the prevention of osteoporosis, 1250-3750 mg Calcium Carbonate (500-1500 mg calcium) daily is recommended in general, but again this will need to be tailored to the individual patient depending on any specific disease such as Calcium deficiency, malabsorption or parathyroid function. In pregnancy and lactation the recommended daily dose of calcium is 1200-1500 mg. In chronic renal failure the doses used vary from 2.5-9.0 gm Calcium Carbonate per day and need to be adjusted according to the individual patient. To maximize effective phosphate binding in this context the Calcium Carbonate should be given with meals.

1000 mg tablet: 2000-3000 mg tablet when symptoms occur; may be repeated hourly if needed or as directed by the physician.

Orally administered Calcium Carbonate may be irritating to the GI tract. It may also cause constipation. Hypercalcaemia is rarely produced by administration of calcium alone, but may occur when large doses are given to patients with chronic renal failure.

• Hypercalcaemia and hyperparathyroidism
• Hypercalciuria and nephrolithiasis
• Zollinger-Ellison syndrome
• Concomitant digoxin therapy (requires careful monitoring of serum calcium level)

When hypercalcaemia occurs, discontinuation of the drug is usually sufficient to return serum calcium concentrations to normal. Calcium salts should be used cautiously in patients with sarcoidosis, renal or cardiac disease, and in patients receiving cardiac glycosides.

Calcium Carbonate may enhance the cardiac effects of digoxin and other cardiac glycosides, if systemic hypercalcaemia occurs. Calcium Carbonate may interfere with the absorption of concomitantly administered tetracycline preparations and in chronic renal failure modification of vitamin D therapy may be required to avoid hypercalcaemia when Calcium Carbonate is used as the primary phosphate binder.

Calcium containing drugs have been widely used in pregnancy by way of oral calcium supplementation or antacid therapy. Calcium Carbonate can be used in lactating women too.

Use in children: Calcium carbonate has been extensively studied in children and infants with chronic renal failure and is both safe and effective.

Use in elderly: In case of elderly patients with renal failure when calcium carbonate is taken constipation may be troublesome one for this group. For this reason, monitoring of serum calcium and phosphate is of course indicated for elderly patients.

Store in a cool, dry place in controlled room temperature.

Renal Cell Carcinoma: Cabozantinib is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

Hepatocellular Carcinoma: Cabozantinib is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with Sorafenib.

Tyrosine Kinase Inhibitor

In vitro biochemical and/or cellular assays have shown that Cabozantinib inhibits the tyrosine kinase activity of MET, VEGFR-1, -2 and -3, AXL, RET, ROS1, TYRO3, MER, KIT, TRKB, FLT-3, and TIE-2. These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, drug resistance, and maintenance of the tumor microenvironment.

Absorption: Median time to peak cabozantinib concentrations (T_max) ranged from 3 to 4 hours post-dose. A 19% increase in the Cmax of Cabozantinib compared to a Cabozantinib capsule formulation was observed following a single 140 mg dose. A less than 10% difference in the AUC was observed between Cabozantinib and a Cabozantinib capsule formulation.

Distribution: The oral volume of distribution (Vz/F) of Cabozantinib is approximately 319 L. Cabozantinib is highly protein-bound in human plasma (≥99.7%).

Elimination: The predicted terminal half-life is approximately 99 hours and the clearance (CL/F) at steady state is estimated to be 2.2 L/hr.

Metabolism: Cabozantinib is a substrate of CYP3A4 in vitro.

Excretion: Approximately 81% of the total administered radioactivity was recovered within a 48-day collection period following a single dose of radiolabeled 14 C- Cabozantinib in healthy subjects. Approximately 54% was recovered in feces and 27% in urine. Unchanged Cabozantinib accounted for 43% of the total radioactivity in feces and was not detectable in urine following a 72-hour collection.

Recommended Dosage for Renal Cell Carcinoma: The recommended dosage of Cabozantinib is 60 mg once daily without food until the patient no longer experiences clinical benefit or experiences unacceptable toxicity.

Recommended Dosage for Hepatocellular Carcinoma: The recommended dosage of Cabozantinib is 60 mg once daily without food until disease progression or unacceptable toxicity. Or, as directed by the registered physicians.

• Stop treatment with Cabozantinib at least 28 days prior to scheduled surgery, including dental surgery.
• Do not substitute Cabozantinib tablets with Cabozantinib capsules.
• Do not administer Cabozantinib with food. Administer at least 1 hour before or at least 2 hours after eating.
• Swallow Cabozantinib tablets whole. Do not crush Cabozantinib tablets.
• Do not take a missed dose within 12 hours of the next dose.
• Modify the dose for certain patients with hepatic impairment and for patients taking drugs known to strongly induce or inhibit CYP450.

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

It is contraindicated in patients with known hypersensitivity to Cabozantinib or any other components of this product.

Hemorrhage: Severe and fatal hemorrhages occurred with Cabozantinib. Discontinue Cabozantinib for Grade 3 or 4 hemorrhage. Do not administer Cabozantinib to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

Perforations and Fistulas: Fistulas, including fatal cases, occurred in 1% of Cabozantinib-treated patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of Cabozantinib-treated patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue Cabozantinib in patients who experience a fistula that cannot be appropriately managed or a GI perforation.

Thrombotic Events: Cabozantinib increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism occurred in 2% of Cabozantinib
-treated patients. Fatal thrombotic events occurred in Cabozantinib-treated patients. Discontinue Cabozantinib in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention.

Hypertension and Hypertensive Crisis: Cabozantinib can cause hypertension, including hypertensive crisis. Do not initiate Cabozantinib in patients with uncontrolled hypertension. Monitor blood pressure regularly during Cabozantinib treatment. Withhold Cabozantinib for hypertension that is not adequately controlled with medical management; when controlled, resume Cabozantinib at a reduced dose. Discontinue Cabozantinib for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.

Diarrhea: Diarrhea occurred in 63% of patients treated with Cabozantinib. Withhold Cabozantinib until improvement to Grade 1 and resume Cabozantinib at a reduced dose for intolerable Grade 2 diarrhea, Grade 3 diarrhea that cannot be managed with standard antidiarrheal treatments, or Grade 4 diarrhea.

Palmar-Plantar Erythrodysesthesia: Palmar-plantar erythrodysesthesia (PPE) occurred in 44% of patients treated with Cabozantinib. Withhold Cabozantinib until improvement to Grade 1 and resume Cabozantinib at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.

Proteinuria: Proteinuria was observed in 7% of patients receiving Cabozantinib. Monitor urine protein regularly during Cabozantinib treatment. Discontinue Cabozantinib in patients who develop nephrotic syndrome.

Osteonecrosis of the Jaw: Osteonecrosis of the jaw (ONJ) occurred in <1% of patients treated with Cabozantinib. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of Cabozantinib and periodically during Cabozantinib. Advise patients regarding good oral hygiene practices. Withhold Cabozantinib for at least 28 days prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold Cabozantinib for development of ONJ until complete resolution.

Wound Complications: Wound complications have been reported with Cabozantinib. Stop Cabozantinib at least 28 days prior to scheduled surgery. Resume Cabozantinib after surgery based on clinical judgment of adequate wound healing. Withhold Cabozantinib in patients with dehiscence or wound healing complications requiring medical intervention.

Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, can occur with Cabozantinib. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue Cabozantinib in patients who develop RPLS.

Embryo-Fetal Toxicity: Based on data from animal studies and its mechanism of action, Cabozantinib can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Cabozantinib and for 4 months after the last dose.

Strong CYP3A4 Inhibitors: Coadministration of a Cabozantinib capsule formulation with a strong CYP3A4 inhibitor increased the exposure of Cabozantinib, which may increase the risk of exposure-related adverse reactions. Avoid coadministration of Cabozantinib with strong CYP3A4 inhibitors. Reduce the dosage of Cabozantinib if coadministration with strong CYP3A4 inhibitors cannot be avoided. Avoid grapefruit or grapefruit juice which may also increase exposure of Cabozantinib.

Strong CYP3A Inducers: Coadministration of a Cabozantinib capsule formulation with a strong CYP3A4 inducer decreased the exposure of Cabozantinib, which may reduce efficacy. Avoid coadministration of Cabozantinib with strong CYP3A4 inducers. Increase the dosage of Cabozantinib if coadministration with strong CYP3A4 inducers cannot be avoided. Avoid St. John's Wort which may also decrease exposure of Cabozantinib.

Pregnancy: Cabozantinib can cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk.

Lactation: There is no information regarding the presence of Cabozantinib or its metabolites in human milk, or their effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in breastfed children, women should be advised not to breastfeed during treatment with Cabozantinib and for 4 months after the final dose.

Contraception: Cabozantinib can cause fetal harm when administered to a pregnant woman.

Females: Females of reproductive potential should be advised to use effective contraception during treatment with Cabozantinib and for 4 months after the final dose.

Infertility: Females and Males: Based on findings in animals, Cabozantinib may impair fertility in females and males of reproductive potential.

One case of overdosage was reported following administration of another formulation of cabozantinib; a patient inadvertently took twice the intended dose for 9 days. The patient suffered Grade 3 memory impairment, Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in BUN. The extent of recovery was not documented.

Store below 30°C in a cool and dry place, away from sunlight. Keep out of reach of children.

Renal Cell Carcinoma: Cabozantinib is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

Hepatocellular Carcinoma: Cabozantinib is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with Sorafenib.

Tyrosine Kinase Inhibitor

In vitro biochemical and/or cellular assays have shown that Cabozantinib inhibits the tyrosine kinase activity of MET, VEGFR-1, -2 and -3, AXL, RET, ROS1, TYRO3, MER, KIT, TRKB, FLT-3, and TIE-2. These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, drug resistance, and maintenance of the tumor microenvironment.

Absorption: Median time to peak cabozantinib concentrations (T_max) ranged from 3 to 4 hours post-dose. A 19% increase in the Cmax of Cabozantinib compared to a Cabozantinib capsule formulation was observed following a single 140 mg dose. A less than 10% difference in the AUC was observed between Cabozantinib and a Cabozantinib capsule formulation.

Distribution: The oral volume of distribution (Vz/F) of Cabozantinib is approximately 319 L. Cabozantinib is highly protein-bound in human plasma (≥99.7%).

Elimination: The predicted terminal half-life is approximately 99 hours and the clearance (CL/F) at steady state is estimated to be 2.2 L/hr.

Metabolism: Cabozantinib is a substrate of CYP3A4 in vitro.

Excretion: Approximately 81% of the total administered radioactivity was recovered within a 48-day collection period following a single dose of radiolabeled 14 C- Cabozantinib in healthy subjects. Approximately 54% was recovered in feces and 27% in urine. Unchanged Cabozantinib accounted for 43% of the total radioactivity in feces and was not detectable in urine following a 72-hour collection.

Recommended Dosage for Renal Cell Carcinoma: The recommended dosage of Cabozantinib is 60 mg once daily without food until the patient no longer experiences clinical benefit or experiences unacceptable toxicity.

Recommended Dosage for Hepatocellular Carcinoma: The recommended dosage of Cabozantinib is 60 mg once daily without food until disease progression or unacceptable toxicity. Or, as directed by the registered physicians.

• Stop treatment with Cabozantinib at least 28 days prior to scheduled surgery, including dental surgery.
• Do not substitute Cabozantinib tablets with Cabozantinib capsules.
• Do not administer Cabozantinib with food. Administer at least 1 hour before or at least 2 hours after eating.
• Swallow Cabozantinib tablets whole. Do not crush Cabozantinib tablets.
• Do not take a missed dose within 12 hours of the next dose.
• Modify the dose for certain patients with hepatic impairment and for patients taking drugs known to strongly induce or inhibit CYP450.

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

It is contraindicated in patients with known hypersensitivity to Cabozantinib or any other components of this product.

Hemorrhage: Severe and fatal hemorrhages occurred with Cabozantinib. Discontinue Cabozantinib for Grade 3 or 4 hemorrhage. Do not administer Cabozantinib to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

Perforations and Fistulas: Fistulas, including fatal cases, occurred in 1% of Cabozantinib-treated patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of Cabozantinib-treated patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue Cabozantinib in patients who experience a fistula that cannot be appropriately managed or a GI perforation.

Thrombotic Events: Cabozantinib increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism occurred in 2% of Cabozantinib
-treated patients. Fatal thrombotic events occurred in Cabozantinib-treated patients. Discontinue Cabozantinib in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention.

Hypertension and Hypertensive Crisis: Cabozantinib can cause hypertension, including hypertensive crisis. Do not initiate Cabozantinib in patients with uncontrolled hypertension. Monitor blood pressure regularly during Cabozantinib treatment. Withhold Cabozantinib for hypertension that is not adequately controlled with medical management; when controlled, resume Cabozantinib at a reduced dose. Discontinue Cabozantinib for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.

Diarrhea: Diarrhea occurred in 63% of patients treated with Cabozantinib. Withhold Cabozantinib until improvement to Grade 1 and resume Cabozantinib at a reduced dose for intolerable Grade 2 diarrhea, Grade 3 diarrhea that cannot be managed with standard antidiarrheal treatments, or Grade 4 diarrhea.

Palmar-Plantar Erythrodysesthesia: Palmar-plantar erythrodysesthesia (PPE) occurred in 44% of patients treated with Cabozantinib. Withhold Cabozantinib until improvement to Grade 1 and resume Cabozantinib at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.

Proteinuria: Proteinuria was observed in 7% of patients receiving Cabozantinib. Monitor urine protein regularly during Cabozantinib treatment. Discontinue Cabozantinib in patients who develop nephrotic syndrome.

Osteonecrosis of the Jaw: Osteonecrosis of the jaw (ONJ) occurred in <1% of patients treated with Cabozantinib. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of Cabozantinib and periodically during Cabozantinib. Advise patients regarding good oral hygiene practices. Withhold Cabozantinib for at least 28 days prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold Cabozantinib for development of ONJ until complete resolution.

Wound Complications: Wound complications have been reported with Cabozantinib. Stop Cabozantinib at least 28 days prior to scheduled surgery. Resume Cabozantinib after surgery based on clinical judgment of adequate wound healing. Withhold Cabozantinib in patients with dehiscence or wound healing complications requiring medical intervention.

Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, can occur with Cabozantinib. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue Cabozantinib in patients who develop RPLS.

Embryo-Fetal Toxicity: Based on data from animal studies and its mechanism of action, Cabozantinib can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Cabozantinib and for 4 months after the last dose.

Strong CYP3A4 Inhibitors: Coadministration of a Cabozantinib capsule formulation with a strong CYP3A4 inhibitor increased the exposure of Cabozantinib, which may increase the risk of exposure-related adverse reactions. Avoid coadministration of Cabozantinib with strong CYP3A4 inhibitors. Reduce the dosage of Cabozantinib if coadministration with strong CYP3A4 inhibitors cannot be avoided. Avoid grapefruit or grapefruit juice which may also increase exposure of Cabozantinib.

Strong CYP3A Inducers: Coadministration of a Cabozantinib capsule formulation with a strong CYP3A4 inducer decreased the exposure of Cabozantinib, which may reduce efficacy. Avoid coadministration of Cabozantinib with strong CYP3A4 inducers. Increase the dosage of Cabozantinib if coadministration with strong CYP3A4 inducers cannot be avoided. Avoid St. John's Wort which may also decrease exposure of Cabozantinib.

Pregnancy: Cabozantinib can cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk.

Lactation: There is no information regarding the presence of Cabozantinib or its metabolites in human milk, or their effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in breastfed children, women should be advised not to breastfeed during treatment with Cabozantinib and for 4 months after the final dose.

Contraception: Cabozantinib can cause fetal harm when administered to a pregnant woman.

Females: Females of reproductive potential should be advised to use effective contraception during treatment with Cabozantinib and for 4 months after the final dose.

Infertility: Females and Males: Based on findings in animals, Cabozantinib may impair fertility in females and males of reproductive potential.

One case of overdosage was reported following administration of another formulation of cabozantinib; a patient inadvertently took twice the intended dose for 9 days. The patient suffered Grade 3 memory impairment, Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in BUN. The extent of recovery was not documented.

Store below 30°C in a cool and dry place, away from sunlight. Keep out of reach of children.

Renal Cell Carcinoma: Cabozantinib is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

Hepatocellular Carcinoma: Cabozantinib is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with Sorafenib.

Tyrosine Kinase Inhibitor

In vitro biochemical and/or cellular assays have shown that Cabozantinib inhibits the tyrosine kinase activity of MET, VEGFR-1, -2 and -3, AXL, RET, ROS1, TYRO3, MER, KIT, TRKB, FLT-3, and TIE-2. These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, drug resistance, and maintenance of the tumor microenvironment.

Absorption: Median time to peak cabozantinib concentrations (T_max) ranged from 3 to 4 hours post-dose. A 19% increase in the Cmax of Cabozantinib compared to a Cabozantinib capsule formulation was observed following a single 140 mg dose. A less than 10% difference in the AUC was observed between Cabozantinib and a Cabozantinib capsule formulation.

Distribution: The oral volume of distribution (Vz/F) of Cabozantinib is approximately 319 L. Cabozantinib is highly protein-bound in human plasma (≥99.7%).

Elimination: The predicted terminal half-life is approximately 99 hours and the clearance (CL/F) at steady state is estimated to be 2.2 L/hr.

Metabolism: Cabozantinib is a substrate of CYP3A4 in vitro.

Excretion: Approximately 81% of the total administered radioactivity was recovered within a 48-day collection period following a single dose of radiolabeled 14 C- Cabozantinib in healthy subjects. Approximately 54% was recovered in feces and 27% in urine. Unchanged Cabozantinib accounted for 43% of the total radioactivity in feces and was not detectable in urine following a 72-hour collection.

Recommended Dosage for Renal Cell Carcinoma: The recommended dosage of Cabozantinib is 60 mg once daily without food until the patient no longer experiences clinical benefit or experiences unacceptable toxicity.

Recommended Dosage for Hepatocellular Carcinoma: The recommended dosage of Cabozantinib is 60 mg once daily without food until disease progression or unacceptable toxicity. Or, as directed by the registered physicians.

• Stop treatment with Cabozantinib at least 28 days prior to scheduled surgery, including dental surgery.
• Do not substitute Cabozantinib tablets with Cabozantinib capsules.
• Do not administer Cabozantinib with food. Administer at least 1 hour before or at least 2 hours after eating.
• Swallow Cabozantinib tablets whole. Do not crush Cabozantinib tablets.
• Do not take a missed dose within 12 hours of the next dose.
• Modify the dose for certain patients with hepatic impairment and for patients taking drugs known to strongly induce or inhibit CYP450.

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

It is contraindicated in patients with known hypersensitivity to Cabozantinib or any other components of this product.

Hemorrhage: Severe and fatal hemorrhages occurred with Cabozantinib. Discontinue Cabozantinib for Grade 3 or 4 hemorrhage. Do not administer Cabozantinib to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

Perforations and Fistulas: Fistulas, including fatal cases, occurred in 1% of Cabozantinib-treated patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of Cabozantinib-treated patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue Cabozantinib in patients who experience a fistula that cannot be appropriately managed or a GI perforation.

Thrombotic Events: Cabozantinib increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism occurred in 2% of Cabozantinib
-treated patients. Fatal thrombotic events occurred in Cabozantinib-treated patients. Discontinue Cabozantinib in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention.

Hypertension and Hypertensive Crisis: Cabozantinib can cause hypertension, including hypertensive crisis. Do not initiate Cabozantinib in patients with uncontrolled hypertension. Monitor blood pressure regularly during Cabozantinib treatment. Withhold Cabozantinib for hypertension that is not adequately controlled with medical management; when controlled, resume Cabozantinib at a reduced dose. Discontinue Cabozantinib for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.

Diarrhea: Diarrhea occurred in 63% of patients treated with Cabozantinib. Withhold Cabozantinib until improvement to Grade 1 and resume Cabozantinib at a reduced dose for intolerable Grade 2 diarrhea, Grade 3 diarrhea that cannot be managed with standard antidiarrheal treatments, or Grade 4 diarrhea.

Palmar-Plantar Erythrodysesthesia: Palmar-plantar erythrodysesthesia (PPE) occurred in 44% of patients treated with Cabozantinib. Withhold Cabozantinib until improvement to Grade 1 and resume Cabozantinib at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.

Proteinuria: Proteinuria was observed in 7% of patients receiving Cabozantinib. Monitor urine protein regularly during Cabozantinib treatment. Discontinue Cabozantinib in patients who develop nephrotic syndrome.

Osteonecrosis of the Jaw: Osteonecrosis of the jaw (ONJ) occurred in <1% of patients treated with Cabozantinib. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of Cabozantinib and periodically during Cabozantinib. Advise patients regarding good oral hygiene practices. Withhold Cabozantinib for at least 28 days prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold Cabozantinib for development of ONJ until complete resolution.

Wound Complications: Wound complications have been reported with Cabozantinib. Stop Cabozantinib at least 28 days prior to scheduled surgery. Resume Cabozantinib after surgery based on clinical judgment of adequate wound healing. Withhold Cabozantinib in patients with dehiscence or wound healing complications requiring medical intervention.

Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, can occur with Cabozantinib. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue Cabozantinib in patients who develop RPLS.

Embryo-Fetal Toxicity: Based on data from animal studies and its mechanism of action, Cabozantinib can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Cabozantinib and for 4 months after the last dose.

Strong CYP3A4 Inhibitors: Coadministration of a Cabozantinib capsule formulation with a strong CYP3A4 inhibitor increased the exposure of Cabozantinib, which may increase the risk of exposure-related adverse reactions. Avoid coadministration of Cabozantinib with strong CYP3A4 inhibitors. Reduce the dosage of Cabozantinib if coadministration with strong CYP3A4 inhibitors cannot be avoided. Avoid grapefruit or grapefruit juice which may also increase exposure of Cabozantinib.

Strong CYP3A Inducers: Coadministration of a Cabozantinib capsule formulation with a strong CYP3A4 inducer decreased the exposure of Cabozantinib, which may reduce efficacy. Avoid coadministration of Cabozantinib with strong CYP3A4 inducers. Increase the dosage of Cabozantinib if coadministration with strong CYP3A4 inducers cannot be avoided. Avoid St. John's Wort which may also decrease exposure of Cabozantinib.

Pregnancy: Cabozantinib can cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk.

Lactation: There is no information regarding the presence of Cabozantinib or its metabolites in human milk, or their effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in breastfed children, women should be advised not to breastfeed during treatment with Cabozantinib and for 4 months after the final dose.

Contraception: Cabozantinib can cause fetal harm when administered to a pregnant woman.

Females: Females of reproductive potential should be advised to use effective contraception during treatment with Cabozantinib and for 4 months after the final dose.

Infertility: Females and Males: Based on findings in animals, Cabozantinib may impair fertility in females and males of reproductive potential.

One case of overdosage was reported following administration of another formulation of cabozantinib; a patient inadvertently took twice the intended dose for 9 days. The patient suffered Grade 3 memory impairment, Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in BUN. The extent of recovery was not documented.

Store below 30°C in a cool and dry place, away from sunlight. Keep out of reach of children.

Carbamazepine is indicated for-

• partial and secondary generalized tonic-clonic seizures
• Primary generalized tonic-clonic seizures
• Trigeminal neuralgia
• Prophylaxis of bipolar disorder

Primary anti-epileptic drugs

Carbamazepine depresses activity in the nucleus ventralis of the thalamus, reduces synaptic propagation of excitatory impulses or decreases summation of temporal stimulation leading to neural discharge by limiting influx of Na ions across cell membrane or other unknown mechanisms. It stimulates the release of antidiuretic hormone (ADH) and potentiates its action in promoting reabsorption of water.

Epilepsy:

• Adults and children over 12 years of age- Initial: Either 200 mg b.i.d. for tablets and controlled release tablets, or 1 teaspoon q.i.d. for suspension (400 mg/day). Increase at weekly intervals by adding up to 200 mg/day using a b.i.d or a t.i.d. or q.i.d. regimen of the either formulations until the optimal response is obtained.
• Children 12-15 years of age- Dosage generally should not exceed 1000 mg daily, and 1200 mg daily in patients above 15 years of age. Doses up to 1600 mg daily have been used in adults in rare instances. Maintenance: usually 800-1200 mg daily.
• Children 6-12 years of age- Initial: Either 100 mg b.i.d. for tablets or controlled release tablets, or 1/2 teaspoon q.i.d. for suspension (200 mg/day). Increase at weekly intervals by adding up to 100 mg/day using a b.i.d. or a t.i.d.or q.i.d. regimen of the either formulations until the optimal response is obtained. Dosage generally should not exceed 1000 mg daily. Maintenance:usually 400-800 mg daily.
• Children under 6 years of age- Initial: 10-20 mg/kg/day b.i.d.or t.i.d. as tablets, or q.i.d. as suspension. Increase weekly to achieve optimal clinical response administered t.i.d. or q.i.d. Maintenance: Ordinarily, optimal clinical response is achieved at daily doses below 35 mg/kg. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the therapeutic range. No recommendation regarding the safety of Carbamazepine for use at doses above 35 mg/kg/24 hours can be made.

Combination therapy: Carbamazepine may be used alone or with other anticonvulsants. When added to existing anticonvulsant therapy, the drug should be added gradually while the other anticonvulsants are maintained or gradually decreased, except phenytoin, which may have to be increased.

Trigeminal Neuralgia: Initial: On the first day,either 100 mg b.i.d. for tablets or controlled release tablets, or 1/2 teaspoon q.i.d. for suspension, for a total daily dose of 200 mg. This daily dose may be increased by up to 200 mg/day using increments of 100 mg every 12 hours for tablets or controlled release tablets, or 50 mg (1/2 teaspoon) q.i.d. for suspension, only as needed to achieve freedom from pain. A total dose of 1200 mg daily shouldn't be exceeded. Maintenance: Control of pain can be maintained in most patients with 400-800 mg daily. However, some patients may be maintained on as little as 200 mg daily, while others may require as much as 1200 mg daily. At least once every 3 months throughout the treatment period, attempts should be made to reduce the dose to the minimum effective level or even to discontinue the drug. The tablets or syrup can be taken without regards to meal.

The common side effects are dizziness, drowsiness, ataxia, dry mouth, abdominal pain, nausea, vomiting, anorexia, leucopenia, proteinuria, bradycardia, heart failure and hypotension. Erythematous skin rash, aplastic anemia may also be observed.

The most severe adverse reactions have been observed in the hemopoietic system, the skin and the cardiovascular system.The most frequently observed adverse reactions, particularly during the initial phases of therapy, are dizziness, drowsiness, unsteadiness, nausea, and vomiting. This medicine may cause increased sensitivity to the sun. Exposure to the sun, sunlamps, or tanning booths should be avoided if the increased sensitivity is seen. A sunscreen or protective clothing may be helpful at outside for a prolonged period.

This medicine should not be used if anybody is allergic to one or any of its ingredients. It can not be used also in the following conditions:

• Problems with the electrical message pathways in the heart (atrioventricular block)
• History of decreased blood cell production by the bone marrow (bone marrow depression)
• Hereditary blood disorders called porphyrias
• Allergy to tricyclic antidepressants
• People who have taken a monoamine-oxidase inhibitor antidepressant (MAOI) in the last 14 days

This medicine may cause dizziness and drowsiness.Special care should be taken while performing potentially hazardous activities, such as driving or operating machinery.

This medicine may cause skin reactions. If any rash,skin peeling, itching, or other unexplained skin reaction is seen while taking this medicine the concerned doctor should be informed immediately.

This medicine may rarely cause liver problems.For this reason, consultation with doctor is needed if unexplained itching, yellowing of the skin or eyes, unusually dark urine, nausea and vomiting, abdominal pains, and loss of appetite or flu-like symptoms.

Carbamazepine decreases the blood levels of hormonal contraceptives containing estrogen and/or progesterone, which may make the contraceptive ineffective or result in breakthrough bleeding.

Women taking this medicine who require contraception should be prescribed a contraceptive containing at least 50 micrograms of oestrogen,or use non-hormonal methods of contraception, such as condoms.

Taking this medicine should not be stopped suddenly unless the doctor tells. Otherwise, as suddenly stopping treatment is likely to make the symptoms return.If this medicine is stopped, it should normally be done gradually, under the supervision of a specialist.

Caution should be taken in-

• Mixed seizures including absence seizures
• Elderly people
• History of heart disease
• History of kidney disease
• History of liver disease
• History of psychotic illness
• Raised pressure in the eye (intraocular pressure), eg.glaucoma
• History of blood disorders that were caused by any other medication
• History of previous Carbamazepine therapy that was interrupted due to side effects or allergy

Galactorrhoea has been reported in few women on oral contraceptives within the first two months of Carbamazepine treatment Hepatic enzyme inducers such as Carbamazepine and Phenytoin may interact with Carbamazepine by increasing its metabolism. So an increase in dosage of Carbamazepine may be required.

Pregnancy category D. Carbamazepine and its epoxide metabolite are transferred to breast milk. Because of the potential serious side effects, decision should me made whether to discontinue nursing or discontinue the drug.

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

Carbamazepine is indicated for-

• partial and secondary generalized tonic-clonic seizures
• Primary generalized tonic-clonic seizures
• Trigeminal neuralgia
• Prophylaxis of bipolar disorder

Primary anti-epileptic drugs

Carbamazepine depresses activity in the nucleus ventralis of the thalamus, reduces synaptic propagation of excitatory impulses or decreases summation of temporal stimulation leading to neural discharge by limiting influx of Na ions across cell membrane or other unknown mechanisms. It stimulates the release of antidiuretic hormone (ADH) and potentiates its action in promoting reabsorption of water.

Epilepsy:

• Adults and children over 12 years of age- Initial: Either 200 mg b.i.d. for tablets and controlled release tablets, or 1 teaspoon q.i.d. for suspension (400 mg/day). Increase at weekly intervals by adding up to 200 mg/day using a b.i.d or a t.i.d. or q.i.d. regimen of the either formulations until the optimal response is obtained.
• Children 12-15 years of age- Dosage generally should not exceed 1000 mg daily, and 1200 mg daily in patients above 15 years of age. Doses up to 1600 mg daily have been used in adults in rare instances. Maintenance: usually 800-1200 mg daily.
• Children 6-12 years of age- Initial: Either 100 mg b.i.d. for tablets or controlled release tablets, or 1/2 teaspoon q.i.d. for suspension (200 mg/day). Increase at weekly intervals by adding up to 100 mg/day using a b.i.d. or a t.i.d.or q.i.d. regimen of the either formulations until the optimal response is obtained. Dosage generally should not exceed 1000 mg daily. Maintenance:usually 400-800 mg daily.
• Children under 6 years of age- Initial: 10-20 mg/kg/day b.i.d.or t.i.d. as tablets, or q.i.d. as suspension. Increase weekly to achieve optimal clinical response administered t.i.d. or q.i.d. Maintenance: Ordinarily, optimal clinical response is achieved at daily doses below 35 mg/kg. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the therapeutic range. No recommendation regarding the safety of Carbamazepine for use at doses above 35 mg/kg/24 hours can be made.

Combination therapy: Carbamazepine may be used alone or with other anticonvulsants. When added to existing anticonvulsant therapy, the drug should be added gradually while the other anticonvulsants are maintained or gradually decreased, except phenytoin, which may have to be increased.

Trigeminal Neuralgia: Initial: On the first day,either 100 mg b.i.d. for tablets or controlled release tablets, or 1/2 teaspoon q.i.d. for suspension, for a total daily dose of 200 mg. This daily dose may be increased by up to 200 mg/day using increments of 100 mg every 12 hours for tablets or controlled release tablets, or 50 mg (1/2 teaspoon) q.i.d. for suspension, only as needed to achieve freedom from pain. A total dose of 1200 mg daily shouldn't be exceeded. Maintenance: Control of pain can be maintained in most patients with 400-800 mg daily. However, some patients may be maintained on as little as 200 mg daily, while others may require as much as 1200 mg daily. At least once every 3 months throughout the treatment period, attempts should be made to reduce the dose to the minimum effective level or even to discontinue the drug. The tablets or syrup can be taken without regards to meal.

The common side effects are dizziness, drowsiness, ataxia, dry mouth, abdominal pain, nausea, vomiting, anorexia, leucopenia, proteinuria, bradycardia, heart failure and hypotension. Erythematous skin rash, aplastic anemia may also be observed.

The most severe adverse reactions have been observed in the hemopoietic system, the skin and the cardiovascular system.The most frequently observed adverse reactions, particularly during the initial phases of therapy, are dizziness, drowsiness, unsteadiness, nausea, and vomiting. This medicine may cause increased sensitivity to the sun. Exposure to the sun, sunlamps, or tanning booths should be avoided if the increased sensitivity is seen. A sunscreen or protective clothing may be helpful at outside for a prolonged period.

This medicine should not be used if anybody is allergic to one or any of its ingredients. It can not be used also in the following conditions:

• Problems with the electrical message pathways in the heart (atrioventricular block)
• History of decreased blood cell production by the bone marrow (bone marrow depression)
• Hereditary blood disorders called porphyrias
• Allergy to tricyclic antidepressants
• People who have taken a monoamine-oxidase inhibitor antidepressant (MAOI) in the last 14 days

This medicine may cause dizziness and drowsiness.Special care should be taken while performing potentially hazardous activities, such as driving or operating machinery.

This medicine may cause skin reactions. If any rash,skin peeling, itching, or other unexplained skin reaction is seen while taking this medicine the concerned doctor should be informed immediately.

This medicine may rarely cause liver problems.For this reason, consultation with doctor is needed if unexplained itching, yellowing of the skin or eyes, unusually dark urine, nausea and vomiting, abdominal pains, and loss of appetite or flu-like symptoms.

Carbamazepine decreases the blood levels of hormonal contraceptives containing estrogen and/or progesterone, which may make the contraceptive ineffective or result in breakthrough bleeding.

Women taking this medicine who require contraception should be prescribed a contraceptive containing at least 50 micrograms of oestrogen,or use non-hormonal methods of contraception, such as condoms.

Taking this medicine should not be stopped suddenly unless the doctor tells. Otherwise, as suddenly stopping treatment is likely to make the symptoms return.If this medicine is stopped, it should normally be done gradually, under the supervision of a specialist.

Caution should be taken in-

• Mixed seizures including absence seizures
• Elderly people
• History of heart disease
• History of kidney disease
• History of liver disease
• History of psychotic illness
• Raised pressure in the eye (intraocular pressure), eg.glaucoma
• History of blood disorders that were caused by any other medication
• History of previous Carbamazepine therapy that was interrupted due to side effects or allergy

Galactorrhoea has been reported in few women on oral contraceptives within the first two months of Carbamazepine treatment Hepatic enzyme inducers such as Carbamazepine and Phenytoin may interact with Carbamazepine by increasing its metabolism. So an increase in dosage of Carbamazepine may be required.

Pregnancy category D. Carbamazepine and its epoxide metabolite are transferred to breast milk. Because of the potential serious side effects, decision should me made whether to discontinue nursing or discontinue the drug.

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

This combination is indicated for the treatment of hypertension. This fixed combination drug is not indicated for the initial therapy of hypertension.

Combined antihypertensive preparations

The combination of Amlodipine and Benazepril is used to treat high blood pressure. Benazepril and benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and in animals. While the mechanism through which Benazepril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin aldosterone system, Benazepril has an antihypertensive effect even in patients with low-renin hypertension. Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.

The rate and extent of absorption of Benazepril and Amlodipine are not significantly different, respectively, from the rate and extent of absorption of Benazepril and Amlodipine from individual tablet formulations. Following oral administration of this capsule, peak plasma concentrations of Benazepril are reached in 0.5-2 hours. Peak plasma concentrations of Amlodipine are reached 6-12 hours after administration of this capsule; the extent of absorption is 64%-90%. Over 700 patients received Benazepril/Amlodipine once daily in five double-blind, placebo-controlled studies. Benazepril/Amlodipine lowered blood pressure within 1 hour, with peak reductions achieved 2-8 hours after dosing. The antihypertensive effect of a single dose persisted for 24 hours. Once-daily doses of Benazepril/Amlodipine using Benazepril doses of 10-20 mg and Amlodipine doses of 2.5-10 mg decreased seated pressure (systolic/diastolic) 24 hours after dosing by about 10-25/6-13 mmHg.

Amlodipine is an effective treatment of hypertension in once-daily doses of 2.5-10 mg while Benazepril is effective in doses of 10-80 mg.

It is usually appropriate to begin therapy with this capsule only after a patient has either-

• Failed to achieve the desired antihypertensive effect with one or the other monotherapy, or
• Demonstrated inability to achieve adequate antihypertensive effect with Amlodipine therapy without developing edema.

Dose Titration Guided by Clinical Effect: A patient whose blood pressure is not adequately controlled with Amlodipine (or another dihydropyridine) alone or with Benazepril (or another ACE inhibitor) alone may be switched to combination therapy with this capsule. All patient groups benefit from the reduction in Amlodipine-induced edema. Dosage must be guided by clinical response; steady-state levels of Benazepril an Amlodipine will be reached after approximately 2 and 7 days of dosing respectively.

In patients whose blood pressures are adequately controlled with Amlodipine but who experience unacceptable edema, combination therapy may achieve similar (or better) blood-pressure control without edema. Especially in nonblacks, it may be prudent to minimize the risk of excessive response by reducing the dose of Amlodipine as Benazepril is added to the regimen.

Replacement Therapy: For convenience, patients receiving Amlodipine and Benazepril from separate tablets may instead wish to receive this capsule containing the same component doses. In small, elderly, or hepatically impaired patients, the recommended initial dose of Amlodipine, as monotherapy or as a component of combination therapy, is 2.5 mg.

Benazepril/Amlodipine has been evaluated for safety in patients with hypertension for at least 6 months and more than 1 year. The reported side effects were generally mild and transient, and there was no relationship between side effects and age, sex, race or duration of therapy. Discontinuation of therapy due to side effects was required in approximately 4% of patients treated with Benazepril/Amlodipine and in 3% of patients treated with placebo. The most common reasons for discontinuation of therapy with Benazepril/Amlodipine in U.S. studies were cough and edema. The side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials in more than 1% of patients treated with Benazepril/Amlodipine are cough, headache, dizziness and edema.

The incidence of edema was statistically greater in patients treated with Amlodipine monotherapy than in patients treated with the combination. Edema and certain other side effects are associated with Amlodipine monotherapy in a dose-dependent manner, and appear to affect women more than men. The addition of Benazepril resulted in lower incidences as shown in study; the protective effect of Benazepril was independent of race and (within the range of doses tested) of dose.

Other rare side effects are angioedema, asthenia, fatigue, insomnia, nervousness, anxiety, tremor, decreased libido, flushing, hot flashes, rash, skin nodule, dermatitis, dry mouth, nausea, abdominal pain, constipation, diarrhea, dyspepsia, esophagitis, hypokalemia, pharyngitis etc.

This capsule is contraindicated in patients who are hypersensitive to Benazepril, to any other ACE inhibitor, or to Amlodipine.

Impaired Renal Function: This capsule should be used with caution in patients with severe renal disease.

Hyperkalemia: This may occur in only a few patients but generally are reversible.

Patients With Hepatic Failure: Since Amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t ½) is 56 hours in patients with impaired hepatic function, caution should be exercised when administering this capsule to patients with severe hepatic impairment.

Cough: ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Surgery/Anesthesia: In patients undergoing surgery or during anesthesia with agents that produce hypotension, Benazepril will block the angiotensin II formation that could otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion.

Carcinogenesis, Mutagenesis, Impairment of Fertility: No evidence of carcinogenicity, mutagenicity or impairment of fertility was found when the Benazepril/Amlodipine combination were given orally.

Diuretics: Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with Benazepril/Amlodipine.

Potassium Supplements and Potassium-Sparing Diuretics: Benazepril can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (Spironolactone, Amiloride, Triamterene and others) or potassium supplements can increase the risk of hyperkalemia. If concomitant use of such agents is indicated, they should be given with caution, and the patient's serum potassium should be monitored frequently.

Others: Benazepril has been used concomitantly with oral anticoagulants, beta-adrenergic-blocking agents, calcium-blocking agents, Cimetidine, diuretics, Digoxin, Hydralazine, and Naproxen without evidence of clinically important adverse interactions.

In clinical trials, Amlodipine has been safely administered with thiazide diuretics, beta blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin, Digoxin, Warfarin, nonsteroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic drugs.

Pregnancy Categories C (first trimester) and D (second and third trimesters). ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, this capsule should be discontinued as soon as possible. Minimal amounts of unchanged Benazepril and of benazeprilat are excreted into the breast milk of lactating women treated with Benazepril, so that a newborn child ingesting nothing but breast milk would receive less than 0.1% of the maternal doses of Benazepril and benazeprilat. It is not known whether Amlodipine is excreted in human milk. In the absence of this information, it is recommended that nursing be discontinued while this capsule is administered.

Geriatric Use: Clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

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

Human overdoses with any combination of Amlodipine and Benazepril have not been reported. In scattered reports of human overdoses with Benazepril and other ACE inhibitors, there are no reports of death.

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

This combination is indicated for the treatment of hypertension. This fixed combination drug is not indicated for the initial therapy of hypertension.

Combined antihypertensive preparations

The combination of Amlodipine and Benazepril is used to treat high blood pressure. Benazepril and benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and in animals. While the mechanism through which Benazepril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin aldosterone system, Benazepril has an antihypertensive effect even in patients with low-renin hypertension. Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.

The rate and extent of absorption of Benazepril and Amlodipine are not significantly different, respectively, from the rate and extent of absorption of Benazepril and Amlodipine from individual tablet formulations. Following oral administration of this capsule, peak plasma concentrations of Benazepril are reached in 0.5-2 hours. Peak plasma concentrations of Amlodipine are reached 6-12 hours after administration of this capsule; the extent of absorption is 64%-90%. Over 700 patients received Benazepril/Amlodipine once daily in five double-blind, placebo-controlled studies. Benazepril/Amlodipine lowered blood pressure within 1 hour, with peak reductions achieved 2-8 hours after dosing. The antihypertensive effect of a single dose persisted for 24 hours. Once-daily doses of Benazepril/Amlodipine using Benazepril doses of 10-20 mg and Amlodipine doses of 2.5-10 mg decreased seated pressure (systolic/diastolic) 24 hours after dosing by about 10-25/6-13 mmHg.

Amlodipine is an effective treatment of hypertension in once-daily doses of 2.5-10 mg while Benazepril is effective in doses of 10-80 mg.

It is usually appropriate to begin therapy with this capsule only after a patient has either-

• Failed to achieve the desired antihypertensive effect with one or the other monotherapy, or
• Demonstrated inability to achieve adequate antihypertensive effect with Amlodipine therapy without developing edema.

Dose Titration Guided by Clinical Effect: A patient whose blood pressure is not adequately controlled with Amlodipine (or another dihydropyridine) alone or with Benazepril (or another ACE inhibitor) alone may be switched to combination therapy with this capsule. All patient groups benefit from the reduction in Amlodipine-induced edema. Dosage must be guided by clinical response; steady-state levels of Benazepril an Amlodipine will be reached after approximately 2 and 7 days of dosing respectively.

In patients whose blood pressures are adequately controlled with Amlodipine but who experience unacceptable edema, combination therapy may achieve similar (or better) blood-pressure control without edema. Especially in nonblacks, it may be prudent to minimize the risk of excessive response by reducing the dose of Amlodipine as Benazepril is added to the regimen.

Replacement Therapy: For convenience, patients receiving Amlodipine and Benazepril from separate tablets may instead wish to receive this capsule containing the same component doses. In small, elderly, or hepatically impaired patients, the recommended initial dose of Amlodipine, as monotherapy or as a component of combination therapy, is 2.5 mg.

Benazepril/Amlodipine has been evaluated for safety in patients with hypertension for at least 6 months and more than 1 year. The reported side effects were generally mild and transient, and there was no relationship between side effects and age, sex, race or duration of therapy. Discontinuation of therapy due to side effects was required in approximately 4% of patients treated with Benazepril/Amlodipine and in 3% of patients treated with placebo. The most common reasons for discontinuation of therapy with Benazepril/Amlodipine in U.S. studies were cough and edema. The side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials in more than 1% of patients treated with Benazepril/Amlodipine are cough, headache, dizziness and edema.

The incidence of edema was statistically greater in patients treated with Amlodipine monotherapy than in patients treated with the combination. Edema and certain other side effects are associated with Amlodipine monotherapy in a dose-dependent manner, and appear to affect women more than men. The addition of Benazepril resulted in lower incidences as shown in study; the protective effect of Benazepril was independent of race and (within the range of doses tested) of dose.

Other rare side effects are angioedema, asthenia, fatigue, insomnia, nervousness, anxiety, tremor, decreased libido, flushing, hot flashes, rash, skin nodule, dermatitis, dry mouth, nausea, abdominal pain, constipation, diarrhea, dyspepsia, esophagitis, hypokalemia, pharyngitis etc.

This capsule is contraindicated in patients who are hypersensitive to Benazepril, to any other ACE inhibitor, or to Amlodipine.

Impaired Renal Function: This capsule should be used with caution in patients with severe renal disease.

Hyperkalemia: This may occur in only a few patients but generally are reversible.

Patients With Hepatic Failure: Since Amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t ½) is 56 hours in patients with impaired hepatic function, caution should be exercised when administering this capsule to patients with severe hepatic impairment.

Cough: ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Surgery/Anesthesia: In patients undergoing surgery or during anesthesia with agents that produce hypotension, Benazepril will block the angiotensin II formation that could otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion.

Carcinogenesis, Mutagenesis, Impairment of Fertility: No evidence of carcinogenicity, mutagenicity or impairment of fertility was found when the Benazepril/Amlodipine combination were given orally.

Diuretics: Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with Benazepril/Amlodipine.

Potassium Supplements and Potassium-Sparing Diuretics: Benazepril can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (Spironolactone, Amiloride, Triamterene and others) or potassium supplements can increase the risk of hyperkalemia. If concomitant use of such agents is indicated, they should be given with caution, and the patient's serum potassium should be monitored frequently.

Others: Benazepril has been used concomitantly with oral anticoagulants, beta-adrenergic-blocking agents, calcium-blocking agents, Cimetidine, diuretics, Digoxin, Hydralazine, and Naproxen without evidence of clinically important adverse interactions.

In clinical trials, Amlodipine has been safely administered with thiazide diuretics, beta blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin, Digoxin, Warfarin, nonsteroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic drugs.

Pregnancy Categories C (first trimester) and D (second and third trimesters). ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, this capsule should be discontinued as soon as possible. Minimal amounts of unchanged Benazepril and of benazeprilat are excreted into the breast milk of lactating women treated with Benazepril, so that a newborn child ingesting nothing but breast milk would receive less than 0.1% of the maternal doses of Benazepril and benazeprilat. It is not known whether Amlodipine is excreted in human milk. In the absence of this information, it is recommended that nursing be discontinued while this capsule is administered.

Geriatric Use: Clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

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

Human overdoses with any combination of Amlodipine and Benazepril have not been reported. In scattered reports of human overdoses with Benazepril and other ACE inhibitors, there are no reports of death.

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

This combination is indicated for the treatment of hypertension. This fixed combination drug is not indicated for the initial therapy of hypertension.

Combined antihypertensive preparations

The combination of Amlodipine and Benazepril is used to treat high blood pressure. Benazepril and benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and in animals. While the mechanism through which Benazepril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin aldosterone system, Benazepril has an antihypertensive effect even in patients with low-renin hypertension. Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.

The rate and extent of absorption of Benazepril and Amlodipine are not significantly different, respectively, from the rate and extent of absorption of Benazepril and Amlodipine from individual tablet formulations. Following oral administration of this capsule, peak plasma concentrations of Benazepril are reached in 0.5-2 hours. Peak plasma concentrations of Amlodipine are reached 6-12 hours after administration of this capsule; the extent of absorption is 64%-90%. Over 700 patients received Benazepril/Amlodipine once daily in five double-blind, placebo-controlled studies. Benazepril/Amlodipine lowered blood pressure within 1 hour, with peak reductions achieved 2-8 hours after dosing. The antihypertensive effect of a single dose persisted for 24 hours. Once-daily doses of Benazepril/Amlodipine using Benazepril doses of 10-20 mg and Amlodipine doses of 2.5-10 mg decreased seated pressure (systolic/diastolic) 24 hours after dosing by about 10-25/6-13 mmHg.

Amlodipine is an effective treatment of hypertension in once-daily doses of 2.5-10 mg while Benazepril is effective in doses of 10-80 mg.

It is usually appropriate to begin therapy with this capsule only after a patient has either-

• Failed to achieve the desired antihypertensive effect with one or the other monotherapy, or
• Demonstrated inability to achieve adequate antihypertensive effect with Amlodipine therapy without developing edema.

Dose Titration Guided by Clinical Effect: A patient whose blood pressure is not adequately controlled with Amlodipine (or another dihydropyridine) alone or with Benazepril (or another ACE inhibitor) alone may be switched to combination therapy with this capsule. All patient groups benefit from the reduction in Amlodipine-induced edema. Dosage must be guided by clinical response; steady-state levels of Benazepril an Amlodipine will be reached after approximately 2 and 7 days of dosing respectively.

In patients whose blood pressures are adequately controlled with Amlodipine but who experience unacceptable edema, combination therapy may achieve similar (or better) blood-pressure control without edema. Especially in nonblacks, it may be prudent to minimize the risk of excessive response by reducing the dose of Amlodipine as Benazepril is added to the regimen.

Replacement Therapy: For convenience, patients receiving Amlodipine and Benazepril from separate tablets may instead wish to receive this capsule containing the same component doses. In small, elderly, or hepatically impaired patients, the recommended initial dose of Amlodipine, as monotherapy or as a component of combination therapy, is 2.5 mg.

Benazepril/Amlodipine has been evaluated for safety in patients with hypertension for at least 6 months and more than 1 year. The reported side effects were generally mild and transient, and there was no relationship between side effects and age, sex, race or duration of therapy. Discontinuation of therapy due to side effects was required in approximately 4% of patients treated with Benazepril/Amlodipine and in 3% of patients treated with placebo. The most common reasons for discontinuation of therapy with Benazepril/Amlodipine in U.S. studies were cough and edema. The side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials in more than 1% of patients treated with Benazepril/Amlodipine are cough, headache, dizziness and edema.

The incidence of edema was statistically greater in patients treated with Amlodipine monotherapy than in patients treated with the combination. Edema and certain other side effects are associated with Amlodipine monotherapy in a dose-dependent manner, and appear to affect women more than men. The addition of Benazepril resulted in lower incidences as shown in study; the protective effect of Benazepril was independent of race and (within the range of doses tested) of dose.

Other rare side effects are angioedema, asthenia, fatigue, insomnia, nervousness, anxiety, tremor, decreased libido, flushing, hot flashes, rash, skin nodule, dermatitis, dry mouth, nausea, abdominal pain, constipation, diarrhea, dyspepsia, esophagitis, hypokalemia, pharyngitis etc.

This capsule is contraindicated in patients who are hypersensitive to Benazepril, to any other ACE inhibitor, or to Amlodipine.

Impaired Renal Function: This capsule should be used with caution in patients with severe renal disease.

Hyperkalemia: This may occur in only a few patients but generally are reversible.

Patients With Hepatic Failure: Since Amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t ½) is 56 hours in patients with impaired hepatic function, caution should be exercised when administering this capsule to patients with severe hepatic impairment.

Cough: ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Surgery/Anesthesia: In patients undergoing surgery or during anesthesia with agents that produce hypotension, Benazepril will block the angiotensin II formation that could otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion.

Carcinogenesis, Mutagenesis, Impairment of Fertility: No evidence of carcinogenicity, mutagenicity or impairment of fertility was found when the Benazepril/Amlodipine combination were given orally.

Diuretics: Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with Benazepril/Amlodipine.

Potassium Supplements and Potassium-Sparing Diuretics: Benazepril can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (Spironolactone, Amiloride, Triamterene and others) or potassium supplements can increase the risk of hyperkalemia. If concomitant use of such agents is indicated, they should be given with caution, and the patient's serum potassium should be monitored frequently.

Others: Benazepril has been used concomitantly with oral anticoagulants, beta-adrenergic-blocking agents, calcium-blocking agents, Cimetidine, diuretics, Digoxin, Hydralazine, and Naproxen without evidence of clinically important adverse interactions.

In clinical trials, Amlodipine has been safely administered with thiazide diuretics, beta blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin, Digoxin, Warfarin, nonsteroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic drugs.

Pregnancy Categories C (first trimester) and D (second and third trimesters). ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, this capsule should be discontinued as soon as possible. Minimal amounts of unchanged Benazepril and of benazeprilat are excreted into the breast milk of lactating women treated with Benazepril, so that a newborn child ingesting nothing but breast milk would receive less than 0.1% of the maternal doses of Benazepril and benazeprilat. It is not known whether Amlodipine is excreted in human milk. In the absence of this information, it is recommended that nursing be discontinued while this capsule is administered.

Geriatric Use: Clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

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

Human overdoses with any combination of Amlodipine and Benazepril have not been reported. In scattered reports of human overdoses with Benazepril and other ACE inhibitors, there are no reports of death.

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

Specific mineral & vitamin combined preparations

This is the preparation of Calcium Carbonate and Vitamin D3 (Cholecalciferol). Calcium is necessary for many normal functions of our body, especially bone formation and maintenance. Vitamin D3 helps for the absorption & reabsorption of Calcium. Vitamin D3 also stimulates bone formation. Clinical studies showed that Calcium and Vitamin D3 all together helps in bone growth, and in prevention of osteoporosis & bone fracture.

Calcium 500 mg and Vitamin D3 200 IU Tablet: 2 tablets daily or 1 tablet twice daily. It is best taken with or just after a meal to improve absorption.

Calcium 500 mg and Vitamin D3 400 IU Tablet: 1 tablet twice daily. It is best taken with or just after a meal to improve absorption.

It is generally well tolerated. If there is experience like nausea, vomiting, stomach cramps, dry mouth, increased thirst, increased urination while taking, noticed to physicians. Constipation may occur.

It is contraindicated in case of hypercalcaemia, hyperthyroidism, renal calculi & nephrolithiasis and Zollinger-Ellison Syndrome.

If there is any pre-existing heart disease or kidney disease, precautions should be taken.

It has possible interaction with calcium, aluminium or magnesium containing antacids &  other calcium supplements, calcitriol & other vitamin D3 supplements; digoxin, tetracycline, doxycycline, minocycline or oxytetracycline.

This combination should be used as directed by physician during pregnancy or while breast-feeding.

Symptoms of overdosage may include nausea and vomiting, severe drowsiness, dry mouth, loss of appetite, metallic taste, stomach cramps, diarrhea, headache, constipation.

Keep in a dry place away from light and heat. Keep out of the reach of children.

Specific mineral & vitamin combined preparations

Nutrition is the most important to prevent osteoporosis and other bone related diseases. Calcium, Magnesium & Vitamin D3 are the macronutrients for bone. Without Vitamin D3 very little Calcium is absorbed. Like Calcium, Magnesium increases bone strength and rigidity. Recent epidemiological studies showed that some micronutrients like Copper, Manganese, Zinc & Boron play an important role in bone health. Deficiency of the micronutrients is noticed in patients with osteoporosis.

2 tablets per day, preferably 1 tablet in the morning and 1 tablet in the evening.

It is generally well tolerated. If there is experience like nausea, vomiting, stomach cramps, dry mouth, increased thirst, increased urination while taking, noticed to physicians. Side effects from micronutrient are rare.

It is contraindicated in case of hypercalcaemia, hyperthyroidism, renal calculi & nephrolithiasis and Zollinger-Ellison Syndrome.

If there is any pre-existing heart disease or kidney disease, precautions should be taken.

It has possible interaction with Calcium, Aluminium or Magnesium containing Antacids & other Calcium supplements, Calcitriol & other Vitamin D3 supplements; Digoxin, Tetracycline, Doxycycline, Minocycline or Oxytetracycline.

This combination should be used as directed by physician during pregnancy or while breast-feeding.

Symptoms of overdosage may include nausea and vomiting, severe drowsiness, dry mouth, loss of appetite, metallic taste, stomach cramps, diarrhea, headache & constipation.

Keep in a dry place away from light and heat. Keep out of the reach of children.

Specific mineral & vitamin combined preparations

This is the preparation of Calcium Carbonate and Vitamin D3 (Cholecalciferol). Calcium is necessary for many normal functions of our body, especially bone formation and maintenance. Vitamin D3 helps for the absorption & reabsorption of Calcium. Vitamin D3 also stimulates bone formation. Clinical studies showed that Calcium and Vitamin D3 all together helps in bone growth, and in prevention of osteoporosis & bone fracture.

Calcium 500 mg and Vitamin D3 200 IU Tablet: 2 tablets daily or 1 tablet twice daily. It is best taken with or just after a meal to improve absorption.

Calcium 500 mg and Vitamin D3 400 IU Tablet: 1 tablet twice daily. It is best taken with or just after a meal to improve absorption.

It is generally well tolerated. If there is experience like nausea, vomiting, stomach cramps, dry mouth, increased thirst, increased urination while taking, noticed to physicians. Constipation may occur.

It is contraindicated in case of hypercalcaemia, hyperthyroidism, renal calculi & nephrolithiasis and Zollinger-Ellison Syndrome.

If there is any pre-existing heart disease or kidney disease, precautions should be taken.

It has possible interaction with calcium, aluminium or magnesium containing antacids &  other calcium supplements, calcitriol & other vitamin D3 supplements; digoxin, tetracycline, doxycycline, minocycline or oxytetracycline.

This combination should be used as directed by physician during pregnancy or while breast-feeding.

Symptoms of overdosage may include nausea and vomiting, severe drowsiness, dry mouth, loss of appetite, metallic taste, stomach cramps, diarrhea, headache, constipation.

Keep in a dry place away from light and heat. Keep out of the reach of children.

Calcium Dobesilate is indicated for the treatment of hemorrhoidal syndrome, microcirculation disorders of arteovenous origin, clinical signs of chronic venous insufficiency in the lower limbs (pain, cramps, paresthesia, edema, stasis, dermotosis) and in the particular microangiopathy like diabetic retinopathy. It is also indicated in superficial thrombophlebitis as adjuvant therapy.

Vaso Protective

Calcium dobesilate acts selectively on the capillary walls regulating their physiological functions of resistance and permeability. It lowers blood viscosity and restores normal blood flow. This action is beneficial in all cases of capillary fragility due to metabolic disturbances (constitutional or acquired), and surgical stress or induced by certain medicines.

Calcium Dobesilate capsule once or twice daily should be taken with the main meal. Treatment duration, which generally between a few weeks to several months, depends on the disease and its evolution. Dosage should be adapted individually according to the severity of the disease.

Rarely gastrointestinal disorders including nausea and diarrhea, skin reactions, fever, articular pain and in very rare cases agranulocytosis have been reported. These reactions are generally spontaneously reversible after treatment withdrawal.

Hypersensitivity. Pregnancy and lactation.

Dosage should be reduced in case of severe renal insufficiency requiring dialysis. In patient with agranulocytosis, this medication can decrease the number of white blood cells which affect the body’s ability to fight against various infections. If patients experience flu-like symptoms such as cough, sore throat, fever and others, they are advised to seek medical care as soon as possible.

The safety of Calcium Dobesilate during pregnancy and lactation has not been established. As it is not known whether calcium dobesilate crosses the placental barrier in humans, the drug should be administered during pregnancy only if the benefit to the mother outweighs the potential risk to the fetus. Avoid breastfeeding while using this medicine.

The clinical signs of a possible overdose are not known. If overdose occurs, seek medical advice immediately.

Store in a cool and dry place, away from light. Keep out of the reach of children.

This rectal ointment is indicated in-

• Internal and external hemorrhoids,
• Anal pruritus
• Anal eczema
• Anitis
• Perianitis
• Acute hemorrhoidal thrombosis 
• Anal fissure
• Pre and postoperative treatment in cases of hemorrhoidectomy

A long-lasting treatment is not indicated.

Drugs used in Ano-rectal region

Calcium Dobesilate acts on the capillary walls by regulating their impaired physiological functions- i.e. increased permeability and decreased resistance and on different signs of inflammation. It also has an antithrombotic activity. Lidocaine hydrochloride, a local anesthetic, contributes to relieve pain. Dexamethasone Acetate, a Corticosteroid for topical use, possesses anti-inflammatory and antipruritic actions.

2-3 times daily. Apply in the morning and bedtime and if possible after defecation. If the ointment is preferred, use the applicator by screwing it to the tube. Insert the applicator as deep as possible in the anus then press the tube gently while withdrawing it. In this case, the tube is sufficient for 8 applications. In case of external hemorrhoids or anal pruritus, apply a thin layer of the ointment several times a day. The duration of the treatment is generally of some days. The doctor must be informed if, after 1 to 2 weeks of treatment, the symptomatology has not improved or has worsened.

Calcium Dobesilate, Lidocaine HCI & Dexamethasone Acetate Ointment should be applied 2-3 times daily preferably in the morning and at bedtime, if possible apply after defecation. In the case of internal hemorrhoids apply the ointment by the applicator. In cases of external hemorrhoids and anal pruritus, apply a thin layer of the ointment several times a day. The duration of the treatment is generally of some days. The physician must be informed if, after 1 to 2 weeks of treatment the symptomatology has not improved or has worsened.

Method of use of this ointment:
For internal use-

• Before use remove the cap from the tube.
• Pierce the tube membrane by inverting the cap.
• Attach the applicator (supplied) to the tube.
• Squeeze the tube to fill the applicator and lubricate the tip with ointment for smooth insertion.
• Insert the applicator gently and to full extend into the anus and squeeze once again from the end of the tube to force the required amount of ointment into the anal canal.
• Remove the applicator after application and discard it.
• Try not to have defecation for a couple of hours after an internal application.

For external use-

• Squeeze the tube of ointment and apply a small amount to the finger.
• Apply the ointment around the outside of the anus with a finger.
• Wash the hands thoroughly with warm water and soap after each application.
• Reattach the cap to tube.

Very rare cases have been reported: Modifications of the intestinal transit, temporary burning sensation and local pain. Hypersensitivity reactions together with skin reactions and/or fever can occur. These reactions can be of allergic origin and in this case, the treatment must be discontinued.

Hypersensitivity towards the components of this preparation.

In case of renal insufficiency, this rectal ointment should not be used during longer periods. Avoid long-lasting treatments.

Pregnancy category C. Studies in pregnant women or animals are not available and in humans, it is not known whether Calcium Dobesilate crosses the placental barrier. On the other hand, after topical administration, Lidocaine Hydrochloride and Dexamethasone Acetate are resorbed in variable quantities and can have systemic effects. Moreover, both substances cross the placental barrier. In these conditions, this rectal ointment should be administered during pregnancy only if the potential benefit justifies the potential risk to the fetus. After oral administration, Calcium Dobesilate is excreted in the maternal milk in low amounts but it is not known whether this is the case with local use. After topical administration, Lidocaine Hydrochloride and Dexamethasone Acetate are excreted in the maternal milk. As a precaution, it should be decided between discontinuating the treatment or the breast-feeding.

No overdosage information found yet.

The ointment must be stored protected from heat. Store it below 30°C.

The is indicated in the following condition-

• Headache
• Migraine
• Toothache
• Neuralgia
• Feverishness
• Period pain
• Sore throat
• Backache
• Help to reduce the temperature
• Aches and pain of colds and flu

Non opioid analgesics

This is a combination of Paracetamol and Caffeine. Paracetamol has analgesic and antipyretic properties with weak anti-inflammatory activity. Caffeine is an alkaloid which is a theophylline-like xanthine derivative. By intermolecular association with Paracetamol, Caffeine increases the solubility and transmembrane permeation of Paracetamol. In addition, Caffeine increases the pain threshold and tolerance of pain. Caffeine has also an intrinsic power to raise vessel tone in the brain, which provides another benefit to treat migraine and headache.

Adult dose: 1-2 tablets every 4-6 hours. Maximum dose: 8 tablets daily.
Child dose: Not recommended for children below 12 years.

Side effects of paracetamol are usually mild, though haematological reactions including thrombocytopenia, leukopenia, pancytopenia, neutropenia, and agranulocytosis have been reported. Pancreatitis, skin rashes, and other allergic reactions occur occasionally.

Paracetamol is contraindicated in patients with severe renal function impairment and hepatic disease (Viral Hepatitis). Known hypersensitivity to paracetamol or caffeine.

Paracetamol & Caffeine should be given cautiously in the following cases: In patients with hepatic or renal failure, in patients taking other hepatotoxic medication. Prolonged use of the drug without consulting a physician should be avoided.

May reduce serum levels with anticonvulsants (e.g. phenytoin, barbiturates, carbamazepine). May enhance the anticoagulant effect of warfarin and other coumarins with prolonged use. Accelerated absorption with metoclopramide and domperidone. May increase serum levels with probenecid. May increase serum levels of chloramphenicol. May reduce absorption with colestyramine within 1 hr of admin. May cause severe hypothermia with phenothiazine.

Pregnant mothers should consult with doctors before taking Paracetamol & Caffeine. Paracetamol & Caffeine can be taken whilst breast feeding.

Symptoms of Paracetamol overdose in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 40 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur.

Store in a cool and dry place, protect from light and moisture.Keep all medicines out of the reach of the children.

The is indicated in the following condition-

• Headache
• Migraine
• Toothache
• Neuralgia
• Feverishness
• Period pain
• Sore throat
• Backache
• Help to reduce the temperature
• Aches and pain of colds and flu

Non opioid analgesics

This is a combination of Paracetamol and Caffeine. Paracetamol has analgesic and antipyretic properties with weak anti-inflammatory activity. Caffeine is an alkaloid which is a theophylline-like xanthine derivative. By intermolecular association with Paracetamol, Caffeine increases the solubility and transmembrane permeation of Paracetamol. In addition, Caffeine increases the pain threshold and tolerance of pain. Caffeine has also an intrinsic power to raise vessel tone in the brain, which provides another benefit to treat migraine and headache.

Adult dose: 1-2 tablets every 4-6 hours. Maximum dose: 8 tablets daily.
Child dose: Not recommended for children below 12 years.

Side effects of paracetamol are usually mild, though haematological reactions including thrombocytopenia, leukopenia, pancytopenia, neutropenia, and agranulocytosis have been reported. Pancreatitis, skin rashes, and other allergic reactions occur occasionally.

Paracetamol is contraindicated in patients with severe renal function impairment and hepatic disease (Viral Hepatitis). Known hypersensitivity to paracetamol or caffeine.

Paracetamol & Caffeine should be given cautiously in the following cases: In patients with hepatic or renal failure, in patients taking other hepatotoxic medication. Prolonged use of the drug without consulting a physician should be avoided.

May reduce serum levels with anticonvulsants (e.g. phenytoin, barbiturates, carbamazepine). May enhance the anticoagulant effect of warfarin and other coumarins with prolonged use. Accelerated absorption with metoclopramide and domperidone. May increase serum levels with probenecid. May increase serum levels of chloramphenicol. May reduce absorption with colestyramine within 1 hr of admin. May cause severe hypothermia with phenothiazine.

Pregnant mothers should consult with doctors before taking Paracetamol & Caffeine. Paracetamol & Caffeine can be taken whilst breast feeding.

Symptoms of Paracetamol overdose in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 40 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur.

Store in a cool and dry place, protect from light and moisture.Keep all medicines out of the reach of the children.

The is indicated in the following condition-

• Headache
• Migraine
• Toothache
• Neuralgia
• Feverishness
• Period pain
• Sore throat
• Backache
• Help to reduce the temperature
• Aches and pain of colds and flu

Non opioid analgesics

This is a combination of Paracetamol and Caffeine. Paracetamol has analgesic and antipyretic properties with weak anti-inflammatory activity. Caffeine is an alkaloid which is a theophylline-like xanthine derivative. By intermolecular association with Paracetamol, Caffeine increases the solubility and transmembrane permeation of Paracetamol. In addition, Caffeine increases the pain threshold and tolerance of pain. Caffeine has also an intrinsic power to raise vessel tone in the brain, which provides another benefit to treat migraine and headache.

Adult dose: 1-2 tablets every 4-6 hours. Maximum dose: 8 tablets daily.
Child dose: Not recommended for children below 12 years.

Side effects of paracetamol are usually mild, though haematological reactions including thrombocytopenia, leukopenia, pancytopenia, neutropenia, and agranulocytosis have been reported. Pancreatitis, skin rashes, and other allergic reactions occur occasionally.

Paracetamol is contraindicated in patients with severe renal function impairment and hepatic disease (Viral Hepatitis). Known hypersensitivity to paracetamol or caffeine.

Paracetamol & Caffeine should be given cautiously in the following cases: In patients with hepatic or renal failure, in patients taking other hepatotoxic medication. Prolonged use of the drug without consulting a physician should be avoided.

May reduce serum levels with anticonvulsants (e.g. phenytoin, barbiturates, carbamazepine). May enhance the anticoagulant effect of warfarin and other coumarins with prolonged use. Accelerated absorption with metoclopramide and domperidone. May increase serum levels with probenecid. May increase serum levels of chloramphenicol. May reduce absorption with colestyramine within 1 hr of admin. May cause severe hypothermia with phenothiazine.

Pregnant mothers should consult with doctors before taking Paracetamol & Caffeine. Paracetamol & Caffeine can be taken whilst breast feeding.

Symptoms of Paracetamol overdose in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 40 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur.

Store in a cool and dry place, protect from light and moisture.Keep all medicines out of the reach of the children.

The is indicated in the following condition-

• Headache
• Migraine
• Toothache
• Neuralgia
• Feverishness
• Period pain
• Sore throat
• Backache
• Help to reduce the temperature
• Aches and pain of colds and flu

Non opioid analgesics

This is a combination of Paracetamol and Caffeine. Paracetamol has analgesic and antipyretic properties with weak anti-inflammatory activity. Caffeine is an alkaloid which is a theophylline-like xanthine derivative. By intermolecular association with Paracetamol, Caffeine increases the solubility and transmembrane permeation of Paracetamol. In addition, Caffeine increases the pain threshold and tolerance of pain. Caffeine has also an intrinsic power to raise vessel tone in the brain, which provides another benefit to treat migraine and headache.

Adult dose: 1-2 tablets every 4-6 hours. Maximum dose: 8 tablets daily.
Child dose: Not recommended for children below 12 years.

Side effects of paracetamol are usually mild, though haematological reactions including thrombocytopenia, leukopenia, pancytopenia, neutropenia, and agranulocytosis have been reported. Pancreatitis, skin rashes, and other allergic reactions occur occasionally.

Paracetamol is contraindicated in patients with severe renal function impairment and hepatic disease (Viral Hepatitis). Known hypersensitivity to paracetamol or caffeine.

Paracetamol & Caffeine should be given cautiously in the following cases: In patients with hepatic or renal failure, in patients taking other hepatotoxic medication. Prolonged use of the drug without consulting a physician should be avoided.

May reduce serum levels with anticonvulsants (e.g. phenytoin, barbiturates, carbamazepine). May enhance the anticoagulant effect of warfarin and other coumarins with prolonged use. Accelerated absorption with metoclopramide and domperidone. May increase serum levels with probenecid. May increase serum levels of chloramphenicol. May reduce absorption with colestyramine within 1 hr of admin. May cause severe hypothermia with phenothiazine.

Pregnant mothers should consult with doctors before taking Paracetamol & Caffeine. Paracetamol & Caffeine can be taken whilst breast feeding.

Symptoms of Paracetamol overdose in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 40 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur.

Store in a cool and dry place, protect from light and moisture.Keep all medicines out of the reach of the children.

The is indicated in the following condition-

• Headache
• Migraine
• Toothache
• Neuralgia
• Feverishness
• Period pain
• Sore throat
• Backache
• Help to reduce the temperature
• Aches and pain of colds and flu

Non opioid analgesics

This is a combination of Paracetamol and Caffeine. Paracetamol has analgesic and antipyretic properties with weak anti-inflammatory activity. Caffeine is an alkaloid which is a theophylline-like xanthine derivative. By intermolecular association with Paracetamol, Caffeine increases the solubility and transmembrane permeation of Paracetamol. In addition, Caffeine increases the pain threshold and tolerance of pain. Caffeine has also an intrinsic power to raise vessel tone in the brain, which provides another benefit to treat migraine and headache.

Adult dose: 1-2 tablets every 4-6 hours. Maximum dose: 8 tablets daily.
Child dose: Not recommended for children below 12 years.

Side effects of paracetamol are usually mild, though haematological reactions including thrombocytopenia, leukopenia, pancytopenia, neutropenia, and agranulocytosis have been reported. Pancreatitis, skin rashes, and other allergic reactions occur occasionally.

Paracetamol is contraindicated in patients with severe renal function impairment and hepatic disease (Viral Hepatitis). Known hypersensitivity to paracetamol or caffeine.

Paracetamol & Caffeine should be given cautiously in the following cases: In patients with hepatic or renal failure, in patients taking other hepatotoxic medication. Prolonged use of the drug without consulting a physician should be avoided.

May reduce serum levels with anticonvulsants (e.g. phenytoin, barbiturates, carbamazepine). May enhance the anticoagulant effect of warfarin and other coumarins with prolonged use. Accelerated absorption with metoclopramide and domperidone. May increase serum levels with probenecid. May increase serum levels of chloramphenicol. May reduce absorption with colestyramine within 1 hr of admin. May cause severe hypothermia with phenothiazine.

Pregnant mothers should consult with doctors before taking Paracetamol & Caffeine. Paracetamol & Caffeine can be taken whilst breast feeding.

Symptoms of Paracetamol overdose in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 40 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur.

Store in a cool and dry place, protect from light and moisture.Keep all medicines out of the reach of the children.