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Targeted Cancer Therapy, Tyrosine Kinase Inhibitor

Imatinib is a small molecule protein-tyrosine kinase inhibitor that potently inhibits the activity of the Bcr-Abl tyrosine kinase (TK), as well as several receptor TKs: Kit, the receptor for stem cell factor (SCF) coded for by the c-Kit proto-oncogene, the discoidin domain receptors (DDR1 and DDR2), the colony stimulating factor receptor (CSF-1R) and the platelet-derived growth factor receptors alpha and beta (PDGFR-alpha and PDGFR beta). Imatinib can also inhibit cellular events mediated by activation of these receptor kinases.

Absorption and Distribution: Imatinib is well absorbed after oral administration with Cmax achieved within 2 4 hours post-dose. Mean absolute bioavailability is 98%. Mean Imatinib AUC increases proportionally with increasing doses ranging from 25 mg to 1,000 mg. There is no significant change in the pharmacokinetics of Imatinib on repeated dosing, and accumulation is 1.5- to 2.5- fold at a steady state when Imatinib is dosed once daily. At clinically relevant concentrations of Imatinib, binding to plasma proteins in in vitro experiments is approximately 95%, mostly to albumin and 1-acid glycoprotein.

Metabolism: CYP3A4 is the major enzyme responsible for metabolism of Imatinib. Other cytochrome P450 enzymes, such as CYP1A2, CYP2D6, CYP2C9, and CYP2C19, play a minor role in its metabolism. The main circulating active metabolite in humans is the N-demethylated piperazine derivative, formed predominantly by CYP3A4. It shows in vitro potency similar to the parent Imatinib. The plasma AUC for this metabolite is about 15% of the AUC for Imatinib. The plasma protein binding of N-demethylated metabolite CGP74588 is similar to that of the parent compound.

Excretion: Imatinib elimination is predominately in the feces, mostly as metabolites. Based on the recovery of compound(s) after an oral 14C-labeled dose of Imatinib, approximately 81% of the dose was eliminated within 7 days, in feces (68% of dose) and urine (13% of dose). Unchanged Imatinib accounted for 25% of the dose (5% urine, 20% feces), the remainder being metabolites. Following oral administration in healthy volunteers, the elimination half-lives of Imatinib and its major active metabolite, the N-demethyl derivative (CGP74588), are approximately 18 and 40 hours, respectively.

Adults with Ph+ CML CP: 400 mg/day
Adults with Ph+ CML AP or BC: 600 mg/day
Pediatrics with Ph+ CML CP: 340 mg/m2/day
Adults with Ph+ ALL: 600 mg/day
Pediatrics with Ph+ ALL: 340 mg/m2/day
Adults with MDS/MPD: 400 mg/day
Adults with ASM: 100 mg/day or 400 mg/day
Adults with HES/CEL: 100 mg/day or 400 mg/day
Adults with DFSP: 800 mg/day
Adults with metastatic and/or unresectable GIST: 400 mg/day
Adjuvant treatment of adults with GIST: 400 mg/day
Patients with mild to moderate hepatic impairment: 400 mg/day
Patients with severe hepatic impairment: 300 mg/day

All doses of Imatinib should be taken with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day. Imatinib can be dissolved in water or apple juice for patients having difficulty swallowing. Daily dosing of 800 mg and above should be accomplished using the 400-mg tablet to reduce exposure to iron.

The following serious adverse reactions are described elsewhere in the labeling:

• Fluid Retention and Edema
• Hematologic Toxicity
• Congestive Heart Failure and Left Ventricular Dysfunction
• Hepatotoxicity
• Hemorrhage
• Gastrointestinal Disorders
• Hypereosinophilic Cardiac Toxicity
• Dermatologic Toxicities
• Hypothyroidism
• Growth Retardation in Children and Adolescents
• Tumor Lysis Syndrome
• Impairments Related to Driving and Using Machinery
• Renal Toxicity

Agents Inducing CYP3A Metabolism: Concomitant administration of Imatinib and strong CYP3A4 inducers may reduce total exposure of imatinib; consider alternative agents.

Agents Inhibiting CYP3A Metabolism: Concomitant administration of Imatinib and strong CYP3A4 inhibitors may result in a significant imatinib exposure increase. Grapefruit juice may also increase plasma concentrations of imatinib; avoid grapefruit juice).

Interactions with Drugs Metabolized by CYP3A4: Imatinib will increase plasma concentration of CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.). Use caution when administering Imatinib with CYP3A4 substrates that have a narrow therapeutic window. Because warfarin is metabolized by CYP2C9 and CYP3A4, use low-molecular weight or standard heparin instead of warfarin in patients who require anticoagulation.

Interactions with Drugs Metabolized by CYP2D6: Use caution when administering Imatinib with CYP2D6 substrates that have a narrow therapeutic window.

Women of childbearing potential: Women of childbearing potential must be advised to use effective contraception during treatment and for at least 15 days after stopping treatment with Imatinib.

Pregnancy: There are limited data on the use of imatinib in pregnant women. There have been post-marketing reports of spontaneous abortions and infant congenital anomalies from women who have taken Imatinib. Studies in animals have however shown reproductive toxicity and the potential risk for the foetus is unknown. Imatinib should not be used during pregnancy unless clearly necessary. If it is used during pregnancy, the patient must be informed of the potential risk to the foetus.

Breast-feeding: There is limited information on imatinib distribution on human milk. Studies in two breast feeding women revealed that both imatinib and its active metabolite can be distributed into human milk. The milk plasma ratio studied in a single patient was determined to be 0.5 for imatinib and 0.9 for the metabolite, suggesting greater distribution of the metabolite into the milk. Considering the combined concentration of imatinib and the metabolite and the maximum daily milk intake by infants, the total exposure would be expected to be low (-10% of a therapeutic dose). However, since the effects of low-dose exposure of the infant to imatinib are unknown, women should not breast-feed during treatment and for at least 15 days after stopping treatment with Imatinib.

Fertility: In non-clinical studies, the fertility of male and female rats was not affected, although effects on reproductive parameters were observed. Studies on patients receiving Imatinib and its effect on fertility and gametogenesis have not been performed. Patients concerned about their fertility on Imatinib treatment should consult with their physician.

Experience with doses higher than the recommended therapeutic dose is limited. In the event of overdose the patient should be observed and an appropriate symptomatic treatment given. Generally, the reported outcome in these cases was "improved" or "recovered". Events that have been reported at different dose ranges are as follows:

Adult Population:

• 1200 to 1600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhoea, rash, erythema, oedema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite.
• 1800 to 3200 mg (as high as 3200 mg daily for 6 days): Weakness, myalgia, increased creatine phosphokinase,
• increased bilirubin, gastrointestinal pain.
• 6400 mg (single dose): One case reported in the literature of one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, decreased neutrophil count, and increased transaminases.
• 8 to 10 g (single dose): Vomiting and gastrointestinal pain have been reported.

Paediatric population: One 3-year-old male exposed to a single dose of 400 mg experienced vomiting, diarrhoea and anorexia and another 3-year-old male exposed to a single dose of 980 mg experienced decreased white blood cell count and diarrhoea. In the event of overdose, the patient should be observed and appropriate supportive treatment given.

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

Targeted Cancer Therapy, Tyrosine Kinase Inhibitor

Imatinib is a small molecule protein-tyrosine kinase inhibitor that potently inhibits the activity of the Bcr-Abl tyrosine kinase (TK), as well as several receptor TKs: Kit, the receptor for stem cell factor (SCF) coded for by the c-Kit proto-oncogene, the discoidin domain receptors (DDR1 and DDR2), the colony stimulating factor receptor (CSF-1R) and the platelet-derived growth factor receptors alpha and beta (PDGFR-alpha and PDGFR beta). Imatinib can also inhibit cellular events mediated by activation of these receptor kinases.

Absorption and Distribution: Imatinib is well absorbed after oral administration with Cmax achieved within 2 4 hours post-dose. Mean absolute bioavailability is 98%. Mean Imatinib AUC increases proportionally with increasing doses ranging from 25 mg to 1,000 mg. There is no significant change in the pharmacokinetics of Imatinib on repeated dosing, and accumulation is 1.5- to 2.5- fold at a steady state when Imatinib is dosed once daily. At clinically relevant concentrations of Imatinib, binding to plasma proteins in in vitro experiments is approximately 95%, mostly to albumin and 1-acid glycoprotein.

Metabolism: CYP3A4 is the major enzyme responsible for metabolism of Imatinib. Other cytochrome P450 enzymes, such as CYP1A2, CYP2D6, CYP2C9, and CYP2C19, play a minor role in its metabolism. The main circulating active metabolite in humans is the N-demethylated piperazine derivative, formed predominantly by CYP3A4. It shows in vitro potency similar to the parent Imatinib. The plasma AUC for this metabolite is about 15% of the AUC for Imatinib. The plasma protein binding of N-demethylated metabolite CGP74588 is similar to that of the parent compound.

Excretion: Imatinib elimination is predominately in the feces, mostly as metabolites. Based on the recovery of compound(s) after an oral 14C-labeled dose of Imatinib, approximately 81% of the dose was eliminated within 7 days, in feces (68% of dose) and urine (13% of dose). Unchanged Imatinib accounted for 25% of the dose (5% urine, 20% feces), the remainder being metabolites. Following oral administration in healthy volunteers, the elimination half-lives of Imatinib and its major active metabolite, the N-demethyl derivative (CGP74588), are approximately 18 and 40 hours, respectively.

Adults with Ph+ CML CP: 400 mg/day
Adults with Ph+ CML AP or BC: 600 mg/day
Pediatrics with Ph+ CML CP: 340 mg/m2/day
Adults with Ph+ ALL: 600 mg/day
Pediatrics with Ph+ ALL: 340 mg/m2/day
Adults with MDS/MPD: 400 mg/day
Adults with ASM: 100 mg/day or 400 mg/day
Adults with HES/CEL: 100 mg/day or 400 mg/day
Adults with DFSP: 800 mg/day
Adults with metastatic and/or unresectable GIST: 400 mg/day
Adjuvant treatment of adults with GIST: 400 mg/day
Patients with mild to moderate hepatic impairment: 400 mg/day
Patients with severe hepatic impairment: 300 mg/day

All doses of Imatinib should be taken with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day. Imatinib can be dissolved in water or apple juice for patients having difficulty swallowing. Daily dosing of 800 mg and above should be accomplished using the 400-mg tablet to reduce exposure to iron.

The following serious adverse reactions are described elsewhere in the labeling:

• Fluid Retention and Edema
• Hematologic Toxicity
• Congestive Heart Failure and Left Ventricular Dysfunction
• Hepatotoxicity
• Hemorrhage
• Gastrointestinal Disorders
• Hypereosinophilic Cardiac Toxicity
• Dermatologic Toxicities
• Hypothyroidism
• Growth Retardation in Children and Adolescents
• Tumor Lysis Syndrome
• Impairments Related to Driving and Using Machinery
• Renal Toxicity

Agents Inducing CYP3A Metabolism: Concomitant administration of Imatinib and strong CYP3A4 inducers may reduce total exposure of imatinib; consider alternative agents.

Agents Inhibiting CYP3A Metabolism: Concomitant administration of Imatinib and strong CYP3A4 inhibitors may result in a significant imatinib exposure increase. Grapefruit juice may also increase plasma concentrations of imatinib; avoid grapefruit juice).

Interactions with Drugs Metabolized by CYP3A4: Imatinib will increase plasma concentration of CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.). Use caution when administering Imatinib with CYP3A4 substrates that have a narrow therapeutic window. Because warfarin is metabolized by CYP2C9 and CYP3A4, use low-molecular weight or standard heparin instead of warfarin in patients who require anticoagulation.

Interactions with Drugs Metabolized by CYP2D6: Use caution when administering Imatinib with CYP2D6 substrates that have a narrow therapeutic window.

Women of childbearing potential: Women of childbearing potential must be advised to use effective contraception during treatment and for at least 15 days after stopping treatment with Imatinib.

Pregnancy: There are limited data on the use of imatinib in pregnant women. There have been post-marketing reports of spontaneous abortions and infant congenital anomalies from women who have taken Imatinib. Studies in animals have however shown reproductive toxicity and the potential risk for the foetus is unknown. Imatinib should not be used during pregnancy unless clearly necessary. If it is used during pregnancy, the patient must be informed of the potential risk to the foetus.

Breast-feeding: There is limited information on imatinib distribution on human milk. Studies in two breast feeding women revealed that both imatinib and its active metabolite can be distributed into human milk. The milk plasma ratio studied in a single patient was determined to be 0.5 for imatinib and 0.9 for the metabolite, suggesting greater distribution of the metabolite into the milk. Considering the combined concentration of imatinib and the metabolite and the maximum daily milk intake by infants, the total exposure would be expected to be low (-10% of a therapeutic dose). However, since the effects of low-dose exposure of the infant to imatinib are unknown, women should not breast-feed during treatment and for at least 15 days after stopping treatment with Imatinib.

Fertility: In non-clinical studies, the fertility of male and female rats was not affected, although effects on reproductive parameters were observed. Studies on patients receiving Imatinib and its effect on fertility and gametogenesis have not been performed. Patients concerned about their fertility on Imatinib treatment should consult with their physician.

Experience with doses higher than the recommended therapeutic dose is limited. In the event of overdose the patient should be observed and an appropriate symptomatic treatment given. Generally, the reported outcome in these cases was "improved" or "recovered". Events that have been reported at different dose ranges are as follows:

Adult Population:

• 1200 to 1600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhoea, rash, erythema, oedema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite.
• 1800 to 3200 mg (as high as 3200 mg daily for 6 days): Weakness, myalgia, increased creatine phosphokinase,
• increased bilirubin, gastrointestinal pain.
• 6400 mg (single dose): One case reported in the literature of one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, decreased neutrophil count, and increased transaminases.
• 8 to 10 g (single dose): Vomiting and gastrointestinal pain have been reported.

Paediatric population: One 3-year-old male exposed to a single dose of 400 mg experienced vomiting, diarrhoea and anorexia and another 3-year-old male exposed to a single dose of 980 mg experienced decreased white blood cell count and diarrhoea. In the event of overdose, the patient should be observed and appropriate supportive treatment given.

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

Targeted Cancer Therapy, Tyrosine Kinase Inhibitor

Imatinib is a small molecule protein-tyrosine kinase inhibitor that potently inhibits the activity of the Bcr-Abl tyrosine kinase (TK), as well as several receptor TKs: Kit, the receptor for stem cell factor (SCF) coded for by the c-Kit proto-oncogene, the discoidin domain receptors (DDR1 and DDR2), the colony stimulating factor receptor (CSF-1R) and the platelet-derived growth factor receptors alpha and beta (PDGFR-alpha and PDGFR beta). Imatinib can also inhibit cellular events mediated by activation of these receptor kinases.

Absorption and Distribution: Imatinib is well absorbed after oral administration with Cmax achieved within 2 4 hours post-dose. Mean absolute bioavailability is 98%. Mean Imatinib AUC increases proportionally with increasing doses ranging from 25 mg to 1,000 mg. There is no significant change in the pharmacokinetics of Imatinib on repeated dosing, and accumulation is 1.5- to 2.5- fold at a steady state when Imatinib is dosed once daily. At clinically relevant concentrations of Imatinib, binding to plasma proteins in in vitro experiments is approximately 95%, mostly to albumin and 1-acid glycoprotein.

Metabolism: CYP3A4 is the major enzyme responsible for metabolism of Imatinib. Other cytochrome P450 enzymes, such as CYP1A2, CYP2D6, CYP2C9, and CYP2C19, play a minor role in its metabolism. The main circulating active metabolite in humans is the N-demethylated piperazine derivative, formed predominantly by CYP3A4. It shows in vitro potency similar to the parent Imatinib. The plasma AUC for this metabolite is about 15% of the AUC for Imatinib. The plasma protein binding of N-demethylated metabolite CGP74588 is similar to that of the parent compound.

Excretion: Imatinib elimination is predominately in the feces, mostly as metabolites. Based on the recovery of compound(s) after an oral 14C-labeled dose of Imatinib, approximately 81% of the dose was eliminated within 7 days, in feces (68% of dose) and urine (13% of dose). Unchanged Imatinib accounted for 25% of the dose (5% urine, 20% feces), the remainder being metabolites. Following oral administration in healthy volunteers, the elimination half-lives of Imatinib and its major active metabolite, the N-demethyl derivative (CGP74588), are approximately 18 and 40 hours, respectively.

Adults with Ph+ CML CP: 400 mg/day
Adults with Ph+ CML AP or BC: 600 mg/day
Pediatrics with Ph+ CML CP: 340 mg/m2/day
Adults with Ph+ ALL: 600 mg/day
Pediatrics with Ph+ ALL: 340 mg/m2/day
Adults with MDS/MPD: 400 mg/day
Adults with ASM: 100 mg/day or 400 mg/day
Adults with HES/CEL: 100 mg/day or 400 mg/day
Adults with DFSP: 800 mg/day
Adults with metastatic and/or unresectable GIST: 400 mg/day
Adjuvant treatment of adults with GIST: 400 mg/day
Patients with mild to moderate hepatic impairment: 400 mg/day
Patients with severe hepatic impairment: 300 mg/day

All doses of Imatinib should be taken with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day. Imatinib can be dissolved in water or apple juice for patients having difficulty swallowing. Daily dosing of 800 mg and above should be accomplished using the 400-mg tablet to reduce exposure to iron.

The following serious adverse reactions are described elsewhere in the labeling:

• Fluid Retention and Edema
• Hematologic Toxicity
• Congestive Heart Failure and Left Ventricular Dysfunction
• Hepatotoxicity
• Hemorrhage
• Gastrointestinal Disorders
• Hypereosinophilic Cardiac Toxicity
• Dermatologic Toxicities
• Hypothyroidism
• Growth Retardation in Children and Adolescents
• Tumor Lysis Syndrome
• Impairments Related to Driving and Using Machinery
• Renal Toxicity

Agents Inducing CYP3A Metabolism: Concomitant administration of Imatinib and strong CYP3A4 inducers may reduce total exposure of imatinib; consider alternative agents.

Agents Inhibiting CYP3A Metabolism: Concomitant administration of Imatinib and strong CYP3A4 inhibitors may result in a significant imatinib exposure increase. Grapefruit juice may also increase plasma concentrations of imatinib; avoid grapefruit juice).

Interactions with Drugs Metabolized by CYP3A4: Imatinib will increase plasma concentration of CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.). Use caution when administering Imatinib with CYP3A4 substrates that have a narrow therapeutic window. Because warfarin is metabolized by CYP2C9 and CYP3A4, use low-molecular weight or standard heparin instead of warfarin in patients who require anticoagulation.

Interactions with Drugs Metabolized by CYP2D6: Use caution when administering Imatinib with CYP2D6 substrates that have a narrow therapeutic window.

Women of childbearing potential: Women of childbearing potential must be advised to use effective contraception during treatment and for at least 15 days after stopping treatment with Imatinib.

Pregnancy: There are limited data on the use of imatinib in pregnant women. There have been post-marketing reports of spontaneous abortions and infant congenital anomalies from women who have taken Imatinib. Studies in animals have however shown reproductive toxicity and the potential risk for the foetus is unknown. Imatinib should not be used during pregnancy unless clearly necessary. If it is used during pregnancy, the patient must be informed of the potential risk to the foetus.

Breast-feeding: There is limited information on imatinib distribution on human milk. Studies in two breast feeding women revealed that both imatinib and its active metabolite can be distributed into human milk. The milk plasma ratio studied in a single patient was determined to be 0.5 for imatinib and 0.9 for the metabolite, suggesting greater distribution of the metabolite into the milk. Considering the combined concentration of imatinib and the metabolite and the maximum daily milk intake by infants, the total exposure would be expected to be low (-10% of a therapeutic dose). However, since the effects of low-dose exposure of the infant to imatinib are unknown, women should not breast-feed during treatment and for at least 15 days after stopping treatment with Imatinib.

Fertility: In non-clinical studies, the fertility of male and female rats was not affected, although effects on reproductive parameters were observed. Studies on patients receiving Imatinib and its effect on fertility and gametogenesis have not been performed. Patients concerned about their fertility on Imatinib treatment should consult with their physician.

Experience with doses higher than the recommended therapeutic dose is limited. In the event of overdose the patient should be observed and an appropriate symptomatic treatment given. Generally, the reported outcome in these cases was "improved" or "recovered". Events that have been reported at different dose ranges are as follows:

Adult Population:

• 1200 to 1600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhoea, rash, erythema, oedema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite.
• 1800 to 3200 mg (as high as 3200 mg daily for 6 days): Weakness, myalgia, increased creatine phosphokinase,
• increased bilirubin, gastrointestinal pain.
• 6400 mg (single dose): One case reported in the literature of one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, decreased neutrophil count, and increased transaminases.
• 8 to 10 g (single dose): Vomiting and gastrointestinal pain have been reported.

Paediatric population: One 3-year-old male exposed to a single dose of 400 mg experienced vomiting, diarrhoea and anorexia and another 3-year-old male exposed to a single dose of 980 mg experienced decreased white blood cell count and diarrhoea. In the event of overdose, the patient should be observed and appropriate supportive treatment given.

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

Targeted Cancer Therapy, Tyrosine Kinase Inhibitor

Imatinib is a small molecule protein-tyrosine kinase inhibitor that potently inhibits the activity of the Bcr-Abl tyrosine kinase (TK), as well as several receptor TKs: Kit, the receptor for stem cell factor (SCF) coded for by the c-Kit proto-oncogene, the discoidin domain receptors (DDR1 and DDR2), the colony stimulating factor receptor (CSF-1R) and the platelet-derived growth factor receptors alpha and beta (PDGFR-alpha and PDGFR beta). Imatinib can also inhibit cellular events mediated by activation of these receptor kinases.

Absorption and Distribution: Imatinib is well absorbed after oral administration with Cmax achieved within 2 4 hours post-dose. Mean absolute bioavailability is 98%. Mean Imatinib AUC increases proportionally with increasing doses ranging from 25 mg to 1,000 mg. There is no significant change in the pharmacokinetics of Imatinib on repeated dosing, and accumulation is 1.5- to 2.5- fold at a steady state when Imatinib is dosed once daily. At clinically relevant concentrations of Imatinib, binding to plasma proteins in in vitro experiments is approximately 95%, mostly to albumin and 1-acid glycoprotein.

Metabolism: CYP3A4 is the major enzyme responsible for metabolism of Imatinib. Other cytochrome P450 enzymes, such as CYP1A2, CYP2D6, CYP2C9, and CYP2C19, play a minor role in its metabolism. The main circulating active metabolite in humans is the N-demethylated piperazine derivative, formed predominantly by CYP3A4. It shows in vitro potency similar to the parent Imatinib. The plasma AUC for this metabolite is about 15% of the AUC for Imatinib. The plasma protein binding of N-demethylated metabolite CGP74588 is similar to that of the parent compound.

Excretion: Imatinib elimination is predominately in the feces, mostly as metabolites. Based on the recovery of compound(s) after an oral 14C-labeled dose of Imatinib, approximately 81% of the dose was eliminated within 7 days, in feces (68% of dose) and urine (13% of dose). Unchanged Imatinib accounted for 25% of the dose (5% urine, 20% feces), the remainder being metabolites. Following oral administration in healthy volunteers, the elimination half-lives of Imatinib and its major active metabolite, the N-demethyl derivative (CGP74588), are approximately 18 and 40 hours, respectively.

Adults with Ph+ CML CP: 400 mg/day
Adults with Ph+ CML AP or BC: 600 mg/day
Pediatrics with Ph+ CML CP: 340 mg/m2/day
Adults with Ph+ ALL: 600 mg/day
Pediatrics with Ph+ ALL: 340 mg/m2/day
Adults with MDS/MPD: 400 mg/day
Adults with ASM: 100 mg/day or 400 mg/day
Adults with HES/CEL: 100 mg/day or 400 mg/day
Adults with DFSP: 800 mg/day
Adults with metastatic and/or unresectable GIST: 400 mg/day
Adjuvant treatment of adults with GIST: 400 mg/day
Patients with mild to moderate hepatic impairment: 400 mg/day
Patients with severe hepatic impairment: 300 mg/day

All doses of Imatinib should be taken with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day. Imatinib can be dissolved in water or apple juice for patients having difficulty swallowing. Daily dosing of 800 mg and above should be accomplished using the 400-mg tablet to reduce exposure to iron.

The following serious adverse reactions are described elsewhere in the labeling:

• Fluid Retention and Edema
• Hematologic Toxicity
• Congestive Heart Failure and Left Ventricular Dysfunction
• Hepatotoxicity
• Hemorrhage
• Gastrointestinal Disorders
• Hypereosinophilic Cardiac Toxicity
• Dermatologic Toxicities
• Hypothyroidism
• Growth Retardation in Children and Adolescents
• Tumor Lysis Syndrome
• Impairments Related to Driving and Using Machinery
• Renal Toxicity

Agents Inducing CYP3A Metabolism: Concomitant administration of Imatinib and strong CYP3A4 inducers may reduce total exposure of imatinib; consider alternative agents.

Agents Inhibiting CYP3A Metabolism: Concomitant administration of Imatinib and strong CYP3A4 inhibitors may result in a significant imatinib exposure increase. Grapefruit juice may also increase plasma concentrations of imatinib; avoid grapefruit juice).

Interactions with Drugs Metabolized by CYP3A4: Imatinib will increase plasma concentration of CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.). Use caution when administering Imatinib with CYP3A4 substrates that have a narrow therapeutic window. Because warfarin is metabolized by CYP2C9 and CYP3A4, use low-molecular weight or standard heparin instead of warfarin in patients who require anticoagulation.

Interactions with Drugs Metabolized by CYP2D6: Use caution when administering Imatinib with CYP2D6 substrates that have a narrow therapeutic window.

Women of childbearing potential: Women of childbearing potential must be advised to use effective contraception during treatment and for at least 15 days after stopping treatment with Imatinib.

Pregnancy: There are limited data on the use of imatinib in pregnant women. There have been post-marketing reports of spontaneous abortions and infant congenital anomalies from women who have taken Imatinib. Studies in animals have however shown reproductive toxicity and the potential risk for the foetus is unknown. Imatinib should not be used during pregnancy unless clearly necessary. If it is used during pregnancy, the patient must be informed of the potential risk to the foetus.

Breast-feeding: There is limited information on imatinib distribution on human milk. Studies in two breast feeding women revealed that both imatinib and its active metabolite can be distributed into human milk. The milk plasma ratio studied in a single patient was determined to be 0.5 for imatinib and 0.9 for the metabolite, suggesting greater distribution of the metabolite into the milk. Considering the combined concentration of imatinib and the metabolite and the maximum daily milk intake by infants, the total exposure would be expected to be low (-10% of a therapeutic dose). However, since the effects of low-dose exposure of the infant to imatinib are unknown, women should not breast-feed during treatment and for at least 15 days after stopping treatment with Imatinib.

Fertility: In non-clinical studies, the fertility of male and female rats was not affected, although effects on reproductive parameters were observed. Studies on patients receiving Imatinib and its effect on fertility and gametogenesis have not been performed. Patients concerned about their fertility on Imatinib treatment should consult with their physician.

Experience with doses higher than the recommended therapeutic dose is limited. In the event of overdose the patient should be observed and an appropriate symptomatic treatment given. Generally, the reported outcome in these cases was "improved" or "recovered". Events that have been reported at different dose ranges are as follows:

Adult Population:

• 1200 to 1600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhoea, rash, erythema, oedema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite.
• 1800 to 3200 mg (as high as 3200 mg daily for 6 days): Weakness, myalgia, increased creatine phosphokinase,
• increased bilirubin, gastrointestinal pain.
• 6400 mg (single dose): One case reported in the literature of one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, decreased neutrophil count, and increased transaminases.
• 8 to 10 g (single dose): Vomiting and gastrointestinal pain have been reported.

Paediatric population: One 3-year-old male exposed to a single dose of 400 mg experienced vomiting, diarrhoea and anorexia and another 3-year-old male exposed to a single dose of 980 mg experienced decreased white blood cell count and diarrhoea. In the event of overdose, the patient should be observed and appropriate supportive treatment given.

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

Targeted Cancer Therapy, Tyrosine Kinase Inhibitor

Imatinib is a small molecule protein-tyrosine kinase inhibitor that potently inhibits the activity of the Bcr-Abl tyrosine kinase (TK), as well as several receptor TKs: Kit, the receptor for stem cell factor (SCF) coded for by the c-Kit proto-oncogene, the discoidin domain receptors (DDR1 and DDR2), the colony stimulating factor receptor (CSF-1R) and the platelet-derived growth factor receptors alpha and beta (PDGFR-alpha and PDGFR beta). Imatinib can also inhibit cellular events mediated by activation of these receptor kinases.

Absorption and Distribution: Imatinib is well absorbed after oral administration with Cmax achieved within 2 4 hours post-dose. Mean absolute bioavailability is 98%. Mean Imatinib AUC increases proportionally with increasing doses ranging from 25 mg to 1,000 mg. There is no significant change in the pharmacokinetics of Imatinib on repeated dosing, and accumulation is 1.5- to 2.5- fold at a steady state when Imatinib is dosed once daily. At clinically relevant concentrations of Imatinib, binding to plasma proteins in in vitro experiments is approximately 95%, mostly to albumin and 1-acid glycoprotein.

Metabolism: CYP3A4 is the major enzyme responsible for metabolism of Imatinib. Other cytochrome P450 enzymes, such as CYP1A2, CYP2D6, CYP2C9, and CYP2C19, play a minor role in its metabolism. The main circulating active metabolite in humans is the N-demethylated piperazine derivative, formed predominantly by CYP3A4. It shows in vitro potency similar to the parent Imatinib. The plasma AUC for this metabolite is about 15% of the AUC for Imatinib. The plasma protein binding of N-demethylated metabolite CGP74588 is similar to that of the parent compound.

Excretion: Imatinib elimination is predominately in the feces, mostly as metabolites. Based on the recovery of compound(s) after an oral 14C-labeled dose of Imatinib, approximately 81% of the dose was eliminated within 7 days, in feces (68% of dose) and urine (13% of dose). Unchanged Imatinib accounted for 25% of the dose (5% urine, 20% feces), the remainder being metabolites. Following oral administration in healthy volunteers, the elimination half-lives of Imatinib and its major active metabolite, the N-demethyl derivative (CGP74588), are approximately 18 and 40 hours, respectively.

Adults with Ph+ CML CP: 400 mg/day
Adults with Ph+ CML AP or BC: 600 mg/day
Pediatrics with Ph+ CML CP: 340 mg/m2/day
Adults with Ph+ ALL: 600 mg/day
Pediatrics with Ph+ ALL: 340 mg/m2/day
Adults with MDS/MPD: 400 mg/day
Adults with ASM: 100 mg/day or 400 mg/day
Adults with HES/CEL: 100 mg/day or 400 mg/day
Adults with DFSP: 800 mg/day
Adults with metastatic and/or unresectable GIST: 400 mg/day
Adjuvant treatment of adults with GIST: 400 mg/day
Patients with mild to moderate hepatic impairment: 400 mg/day
Patients with severe hepatic impairment: 300 mg/day

All doses of Imatinib should be taken with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day. Imatinib can be dissolved in water or apple juice for patients having difficulty swallowing. Daily dosing of 800 mg and above should be accomplished using the 400-mg tablet to reduce exposure to iron.

The following serious adverse reactions are described elsewhere in the labeling:

• Fluid Retention and Edema
• Hematologic Toxicity
• Congestive Heart Failure and Left Ventricular Dysfunction
• Hepatotoxicity
• Hemorrhage
• Gastrointestinal Disorders
• Hypereosinophilic Cardiac Toxicity
• Dermatologic Toxicities
• Hypothyroidism
• Growth Retardation in Children and Adolescents
• Tumor Lysis Syndrome
• Impairments Related to Driving and Using Machinery
• Renal Toxicity

Agents Inducing CYP3A Metabolism: Concomitant administration of Imatinib and strong CYP3A4 inducers may reduce total exposure of imatinib; consider alternative agents.

Agents Inhibiting CYP3A Metabolism: Concomitant administration of Imatinib and strong CYP3A4 inhibitors may result in a significant imatinib exposure increase. Grapefruit juice may also increase plasma concentrations of imatinib; avoid grapefruit juice).

Interactions with Drugs Metabolized by CYP3A4: Imatinib will increase plasma concentration of CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.). Use caution when administering Imatinib with CYP3A4 substrates that have a narrow therapeutic window. Because warfarin is metabolized by CYP2C9 and CYP3A4, use low-molecular weight or standard heparin instead of warfarin in patients who require anticoagulation.

Interactions with Drugs Metabolized by CYP2D6: Use caution when administering Imatinib with CYP2D6 substrates that have a narrow therapeutic window.

Women of childbearing potential: Women of childbearing potential must be advised to use effective contraception during treatment and for at least 15 days after stopping treatment with Imatinib.

Pregnancy: There are limited data on the use of imatinib in pregnant women. There have been post-marketing reports of spontaneous abortions and infant congenital anomalies from women who have taken Imatinib. Studies in animals have however shown reproductive toxicity and the potential risk for the foetus is unknown. Imatinib should not be used during pregnancy unless clearly necessary. If it is used during pregnancy, the patient must be informed of the potential risk to the foetus.

Breast-feeding: There is limited information on imatinib distribution on human milk. Studies in two breast feeding women revealed that both imatinib and its active metabolite can be distributed into human milk. The milk plasma ratio studied in a single patient was determined to be 0.5 for imatinib and 0.9 for the metabolite, suggesting greater distribution of the metabolite into the milk. Considering the combined concentration of imatinib and the metabolite and the maximum daily milk intake by infants, the total exposure would be expected to be low (-10% of a therapeutic dose). However, since the effects of low-dose exposure of the infant to imatinib are unknown, women should not breast-feed during treatment and for at least 15 days after stopping treatment with Imatinib.

Fertility: In non-clinical studies, the fertility of male and female rats was not affected, although effects on reproductive parameters were observed. Studies on patients receiving Imatinib and its effect on fertility and gametogenesis have not been performed. Patients concerned about their fertility on Imatinib treatment should consult with their physician.

Experience with doses higher than the recommended therapeutic dose is limited. In the event of overdose the patient should be observed and an appropriate symptomatic treatment given. Generally, the reported outcome in these cases was "improved" or "recovered". Events that have been reported at different dose ranges are as follows:

Adult Population:

• 1200 to 1600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhoea, rash, erythema, oedema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite.
• 1800 to 3200 mg (as high as 3200 mg daily for 6 days): Weakness, myalgia, increased creatine phosphokinase,
• increased bilirubin, gastrointestinal pain.
• 6400 mg (single dose): One case reported in the literature of one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, decreased neutrophil count, and increased transaminases.
• 8 to 10 g (single dose): Vomiting and gastrointestinal pain have been reported.

Paediatric population: One 3-year-old male exposed to a single dose of 400 mg experienced vomiting, diarrhoea and anorexia and another 3-year-old male exposed to a single dose of 980 mg experienced decreased white blood cell count and diarrhoea. In the event of overdose, the patient should be observed and appropriate supportive treatment given.

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

Targeted Cancer Therapy, Tyrosine Kinase Inhibitor

Imatinib is a small molecule protein-tyrosine kinase inhibitor that potently inhibits the activity of the Bcr-Abl tyrosine kinase (TK), as well as several receptor TKs: Kit, the receptor for stem cell factor (SCF) coded for by the c-Kit proto-oncogene, the discoidin domain receptors (DDR1 and DDR2), the colony stimulating factor receptor (CSF-1R) and the platelet-derived growth factor receptors alpha and beta (PDGFR-alpha and PDGFR beta). Imatinib can also inhibit cellular events mediated by activation of these receptor kinases.

Absorption and Distribution: Imatinib is well absorbed after oral administration with Cmax achieved within 2 4 hours post-dose. Mean absolute bioavailability is 98%. Mean Imatinib AUC increases proportionally with increasing doses ranging from 25 mg to 1,000 mg. There is no significant change in the pharmacokinetics of Imatinib on repeated dosing, and accumulation is 1.5- to 2.5- fold at a steady state when Imatinib is dosed once daily. At clinically relevant concentrations of Imatinib, binding to plasma proteins in in vitro experiments is approximately 95%, mostly to albumin and 1-acid glycoprotein.

Metabolism: CYP3A4 is the major enzyme responsible for metabolism of Imatinib. Other cytochrome P450 enzymes, such as CYP1A2, CYP2D6, CYP2C9, and CYP2C19, play a minor role in its metabolism. The main circulating active metabolite in humans is the N-demethylated piperazine derivative, formed predominantly by CYP3A4. It shows in vitro potency similar to the parent Imatinib. The plasma AUC for this metabolite is about 15% of the AUC for Imatinib. The plasma protein binding of N-demethylated metabolite CGP74588 is similar to that of the parent compound.

Excretion: Imatinib elimination is predominately in the feces, mostly as metabolites. Based on the recovery of compound(s) after an oral 14C-labeled dose of Imatinib, approximately 81% of the dose was eliminated within 7 days, in feces (68% of dose) and urine (13% of dose). Unchanged Imatinib accounted for 25% of the dose (5% urine, 20% feces), the remainder being metabolites. Following oral administration in healthy volunteers, the elimination half-lives of Imatinib and its major active metabolite, the N-demethyl derivative (CGP74588), are approximately 18 and 40 hours, respectively.

Adults with Ph+ CML CP: 400 mg/day
Adults with Ph+ CML AP or BC: 600 mg/day
Pediatrics with Ph+ CML CP: 340 mg/m2/day
Adults with Ph+ ALL: 600 mg/day
Pediatrics with Ph+ ALL: 340 mg/m2/day
Adults with MDS/MPD: 400 mg/day
Adults with ASM: 100 mg/day or 400 mg/day
Adults with HES/CEL: 100 mg/day or 400 mg/day
Adults with DFSP: 800 mg/day
Adults with metastatic and/or unresectable GIST: 400 mg/day
Adjuvant treatment of adults with GIST: 400 mg/day
Patients with mild to moderate hepatic impairment: 400 mg/day
Patients with severe hepatic impairment: 300 mg/day

All doses of Imatinib should be taken with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day. Imatinib can be dissolved in water or apple juice for patients having difficulty swallowing. Daily dosing of 800 mg and above should be accomplished using the 400-mg tablet to reduce exposure to iron.

The following serious adverse reactions are described elsewhere in the labeling:

• Fluid Retention and Edema
• Hematologic Toxicity
• Congestive Heart Failure and Left Ventricular Dysfunction
• Hepatotoxicity
• Hemorrhage
• Gastrointestinal Disorders
• Hypereosinophilic Cardiac Toxicity
• Dermatologic Toxicities
• Hypothyroidism
• Growth Retardation in Children and Adolescents
• Tumor Lysis Syndrome
• Impairments Related to Driving and Using Machinery
• Renal Toxicity

Agents Inducing CYP3A Metabolism: Concomitant administration of Imatinib and strong CYP3A4 inducers may reduce total exposure of imatinib; consider alternative agents.

Agents Inhibiting CYP3A Metabolism: Concomitant administration of Imatinib and strong CYP3A4 inhibitors may result in a significant imatinib exposure increase. Grapefruit juice may also increase plasma concentrations of imatinib; avoid grapefruit juice).

Interactions with Drugs Metabolized by CYP3A4: Imatinib will increase plasma concentration of CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.). Use caution when administering Imatinib with CYP3A4 substrates that have a narrow therapeutic window. Because warfarin is metabolized by CYP2C9 and CYP3A4, use low-molecular weight or standard heparin instead of warfarin in patients who require anticoagulation.

Interactions with Drugs Metabolized by CYP2D6: Use caution when administering Imatinib with CYP2D6 substrates that have a narrow therapeutic window.

Women of childbearing potential: Women of childbearing potential must be advised to use effective contraception during treatment and for at least 15 days after stopping treatment with Imatinib.

Pregnancy: There are limited data on the use of imatinib in pregnant women. There have been post-marketing reports of spontaneous abortions and infant congenital anomalies from women who have taken Imatinib. Studies in animals have however shown reproductive toxicity and the potential risk for the foetus is unknown. Imatinib should not be used during pregnancy unless clearly necessary. If it is used during pregnancy, the patient must be informed of the potential risk to the foetus.

Breast-feeding: There is limited information on imatinib distribution on human milk. Studies in two breast feeding women revealed that both imatinib and its active metabolite can be distributed into human milk. The milk plasma ratio studied in a single patient was determined to be 0.5 for imatinib and 0.9 for the metabolite, suggesting greater distribution of the metabolite into the milk. Considering the combined concentration of imatinib and the metabolite and the maximum daily milk intake by infants, the total exposure would be expected to be low (-10% of a therapeutic dose). However, since the effects of low-dose exposure of the infant to imatinib are unknown, women should not breast-feed during treatment and for at least 15 days after stopping treatment with Imatinib.

Fertility: In non-clinical studies, the fertility of male and female rats was not affected, although effects on reproductive parameters were observed. Studies on patients receiving Imatinib and its effect on fertility and gametogenesis have not been performed. Patients concerned about their fertility on Imatinib treatment should consult with their physician.

Experience with doses higher than the recommended therapeutic dose is limited. In the event of overdose the patient should be observed and an appropriate symptomatic treatment given. Generally, the reported outcome in these cases was "improved" or "recovered". Events that have been reported at different dose ranges are as follows:

Adult Population:

• 1200 to 1600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhoea, rash, erythema, oedema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite.
• 1800 to 3200 mg (as high as 3200 mg daily for 6 days): Weakness, myalgia, increased creatine phosphokinase,
• increased bilirubin, gastrointestinal pain.
• 6400 mg (single dose): One case reported in the literature of one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, decreased neutrophil count, and increased transaminases.
• 8 to 10 g (single dose): Vomiting and gastrointestinal pain have been reported.

Paediatric population: One 3-year-old male exposed to a single dose of 400 mg experienced vomiting, diarrhoea and anorexia and another 3-year-old male exposed to a single dose of 980 mg experienced decreased white blood cell count and diarrhoea. In the event of overdose, the patient should be observed and appropriate supportive treatment given.

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

Targeted Cancer Therapy, Tyrosine Kinase Inhibitor

Imatinib is a small molecule protein-tyrosine kinase inhibitor that potently inhibits the activity of the Bcr-Abl tyrosine kinase (TK), as well as several receptor TKs: Kit, the receptor for stem cell factor (SCF) coded for by the c-Kit proto-oncogene, the discoidin domain receptors (DDR1 and DDR2), the colony stimulating factor receptor (CSF-1R) and the platelet-derived growth factor receptors alpha and beta (PDGFR-alpha and PDGFR beta). Imatinib can also inhibit cellular events mediated by activation of these receptor kinases.

Absorption and Distribution: Imatinib is well absorbed after oral administration with Cmax achieved within 2 4 hours post-dose. Mean absolute bioavailability is 98%. Mean Imatinib AUC increases proportionally with increasing doses ranging from 25 mg to 1,000 mg. There is no significant change in the pharmacokinetics of Imatinib on repeated dosing, and accumulation is 1.5- to 2.5- fold at a steady state when Imatinib is dosed once daily. At clinically relevant concentrations of Imatinib, binding to plasma proteins in in vitro experiments is approximately 95%, mostly to albumin and 1-acid glycoprotein.

Metabolism: CYP3A4 is the major enzyme responsible for metabolism of Imatinib. Other cytochrome P450 enzymes, such as CYP1A2, CYP2D6, CYP2C9, and CYP2C19, play a minor role in its metabolism. The main circulating active metabolite in humans is the N-demethylated piperazine derivative, formed predominantly by CYP3A4. It shows in vitro potency similar to the parent Imatinib. The plasma AUC for this metabolite is about 15% of the AUC for Imatinib. The plasma protein binding of N-demethylated metabolite CGP74588 is similar to that of the parent compound.

Excretion: Imatinib elimination is predominately in the feces, mostly as metabolites. Based on the recovery of compound(s) after an oral 14C-labeled dose of Imatinib, approximately 81% of the dose was eliminated within 7 days, in feces (68% of dose) and urine (13% of dose). Unchanged Imatinib accounted for 25% of the dose (5% urine, 20% feces), the remainder being metabolites. Following oral administration in healthy volunteers, the elimination half-lives of Imatinib and its major active metabolite, the N-demethyl derivative (CGP74588), are approximately 18 and 40 hours, respectively.

Adults with Ph+ CML CP: 400 mg/day
Adults with Ph+ CML AP or BC: 600 mg/day
Pediatrics with Ph+ CML CP: 340 mg/m2/day
Adults with Ph+ ALL: 600 mg/day
Pediatrics with Ph+ ALL: 340 mg/m2/day
Adults with MDS/MPD: 400 mg/day
Adults with ASM: 100 mg/day or 400 mg/day
Adults with HES/CEL: 100 mg/day or 400 mg/day
Adults with DFSP: 800 mg/day
Adults with metastatic and/or unresectable GIST: 400 mg/day
Adjuvant treatment of adults with GIST: 400 mg/day
Patients with mild to moderate hepatic impairment: 400 mg/day
Patients with severe hepatic impairment: 300 mg/day

All doses of Imatinib should be taken with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day. Imatinib can be dissolved in water or apple juice for patients having difficulty swallowing. Daily dosing of 800 mg and above should be accomplished using the 400-mg tablet to reduce exposure to iron.

The following serious adverse reactions are described elsewhere in the labeling:

• Fluid Retention and Edema
• Hematologic Toxicity
• Congestive Heart Failure and Left Ventricular Dysfunction
• Hepatotoxicity
• Hemorrhage
• Gastrointestinal Disorders
• Hypereosinophilic Cardiac Toxicity
• Dermatologic Toxicities
• Hypothyroidism
• Growth Retardation in Children and Adolescents
• Tumor Lysis Syndrome
• Impairments Related to Driving and Using Machinery
• Renal Toxicity

Agents Inducing CYP3A Metabolism: Concomitant administration of Imatinib and strong CYP3A4 inducers may reduce total exposure of imatinib; consider alternative agents.

Agents Inhibiting CYP3A Metabolism: Concomitant administration of Imatinib and strong CYP3A4 inhibitors may result in a significant imatinib exposure increase. Grapefruit juice may also increase plasma concentrations of imatinib; avoid grapefruit juice).

Interactions with Drugs Metabolized by CYP3A4: Imatinib will increase plasma concentration of CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.). Use caution when administering Imatinib with CYP3A4 substrates that have a narrow therapeutic window. Because warfarin is metabolized by CYP2C9 and CYP3A4, use low-molecular weight or standard heparin instead of warfarin in patients who require anticoagulation.

Interactions with Drugs Metabolized by CYP2D6: Use caution when administering Imatinib with CYP2D6 substrates that have a narrow therapeutic window.

Women of childbearing potential: Women of childbearing potential must be advised to use effective contraception during treatment and for at least 15 days after stopping treatment with Imatinib.

Pregnancy: There are limited data on the use of imatinib in pregnant women. There have been post-marketing reports of spontaneous abortions and infant congenital anomalies from women who have taken Imatinib. Studies in animals have however shown reproductive toxicity and the potential risk for the foetus is unknown. Imatinib should not be used during pregnancy unless clearly necessary. If it is used during pregnancy, the patient must be informed of the potential risk to the foetus.

Breast-feeding: There is limited information on imatinib distribution on human milk. Studies in two breast feeding women revealed that both imatinib and its active metabolite can be distributed into human milk. The milk plasma ratio studied in a single patient was determined to be 0.5 for imatinib and 0.9 for the metabolite, suggesting greater distribution of the metabolite into the milk. Considering the combined concentration of imatinib and the metabolite and the maximum daily milk intake by infants, the total exposure would be expected to be low (-10% of a therapeutic dose). However, since the effects of low-dose exposure of the infant to imatinib are unknown, women should not breast-feed during treatment and for at least 15 days after stopping treatment with Imatinib.

Fertility: In non-clinical studies, the fertility of male and female rats was not affected, although effects on reproductive parameters were observed. Studies on patients receiving Imatinib and its effect on fertility and gametogenesis have not been performed. Patients concerned about their fertility on Imatinib treatment should consult with their physician.

Experience with doses higher than the recommended therapeutic dose is limited. In the event of overdose the patient should be observed and an appropriate symptomatic treatment given. Generally, the reported outcome in these cases was "improved" or "recovered". Events that have been reported at different dose ranges are as follows:

Adult Population:

• 1200 to 1600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhoea, rash, erythema, oedema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite.
• 1800 to 3200 mg (as high as 3200 mg daily for 6 days): Weakness, myalgia, increased creatine phosphokinase,
• increased bilirubin, gastrointestinal pain.
• 6400 mg (single dose): One case reported in the literature of one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, decreased neutrophil count, and increased transaminases.
• 8 to 10 g (single dose): Vomiting and gastrointestinal pain have been reported.

Paediatric population: One 3-year-old male exposed to a single dose of 400 mg experienced vomiting, diarrhoea and anorexia and another 3-year-old male exposed to a single dose of 980 mg experienced decreased white blood cell count and diarrhoea. In the event of overdose, the patient should be observed and appropriate supportive treatment given.

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

Targeted Cancer Therapy, Tyrosine Kinase Inhibitor

Imatinib is a small molecule protein-tyrosine kinase inhibitor that potently inhibits the activity of the Bcr-Abl tyrosine kinase (TK), as well as several receptor TKs: Kit, the receptor for stem cell factor (SCF) coded for by the c-Kit proto-oncogene, the discoidin domain receptors (DDR1 and DDR2), the colony stimulating factor receptor (CSF-1R) and the platelet-derived growth factor receptors alpha and beta (PDGFR-alpha and PDGFR beta). Imatinib can also inhibit cellular events mediated by activation of these receptor kinases.

Absorption and Distribution: Imatinib is well absorbed after oral administration with Cmax achieved within 2 4 hours post-dose. Mean absolute bioavailability is 98%. Mean Imatinib AUC increases proportionally with increasing doses ranging from 25 mg to 1,000 mg. There is no significant change in the pharmacokinetics of Imatinib on repeated dosing, and accumulation is 1.5- to 2.5- fold at a steady state when Imatinib is dosed once daily. At clinically relevant concentrations of Imatinib, binding to plasma proteins in in vitro experiments is approximately 95%, mostly to albumin and 1-acid glycoprotein.

Metabolism: CYP3A4 is the major enzyme responsible for metabolism of Imatinib. Other cytochrome P450 enzymes, such as CYP1A2, CYP2D6, CYP2C9, and CYP2C19, play a minor role in its metabolism. The main circulating active metabolite in humans is the N-demethylated piperazine derivative, formed predominantly by CYP3A4. It shows in vitro potency similar to the parent Imatinib. The plasma AUC for this metabolite is about 15% of the AUC for Imatinib. The plasma protein binding of N-demethylated metabolite CGP74588 is similar to that of the parent compound.

Excretion: Imatinib elimination is predominately in the feces, mostly as metabolites. Based on the recovery of compound(s) after an oral 14C-labeled dose of Imatinib, approximately 81% of the dose was eliminated within 7 days, in feces (68% of dose) and urine (13% of dose). Unchanged Imatinib accounted for 25% of the dose (5% urine, 20% feces), the remainder being metabolites. Following oral administration in healthy volunteers, the elimination half-lives of Imatinib and its major active metabolite, the N-demethyl derivative (CGP74588), are approximately 18 and 40 hours, respectively.

Adults with Ph+ CML CP: 400 mg/day
Adults with Ph+ CML AP or BC: 600 mg/day
Pediatrics with Ph+ CML CP: 340 mg/m2/day
Adults with Ph+ ALL: 600 mg/day
Pediatrics with Ph+ ALL: 340 mg/m2/day
Adults with MDS/MPD: 400 mg/day
Adults with ASM: 100 mg/day or 400 mg/day
Adults with HES/CEL: 100 mg/day or 400 mg/day
Adults with DFSP: 800 mg/day
Adults with metastatic and/or unresectable GIST: 400 mg/day
Adjuvant treatment of adults with GIST: 400 mg/day
Patients with mild to moderate hepatic impairment: 400 mg/day
Patients with severe hepatic impairment: 300 mg/day

All doses of Imatinib should be taken with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day. Imatinib can be dissolved in water or apple juice for patients having difficulty swallowing. Daily dosing of 800 mg and above should be accomplished using the 400-mg tablet to reduce exposure to iron.

The following serious adverse reactions are described elsewhere in the labeling:

• Fluid Retention and Edema
• Hematologic Toxicity
• Congestive Heart Failure and Left Ventricular Dysfunction
• Hepatotoxicity
• Hemorrhage
• Gastrointestinal Disorders
• Hypereosinophilic Cardiac Toxicity
• Dermatologic Toxicities
• Hypothyroidism
• Growth Retardation in Children and Adolescents
• Tumor Lysis Syndrome
• Impairments Related to Driving and Using Machinery
• Renal Toxicity

Agents Inducing CYP3A Metabolism: Concomitant administration of Imatinib and strong CYP3A4 inducers may reduce total exposure of imatinib; consider alternative agents.

Agents Inhibiting CYP3A Metabolism: Concomitant administration of Imatinib and strong CYP3A4 inhibitors may result in a significant imatinib exposure increase. Grapefruit juice may also increase plasma concentrations of imatinib; avoid grapefruit juice).

Interactions with Drugs Metabolized by CYP3A4: Imatinib will increase plasma concentration of CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.). Use caution when administering Imatinib with CYP3A4 substrates that have a narrow therapeutic window. Because warfarin is metabolized by CYP2C9 and CYP3A4, use low-molecular weight or standard heparin instead of warfarin in patients who require anticoagulation.

Interactions with Drugs Metabolized by CYP2D6: Use caution when administering Imatinib with CYP2D6 substrates that have a narrow therapeutic window.

Women of childbearing potential: Women of childbearing potential must be advised to use effective contraception during treatment and for at least 15 days after stopping treatment with Imatinib.

Pregnancy: There are limited data on the use of imatinib in pregnant women. There have been post-marketing reports of spontaneous abortions and infant congenital anomalies from women who have taken Imatinib. Studies in animals have however shown reproductive toxicity and the potential risk for the foetus is unknown. Imatinib should not be used during pregnancy unless clearly necessary. If it is used during pregnancy, the patient must be informed of the potential risk to the foetus.

Breast-feeding: There is limited information on imatinib distribution on human milk. Studies in two breast feeding women revealed that both imatinib and its active metabolite can be distributed into human milk. The milk plasma ratio studied in a single patient was determined to be 0.5 for imatinib and 0.9 for the metabolite, suggesting greater distribution of the metabolite into the milk. Considering the combined concentration of imatinib and the metabolite and the maximum daily milk intake by infants, the total exposure would be expected to be low (-10% of a therapeutic dose). However, since the effects of low-dose exposure of the infant to imatinib are unknown, women should not breast-feed during treatment and for at least 15 days after stopping treatment with Imatinib.

Fertility: In non-clinical studies, the fertility of male and female rats was not affected, although effects on reproductive parameters were observed. Studies on patients receiving Imatinib and its effect on fertility and gametogenesis have not been performed. Patients concerned about their fertility on Imatinib treatment should consult with their physician.

Experience with doses higher than the recommended therapeutic dose is limited. In the event of overdose the patient should be observed and an appropriate symptomatic treatment given. Generally, the reported outcome in these cases was "improved" or "recovered". Events that have been reported at different dose ranges are as follows:

Adult Population:

• 1200 to 1600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhoea, rash, erythema, oedema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite.
• 1800 to 3200 mg (as high as 3200 mg daily for 6 days): Weakness, myalgia, increased creatine phosphokinase,
• increased bilirubin, gastrointestinal pain.
• 6400 mg (single dose): One case reported in the literature of one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, decreased neutrophil count, and increased transaminases.
• 8 to 10 g (single dose): Vomiting and gastrointestinal pain have been reported.

Paediatric population: One 3-year-old male exposed to a single dose of 400 mg experienced vomiting, diarrhoea and anorexia and another 3-year-old male exposed to a single dose of 980 mg experienced decreased white blood cell count and diarrhoea. In the event of overdose, the patient should be observed and appropriate supportive treatment given.

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

Targeted Cancer Therapy, Tyrosine Kinase Inhibitor

Imatinib is a small molecule protein-tyrosine kinase inhibitor that potently inhibits the activity of the Bcr-Abl tyrosine kinase (TK), as well as several receptor TKs: Kit, the receptor for stem cell factor (SCF) coded for by the c-Kit proto-oncogene, the discoidin domain receptors (DDR1 and DDR2), the colony stimulating factor receptor (CSF-1R) and the platelet-derived growth factor receptors alpha and beta (PDGFR-alpha and PDGFR beta). Imatinib can also inhibit cellular events mediated by activation of these receptor kinases.

Absorption and Distribution: Imatinib is well absorbed after oral administration with Cmax achieved within 2 4 hours post-dose. Mean absolute bioavailability is 98%. Mean Imatinib AUC increases proportionally with increasing doses ranging from 25 mg to 1,000 mg. There is no significant change in the pharmacokinetics of Imatinib on repeated dosing, and accumulation is 1.5- to 2.5- fold at a steady state when Imatinib is dosed once daily. At clinically relevant concentrations of Imatinib, binding to plasma proteins in in vitro experiments is approximately 95%, mostly to albumin and 1-acid glycoprotein.

Metabolism: CYP3A4 is the major enzyme responsible for metabolism of Imatinib. Other cytochrome P450 enzymes, such as CYP1A2, CYP2D6, CYP2C9, and CYP2C19, play a minor role in its metabolism. The main circulating active metabolite in humans is the N-demethylated piperazine derivative, formed predominantly by CYP3A4. It shows in vitro potency similar to the parent Imatinib. The plasma AUC for this metabolite is about 15% of the AUC for Imatinib. The plasma protein binding of N-demethylated metabolite CGP74588 is similar to that of the parent compound.

Excretion: Imatinib elimination is predominately in the feces, mostly as metabolites. Based on the recovery of compound(s) after an oral 14C-labeled dose of Imatinib, approximately 81% of the dose was eliminated within 7 days, in feces (68% of dose) and urine (13% of dose). Unchanged Imatinib accounted for 25% of the dose (5% urine, 20% feces), the remainder being metabolites. Following oral administration in healthy volunteers, the elimination half-lives of Imatinib and its major active metabolite, the N-demethyl derivative (CGP74588), are approximately 18 and 40 hours, respectively.

Adults with Ph+ CML CP: 400 mg/day
Adults with Ph+ CML AP or BC: 600 mg/day
Pediatrics with Ph+ CML CP: 340 mg/m2/day
Adults with Ph+ ALL: 600 mg/day
Pediatrics with Ph+ ALL: 340 mg/m2/day
Adults with MDS/MPD: 400 mg/day
Adults with ASM: 100 mg/day or 400 mg/day
Adults with HES/CEL: 100 mg/day or 400 mg/day
Adults with DFSP: 800 mg/day
Adults with metastatic and/or unresectable GIST: 400 mg/day
Adjuvant treatment of adults with GIST: 400 mg/day
Patients with mild to moderate hepatic impairment: 400 mg/day
Patients with severe hepatic impairment: 300 mg/day

All doses of Imatinib should be taken with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day. Imatinib can be dissolved in water or apple juice for patients having difficulty swallowing. Daily dosing of 800 mg and above should be accomplished using the 400-mg tablet to reduce exposure to iron.

The following serious adverse reactions are described elsewhere in the labeling:

• Fluid Retention and Edema
• Hematologic Toxicity
• Congestive Heart Failure and Left Ventricular Dysfunction
• Hepatotoxicity
• Hemorrhage
• Gastrointestinal Disorders
• Hypereosinophilic Cardiac Toxicity
• Dermatologic Toxicities
• Hypothyroidism
• Growth Retardation in Children and Adolescents
• Tumor Lysis Syndrome
• Impairments Related to Driving and Using Machinery
• Renal Toxicity

Agents Inducing CYP3A Metabolism: Concomitant administration of Imatinib and strong CYP3A4 inducers may reduce total exposure of imatinib; consider alternative agents.

Agents Inhibiting CYP3A Metabolism: Concomitant administration of Imatinib and strong CYP3A4 inhibitors may result in a significant imatinib exposure increase. Grapefruit juice may also increase plasma concentrations of imatinib; avoid grapefruit juice).

Interactions with Drugs Metabolized by CYP3A4: Imatinib will increase plasma concentration of CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.). Use caution when administering Imatinib with CYP3A4 substrates that have a narrow therapeutic window. Because warfarin is metabolized by CYP2C9 and CYP3A4, use low-molecular weight or standard heparin instead of warfarin in patients who require anticoagulation.

Interactions with Drugs Metabolized by CYP2D6: Use caution when administering Imatinib with CYP2D6 substrates that have a narrow therapeutic window.

Women of childbearing potential: Women of childbearing potential must be advised to use effective contraception during treatment and for at least 15 days after stopping treatment with Imatinib.

Pregnancy: There are limited data on the use of imatinib in pregnant women. There have been post-marketing reports of spontaneous abortions and infant congenital anomalies from women who have taken Imatinib. Studies in animals have however shown reproductive toxicity and the potential risk for the foetus is unknown. Imatinib should not be used during pregnancy unless clearly necessary. If it is used during pregnancy, the patient must be informed of the potential risk to the foetus.

Breast-feeding: There is limited information on imatinib distribution on human milk. Studies in two breast feeding women revealed that both imatinib and its active metabolite can be distributed into human milk. The milk plasma ratio studied in a single patient was determined to be 0.5 for imatinib and 0.9 for the metabolite, suggesting greater distribution of the metabolite into the milk. Considering the combined concentration of imatinib and the metabolite and the maximum daily milk intake by infants, the total exposure would be expected to be low (-10% of a therapeutic dose). However, since the effects of low-dose exposure of the infant to imatinib are unknown, women should not breast-feed during treatment and for at least 15 days after stopping treatment with Imatinib.

Fertility: In non-clinical studies, the fertility of male and female rats was not affected, although effects on reproductive parameters were observed. Studies on patients receiving Imatinib and its effect on fertility and gametogenesis have not been performed. Patients concerned about their fertility on Imatinib treatment should consult with their physician.

Experience with doses higher than the recommended therapeutic dose is limited. In the event of overdose the patient should be observed and an appropriate symptomatic treatment given. Generally, the reported outcome in these cases was "improved" or "recovered". Events that have been reported at different dose ranges are as follows:

Adult Population:

• 1200 to 1600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhoea, rash, erythema, oedema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite.
• 1800 to 3200 mg (as high as 3200 mg daily for 6 days): Weakness, myalgia, increased creatine phosphokinase,
• increased bilirubin, gastrointestinal pain.
• 6400 mg (single dose): One case reported in the literature of one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, decreased neutrophil count, and increased transaminases.
• 8 to 10 g (single dose): Vomiting and gastrointestinal pain have been reported.

Paediatric population: One 3-year-old male exposed to a single dose of 400 mg experienced vomiting, diarrhoea and anorexia and another 3-year-old male exposed to a single dose of 980 mg experienced decreased white blood cell count and diarrhoea. In the event of overdose, the patient should be observed and appropriate supportive treatment given.

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

Other beta-lactam Antibiotics

Imipenem acts as an antimicrobial through the inhibition of cell wall synthesis of various gram-positive and gram-negative bacteria. This inhibition of cell wall synthesis in gram-negative bateria is attained by binding to pencillin binding proteins (PBPs). In E. coli and selected strains of P. aeruginosa, imipenem has shown to have the highest affinity to PBP-2, PBP-1a, and PBP-1b. This preferential binding to PBP-2 and PBP-1b results in the direct conversion of the individual cell to a spheroblast, which leads to rapid cell lysis and death without filament formation.

Cilastatin is a specific and reversible renal dehydropeptidase-I inhibitor. Since the antibiotic, imipenem, is hydrolyzed by dehydropeptidase-I, which resides in the brush border of the renal tubule, cilastatin is administered with imipenem to block the metabolism and thus the inactivation of imipenem so that antibacterial levels of imipenem can be attained in the urine. The drug also prevents the metabolism of leukotriene D4 to leukotriene E4 through the inhibition of leukotriene D4 dipeptidase.

The total daily dosage of Imipenem should be based on the type or severity of infection and given in equally divided doses based on consideration of degree of susceptibility of the pathogens, renal function and body-weight.

Imipenem & Cilastatin IV: Up to 500 mg dose should be given over 20 to 30 minutes; > 500 mg dose should be infused over 40 to 60 minutes. In patients who develop nausea during the infusion, the rate of infusion may be slowed.

Adult: Normal daily dose is 1-2 g administered in 3-4 divided doses. For the treatment of moderate infection, a 1 g b.i.d. dosage regimen may also be used. In infections due to less susceptible organisms, the daily dosage may be increased to a maximum of 4 g/day or 50 mg/kg/day, whichever is lower.

• Mild infection: 250 mg 6 hourly (1 gm/day)
• Moderate infection: 500 mg 8 hourly or 1 gm 12 hourly (1.5-2 gm/day)
• Severe infection with fully susceptible microorganism: 500 mg 6 hourly (2gm/day)
• Severe infection with less susceptible organisms (primarily some strains of P. aeruginosa): 1 gm 3-4 times daily (3-4 gm/day)

Paediatric Dosing Schedule:

• ≥ 3 months of age: the recommended dose for non-CNS infections is 15-25 mg/kg/dose administered every six hours. The maximum daily dose for treatment of infections with fully susceptible organisms is 2.0 g per day, and of infections with moderately susceptible organisms is 4.0 g/day. Higher doses (up to 90 mg/kg/day in older children) have been used in patients with cystic fibrosis.
• ≤3 months of age: Following dosage schedule is recommended for non-CNS infections:
• <1 week of age: 25 mg/kg every 12 hrs
• 1-4 weeks of age: 25 mg/kg every 8 hrs
• 4 weeks-3 months of age: 25 mg/kg every 6 hrs.

Imipenem is not recommended for the therapy of meningitis. If meningitis is suspected, an appropriate antibiotic should be used. Imipenem and cilastatin for injection is not recommended in pediatric patients <30 kg with impaired renal function, as no data are available.

Most common side effects with imipenem are nausea and vomiting. Other side effects reported with this drug are diarrhea, rash, thrombophlebitis, thrombocytosis, neutro-penia, eosinophilia and derangements of liver and renal functions. Use of imipenem is not recommended for patient with history of anaphylactic reaction with penicillin.

Contraindicated in patients who have demonstrated hypersensitivity to this product.

Caution when used in patients with known hypersensitivity to other β-lactams due to possibility of cross-sensitivity. CNS disorders such as epilepsy; renal, hepatic impairment; pregnancy, lactation.

Concurrent admin with probenecid may increase the half-life of cilastatin. Increased risk of generalised seizures when used concurrently with ganciclovir.

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

Lactation: Imipenem has been detected in human milk. If the use of Cispenam is deemed essential, the patient should stop nursing.

Dosage adjustment in renal impairment:

• CrCl >71: No changes.
• CrCl 41-70: Max 37.5 mg/kg/day or 3 g/day. (Range: 9.4 - 37.5 mg/kg/day) divided q6-8h.
• CrCl 21-40: Max 25 mg/kg/day or 2 g/day. (Range: 6.25 - 25 mg/kg/day) divided q6-12h.
• CrCl 6-20: Max 12.5 mg/kg/day (max dose 1 g/day). Range: 6.25 - 12.5 mg/kg/day) divided q12h. (Usual: 250mg q12h)
• Dialysis Hemodialysis: 125 - 500 mg q12h. (Max 12.5 mg/kg/day). Give dose after dialysis.
• Peritonial Dialysis: 125 - 250 mg q12h

In the case of overdosage, discontinue Imipenem/Cilastatin, treat symptomatically, and institute supportive measures as required. Imipenem/Cilastatin Sodium is hemodialyzable.

Anthelmintic

Ivermectin selectively binds and with high affinity to glutamate-gated chloride ion channels, which occur in invertebrate nerve and muscle cells leading to an increase in the permeability of cell membranes to chloride ions with hyperpolarization of the nerve or muscle cell and, ultimately, death of the parasite.

For Treatment (If COVIO Positive): 2 Tablets of Ivermectin 6 mg once daily for 5 days. (2+0+0 for 5 days).
For Prophylaxis: Single-dose as mentioned below to be taken on Day 1 & same dose on Day 7.

• Body Weight 15-24 kg: 1 Tablet of Ivermectin 3 mg
• Body Weight 25-35 kg: 1 Tablet of Ivermectin 6 mg
• Body Weight 36-50 kg: 1 Tablet of Ivermectin 6 mg + 1 Tablet of Ivermectin 3 mg
• Body Weight 51-65 kg: 2 Tablets of Ivermectin 6 mg
• Body Weight 66-79 kg: 2 Tablets of Ivermectin 6 mg + 1 Tablet of Ivermectin 3 mg
• Body Weight >80 kg: 3 Tablets of Ivermectin 6 mg

Strongyloidiasis: The recommended dosage of Ivermectin for the treatment of strongyloidiasis is a single oral dose designed to provide approximately 200 mcg/kg of body weight. Patients should take tablets on an empty stomach with water. In general, additional doses are not necessary. However, follow-up stool examinations should be performed to verify eradication of infection.

Dosage Guidelines for Ivermectin for Strongyloidiasis:

• Body Weight (kg) 15-24: Dose 3 mg/kg
• Body Weight (kg) 25-35: Dose 6 mg/kg
• Body Weight (kg) 36-50: Dose 9 mg/kg
• Body Weight (kg) 51-65: Dose 12 mg/kg
• Body Weight (kg) 66-79: Dose 15 mg/kg
• Body Weight (kg) >80: Dose 200 mcg/kg

Onchocerciasis: The recommended dosage of Ivermectin is a single oral dose designed to provide approximately 150 mcg of Ivermectin per kg of body weight on an empty stomach with water, the most commonly used dose interval is 12 months. For the treatment of individual patients, retreatment may be considered at intervals as short as 3 months.

Dosage Guidelines for Ivermectin for Onchocerciasis:

• Body Weight (kg) 15-25: Dose 3 mg/kg
• Body Weight (kg) 26-44: Dose 6 mg/kg
• Body Weight (kg) 45-64: Dose 9 mg/kg
• Body Weight (kg) 65-84: Dose 12 mg/kg
• Body Weight (kg) >85: Dose 150 mcg/kg

Strongyloidiasis: In four clinical studies involving a total of 109 patients given either one or two doses of 170 to 200 mcg/kg of Ivermectin, the following adverse reactions were reported as possibly, probably, or definitely related to Ivermectin.

• Body as a whole: asthenia/fatigue (0.9%), abdominal pain (0.9%)
• Gastrointestinal: anorexia (0.9%), constipation (0.9%), diarrhea (1.8%), nausea (1.8%), vomiting (0.9%) Nervous System/Psychiatric: dizziness (2.8%), somnolence (0.9%), vertigo (0.9%), tremor (0.9%)
• Skin: pruritus (2.8%), rash (0.9%), and urticaria (0.9%).

Onchocerciasis: arthralgia/synovitis (19.3%), axillary lymph node enlargement and tenderness (11.0% and 4.4%, respectively), cervical lymph node enlargement and tenderness (5.3% and 1.2%, respectively), inguinal lymph node enlargement and tenderness (12.6% and 13.9%, respectively), other lymph node enlargement and tenderness (3.0% and 1.9%, respectively), pruritus (27.5%), skin involvement including edema, papular and pustular or frank urticarial rash (22.7%), and fever (22.6%), abnormal sensation in the eyes, eyelid edema, anterior uveitis, conjunctivitis, limbitis, keratitis, and chorioretinitis or choroiditis. These have rarely been severe or associated with loss of vision and have generally resolved without corticosteroid treatment. The following adverse reactions have been reported since the drug was registered overseas: hypotension (mainly orthostatic hypotension), worsening of bronchial asthma, toxic epidermal necrolysis, and Stevens-Johnson syndrome.

It is contraindicated in patients who are hypersensitive to any component of this product.

Historical data have shown that microfilaricidal drugs, such as diethylcarbamazine citrate (DEC-C), might cause cutaneous and/or systemic reactions of varying severity (the Mazzotti reaction) and ophthalmological reactions in patients with onchocerciasis. These reactions are probably due to allergic and inflammatory responses to the death of microfilariae. Patients treated with Ivermectin for onchocerciasis may experience these reactions in addition to clinical adverse reactions possibly, probably, or definitely related to the drug itself. The treatment of severe Mazzotti reactions has not been subjected to controlled clinical trials. Oral hydration, recumbency, intravenous normal saline, and/or parenteral corticosteroids have been used to treat postural hypotension. Antihistamines and/or aspirin have been used for most mild to moderate cases. After treatment with microfilaricidal drugs, patients with hyperreactive onchodermatitis (sowda) may be more likely than others to experience severe adverse reactions, especially edema and aggravation of onchodermatitis. Rarely, patients with onchocerciasis who are also heavily infected with Loa loa may develop a serious or even fatal encephalopathy either spontaneously or following treatment with an effective microfilaricide. In these patients, the following adverse experiences have also been reported: back pain, conjunctival hemorrhage, dyspnea, urinary and/or fecal incontinence, difficulty in standing/walking, mental status changes, confusion, lethargy, stupor, or coma.

Post-marketing reports of increased INR (International Normalized Ratio) have been rarely reported when ivermectin was co-administered with warfarin.

Pregnancy Category C. Ivermectin does not appear to be selectively fetotoxic to the developing fetus. There are, however, no adequate and well-controlled studies in pregnant women. Ivermectin should not be used during pregnancy since safety in pregnancy has not been established.

Nursing Mothers: Ivermectin is excreted in human milk in low concentrations. Treatment of mothers who intend to breast feed should only be undertaken when the risk of delayed treatment to the mother outweighs the possible risk to the newborn

Pediatric Use: Safety and effectiveness in pediatric patients weighing less than 15 kg have not been established.

Geriatric Use: Clinical studies of Ivermectin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Keep in a dry place, below 30°C. Protect from light. Keep out of the reach of children.

Anthelmintic

Ivermectin selectively binds and with high affinity to glutamate-gated chloride ion channels, which occur in invertebrate nerve and muscle cells leading to an increase in the permeability of cell membranes to chloride ions with hyperpolarization of the nerve or muscle cell and, ultimately, death of the parasite.

For Treatment (If COVIO Positive): 2 Tablets of Ivermectin 6 mg once daily for 5 days. (2+0+0 for 5 days).
For Prophylaxis: Single-dose as mentioned below to be taken on Day 1 & same dose on Day 7.

• Body Weight 15-24 kg: 1 Tablet of Ivermectin 3 mg
• Body Weight 25-35 kg: 1 Tablet of Ivermectin 6 mg
• Body Weight 36-50 kg: 1 Tablet of Ivermectin 6 mg + 1 Tablet of Ivermectin 3 mg
• Body Weight 51-65 kg: 2 Tablets of Ivermectin 6 mg
• Body Weight 66-79 kg: 2 Tablets of Ivermectin 6 mg + 1 Tablet of Ivermectin 3 mg
• Body Weight >80 kg: 3 Tablets of Ivermectin 6 mg

Strongyloidiasis: The recommended dosage of Ivermectin for the treatment of strongyloidiasis is a single oral dose designed to provide approximately 200 mcg/kg of body weight. Patients should take tablets on an empty stomach with water. In general, additional doses are not necessary. However, follow-up stool examinations should be performed to verify eradication of infection.

Dosage Guidelines for Ivermectin for Strongyloidiasis:

• Body Weight (kg) 15-24: Dose 3 mg/kg
• Body Weight (kg) 25-35: Dose 6 mg/kg
• Body Weight (kg) 36-50: Dose 9 mg/kg
• Body Weight (kg) 51-65: Dose 12 mg/kg
• Body Weight (kg) 66-79: Dose 15 mg/kg
• Body Weight (kg) >80: Dose 200 mcg/kg

Onchocerciasis: The recommended dosage of Ivermectin is a single oral dose designed to provide approximately 150 mcg of Ivermectin per kg of body weight on an empty stomach with water, the most commonly used dose interval is 12 months. For the treatment of individual patients, retreatment may be considered at intervals as short as 3 months.

Dosage Guidelines for Ivermectin for Onchocerciasis:

• Body Weight (kg) 15-25: Dose 3 mg/kg
• Body Weight (kg) 26-44: Dose 6 mg/kg
• Body Weight (kg) 45-64: Dose 9 mg/kg
• Body Weight (kg) 65-84: Dose 12 mg/kg
• Body Weight (kg) >85: Dose 150 mcg/kg

Strongyloidiasis: In four clinical studies involving a total of 109 patients given either one or two doses of 170 to 200 mcg/kg of Ivermectin, the following adverse reactions were reported as possibly, probably, or definitely related to Ivermectin.

• Body as a whole: asthenia/fatigue (0.9%), abdominal pain (0.9%)
• Gastrointestinal: anorexia (0.9%), constipation (0.9%), diarrhea (1.8%), nausea (1.8%), vomiting (0.9%) Nervous System/Psychiatric: dizziness (2.8%), somnolence (0.9%), vertigo (0.9%), tremor (0.9%)
• Skin: pruritus (2.8%), rash (0.9%), and urticaria (0.9%).

Onchocerciasis: arthralgia/synovitis (19.3%), axillary lymph node enlargement and tenderness (11.0% and 4.4%, respectively), cervical lymph node enlargement and tenderness (5.3% and 1.2%, respectively), inguinal lymph node enlargement and tenderness (12.6% and 13.9%, respectively), other lymph node enlargement and tenderness (3.0% and 1.9%, respectively), pruritus (27.5%), skin involvement including edema, papular and pustular or frank urticarial rash (22.7%), and fever (22.6%), abnormal sensation in the eyes, eyelid edema, anterior uveitis, conjunctivitis, limbitis, keratitis, and chorioretinitis or choroiditis. These have rarely been severe or associated with loss of vision and have generally resolved without corticosteroid treatment. The following adverse reactions have been reported since the drug was registered overseas: hypotension (mainly orthostatic hypotension), worsening of bronchial asthma, toxic epidermal necrolysis, and Stevens-Johnson syndrome.

It is contraindicated in patients who are hypersensitive to any component of this product.

Historical data have shown that microfilaricidal drugs, such as diethylcarbamazine citrate (DEC-C), might cause cutaneous and/or systemic reactions of varying severity (the Mazzotti reaction) and ophthalmological reactions in patients with onchocerciasis. These reactions are probably due to allergic and inflammatory responses to the death of microfilariae. Patients treated with Ivermectin for onchocerciasis may experience these reactions in addition to clinical adverse reactions possibly, probably, or definitely related to the drug itself. The treatment of severe Mazzotti reactions has not been subjected to controlled clinical trials. Oral hydration, recumbency, intravenous normal saline, and/or parenteral corticosteroids have been used to treat postural hypotension. Antihistamines and/or aspirin have been used for most mild to moderate cases. After treatment with microfilaricidal drugs, patients with hyperreactive onchodermatitis (sowda) may be more likely than others to experience severe adverse reactions, especially edema and aggravation of onchodermatitis. Rarely, patients with onchocerciasis who are also heavily infected with Loa loa may develop a serious or even fatal encephalopathy either spontaneously or following treatment with an effective microfilaricide. In these patients, the following adverse experiences have also been reported: back pain, conjunctival hemorrhage, dyspnea, urinary and/or fecal incontinence, difficulty in standing/walking, mental status changes, confusion, lethargy, stupor, or coma.

Post-marketing reports of increased INR (International Normalized Ratio) have been rarely reported when ivermectin was co-administered with warfarin.

Pregnancy Category C. Ivermectin does not appear to be selectively fetotoxic to the developing fetus. There are, however, no adequate and well-controlled studies in pregnant women. Ivermectin should not be used during pregnancy since safety in pregnancy has not been established.

Nursing Mothers: Ivermectin is excreted in human milk in low concentrations. Treatment of mothers who intend to breast feed should only be undertaken when the risk of delayed treatment to the mother outweighs the possible risk to the newborn

Pediatric Use: Safety and effectiveness in pediatric patients weighing less than 15 kg have not been established.

Geriatric Use: Clinical studies of Ivermectin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Keep in a dry place, below 30°C. Protect from light. Keep out of the reach of children.

Indomethacin is indicated in-

• Rheumatoid arthritis
• Ankylosing spondylitis
• Osteoarthritis (degenerative joint disease)
• Gout
• Acute non-articular rheumatism (bursitis, synovitis, tendinitis).

Drugs for Osteoarthritis, Drugs used for Rheumatoid Arthritis, Non-steroidal Anti-inflammatory Drugs (NSAIDs)

Indomethacin is NSAID having property of antipyretic and analgesic effect. A great number of pharmacological studies have proved that Indomethacin has strong anti-inflammatory, analgesic, and antipyretic properties. Unlike the corticosteriods, the effect of Indomethacin is not related to the pituitary gland or the adrenals. Indomethacin is absorbed promptly following oral administration and peak plasma levels occur within 2 hours. Approximately two thirds of this amount is excreted in the urine and the remainder is excreted in the feces. About 90% of a single dose is excreted in 24-48 hours. In a number of controlled clinical trials, Indomethacin has proved to be of great value in the treatment of rheumatic diseases, It relieves pain, reduces joints swelling edema and improves joint mobility.

75 mg sustained-release capsule:

• Rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis (degenerative joint disease): The initial dose is 75 mg sustained-release capsule once daily. If severe then twice daily is required.
• Acute attacks of gout: May control with a dose of 75 mg sustained-release capsule twice daily.
• Acute non-articular rheumatism (bursitis, synovitis, tendinitis): 1-2 sustained-release capsule daily according to the severity of this case.

25 mg capsule:

• Rheumatic diseases: 50-200 mg daily in divided doses
• Acute gout: 150-200 mg daily in divided doses
• Dysmenorrhea: up to 75 mg daily 

Headaches, usually in the morning and kild vertigo may occur during the early weeks of therapy. These symptoms are transient and usually disappear with continued use or by reduction of the dose. Rare case of mild psychic disturbances was also reported which subsided after few days of treatment, Gastrointestinal reactions such as nausea, vomiting, diarrhoea, epigastric and abdominal pain are often due to large doses of the drug and disappear when the dose is reduced. Administration of the capsule immediately after meals with an antacid it necessary, minimize the frequency and the severity of these untoward effects.

Indomethacin is contraindicated in patients with ulcer, gastritis, active ulcerative colitis, and it should be used with caution in patients with a history of these disorders. In these cases, administration of Indomethacin suppositories should be preferred. It is also contraindicated in the previously hypersensitive patients.

Indomethacin capsule should be used with caution with psychiatric problems, epilepsy or parkinsonism since the drug may aggravate these conditions. It is not recommended for pregnant women, because at the present time clinical studies are insufficient. Indomethacin is not given nomally in neonates except when used to assist closure of a patent ductus arteriosus.

It may interact with anticoagulants, Lithium, diuretics, antihypertensive drugs, diflunisal and sulfonylureas.

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

Indomethacin is indicated in-

• Rheumatoid arthritis
• Ankylosing spondylitis
• Osteoarthritis (degenerative joint disease)
• Gout
• Acute non-articular rheumatism (bursitis, synovitis, tendinitis).

Drugs for Osteoarthritis, Drugs used for Rheumatoid Arthritis, Non-steroidal Anti-inflammatory Drugs (NSAIDs)

Indomethacin is NSAID having property of antipyretic and analgesic effect. A great number of pharmacological studies have proved that Indomethacin has strong anti-inflammatory, analgesic, and antipyretic properties. Unlike the corticosteriods, the effect of Indomethacin is not related to the pituitary gland or the adrenals. Indomethacin is absorbed promptly following oral administration and peak plasma levels occur within 2 hours. Approximately two thirds of this amount is excreted in the urine and the remainder is excreted in the feces. About 90% of a single dose is excreted in 24-48 hours. In a number of controlled clinical trials, Indomethacin has proved to be of great value in the treatment of rheumatic diseases, It relieves pain, reduces joints swelling edema and improves joint mobility.

75 mg sustained-release capsule:

• Rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis (degenerative joint disease): The initial dose is 75 mg sustained-release capsule once daily. If severe then twice daily is required.
• Acute attacks of gout: May control with a dose of 75 mg sustained-release capsule twice daily.
• Acute non-articular rheumatism (bursitis, synovitis, tendinitis): 1-2 sustained-release capsule daily according to the severity of this case.

25 mg capsule:

• Rheumatic diseases: 50-200 mg daily in divided doses
• Acute gout: 150-200 mg daily in divided doses
• Dysmenorrhea: up to 75 mg daily 

Headaches, usually in the morning and kild vertigo may occur during the early weeks of therapy. These symptoms are transient and usually disappear with continued use or by reduction of the dose. Rare case of mild psychic disturbances was also reported which subsided after few days of treatment, Gastrointestinal reactions such as nausea, vomiting, diarrhoea, epigastric and abdominal pain are often due to large doses of the drug and disappear when the dose is reduced. Administration of the capsule immediately after meals with an antacid it necessary, minimize the frequency and the severity of these untoward effects.

Indomethacin is contraindicated in patients with ulcer, gastritis, active ulcerative colitis, and it should be used with caution in patients with a history of these disorders. In these cases, administration of Indomethacin suppositories should be preferred. It is also contraindicated in the previously hypersensitive patients.

Indomethacin capsule should be used with caution with psychiatric problems, epilepsy or parkinsonism since the drug may aggravate these conditions. It is not recommended for pregnant women, because at the present time clinical studies are insufficient. Indomethacin is not given nomally in neonates except when used to assist closure of a patent ductus arteriosus.

It may interact with anticoagulants, Lithium, diuretics, antihypertensive drugs, diflunisal and sulfonylureas.

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

Imiquimod cream is indicated for the topical treatment of-

• External genital and perianal warts in adults.
• Small superficial basal cell carcinomas in adults.
• Clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratoses on the face or scalp in immunocompetent adult patients when size or number of lesions limit the efficacy and/or acceptability of cryotherapy and other topical treatment options are contraindicated or less appropriate.

Immunosuppressant, Miscellaneous topical agents

Imiquimod is a toll-like receptor-7 agonist enhancing both the innate and acquired immune response. It activates the production of numerous compounds, including IFN-α, IL-1, -6, -8, -10, -12, and TNF-α, stimulates natural killer cells and the proliferation of B-cells. It also activates Langerhans cells and promotes their migration to the regional lymph nodes. Imiquimod stimulates TH-1 cells to produce IFN-g, which in turn can activate cytotoxic T lymphocytes. These cells provide long-term immune memory, which can offer future protection against the previously encountered virus or tumor.

External genital warts in adults: Imiquimod cream should be applied 3 times per week (example: Monday, Wednesday, and Friday; or Tuesday, Thursday, and Saturday) prior to normal sleeping hours, and should remain on the skin for 6 to 10 hours. Imiquimod cream treatment should continue until the clearance of visible genital or perianal warts or for a maximum of 16 weeks per episode of warts.

Imiquimod cream should be applied in a thin layer and rubbed on the clean wart area until the cream vanishes. Only apply to affected areas and avoid any application on internal surfaces. Imiquimod cream should be applied prior to normal sleeping hours. During the 6 to 10 hour treatment period, showering or bathing should be avoided. After this period it is essential that Imiquimod cream is removed with mild soap and water. Application of an excess of cream or prolonged contact with the skin may result in a severe application site reaction. A single use sachet is sufficient to cover a wart area of 20 cm2 (approx. 3 inches2). Sachets should not be re-used once opened. Hands should be washed carefully before and after application of cream. Uncircumcised males treating warts under the foreskin should retract the foreskin and wash the area daily.

Superficial basal cell carcinoma in adults: Apply Imiquimod cream for 6 weeks, 5 times per week (example: Monday to Friday) prior to normal sleeping hours, and leave on the skin for approximately 8 hours. Before applying Imiquimod cream, patients should wash the treatment area with mild soap and water and dry thoroughly. Sufficient cream should be applied to cover the treatment area, including one centimetre of skin surrounding the tumour. The cream should be rubbed into the treatment area until the cream vanishes. The cream should be applied prior to normal sleeping hours and remain on the skin for approximately 8 hours. During this period, showering and bathing should be avoided. After this period it is essential that Imiquimod cream is removed with mild soap and water. Sachets should not be re-used once opened. Hands should be washed carefully before and after application of cream. Response of the treated tumour to Imiquimod cream should be assessed 12 weeks after the end of treatment. If the treated tumour shows an incomplete response, a different therapy should be used. A rest period of several days may be taken if the local skin reaction to Imiquimod cream causes excessive discomfort to the patient, or if infection is observed at the treatment site. In this latter case, appropriate other measures should be taken.

Actinic keratosis in adults: Treatment should be initiated and monitored by a physician. Imiquimod cream should be applied 3 times per week (example: Monday, Wednesday and Friday) for four weeks prior to normal sleeping hours, and left on the skin for approximately 8 hours. Sufficient cream should be applied to cover the treatment area. After a 4-week treatment-free period, clearance of Actinic Keratosis should be assessed. If any lesions persist, treatment should be repeated for another four weeks. An interruption of dosing should be considered if intense local inflammatory reactions occur or if infection is observed at the treatment site. In this latter case, appropriate other measures should be taken. Each treatment period should not be extended beyond 4 weeks due to missed doses or rest periods. If the treated area does not show complete clearance at a follow-up examination about 8 weeks after the last 4-weeks course of treatment, an additional 4-weeks course of Imiquimod treatment may be considered. A different therapy is recommended if the treated lesion(s) shows insufficient response to Imiquimod. Actinic keratosis lesions that have cleared after one or two courses of treatment and subsequently recur can be re-treated with one or two further courses of Imiquimod cream following an at least 12 weeks treatment pause. Before applying Imiquimod cream, patients should wash the treatment area with mild soap and water and dry thoroughly. Sufficient cream should be applied to cover the treatment area, including one centimetre of skin surrounding the tumour. The cream should be rubbed into the treatment area until the cream vanishes. The cream should be applied prior to normal sleeping hours and remain on the skin for approximately 8 hours. During this period, showering and bathing should be avoided. After this period it is essential that Imiquimod cream is removed with mild soap and water. Sachets should not be re-used once opened. Hands should be washed carefully before and after application of cream.

Information applicable to all indications: If a dose is missed, the patient should apply the cream as soon as he/she remember and then he/she should continue with the regular schedule. However the cream should not be applied more than once a day.

Reported side effects are pustules, genital candidiasis, vaginitis, bacterial infection, fungal infection, upper respiratory tract infection, vulvitis, rhinitis, influenza, lymphadenopathy, anorexia, insomnia, depression, irritability, headache, paraesthesia, dizziness, migraine, somnolence, conjunctival irritation, eyelid oedema, tinnitus, flushing, pharyngitis, nasal congestion, pharyngo laryngeal pain, nausea, abdominal pain, diarrhoea, vomitting, rectal disorder, rectal tenesmus, dry mouth, pruritus, folliculitis, rash erythematous, eczema, rash, increased sweating, urticaria, erythema, face oedema, skin ulcer, myalgia, arthralgia, back pain, pain in extremity, dysuria, genital pain in male, penile disorder, dyspareunia, erectile dysfunction, uterovaginal prolapse, vaginal pain, vaginitis atrophic, vulval disorder, and general disorders and administration site disorders such as pruritus, pain, burning, irritation, erythema, reaction, bleeding, papules, rash, inflammation asthenia, malaise, rigors, lethargy, discomfort, fatigue, discharge, oedema, scar, ulcer, vesicle, warmth, pyrexia etc. Reports have been received of localised hypopigmentation and hyperpigmentation following Imiquimod cream use. Clinical studies investigating the use of Imiquimod for the treatment of actinic keratosis have detected a 0.4% frequency of alopecia at the treatment site or surrounding area. Reductions in haemoglobin, white blood cell count, absolute neutrophils and platelets have been observed in clinical trials.

Imiquimod cream is contraindicated in patients with hypersensitivity to imiquimod or cream excipients.

Hypersensitivity to the active substance or to any of the excipients.

No interaction studies have been performed. This includes studies with immunosuppressive drugs. Interactions with systemic drugs would be limited by the minimal percutaneous absorption of Imiquimod cream. Due to its immunostimulating properties, Imiquimod cream should be used with caution in patients who are receiving immunosuppressive medication.

Use in Pregnancy B1. No human study is available. Imiquimod cream should only be used during pregnancy, if the potential benefit justifies the potential risk of fetus. No human study is available. Imiquimod cream should only be used during lactation if the potential benefit justifies the potential risk to the new-born baby.

Use in Children: Imiquimod cream is not recommended below the age of 12 years.
Use in Elderly: Imiquimod cream is recommended in elderly patient.
Effect on ability to drive and use machineries: Imiquimod cream is unlikely to produce any effect.

When applied topically, systemic overdosage with Imiquimod cream is unlikely due to minimal percutaneous absorption. Persistent dermal overdosing of Imiquimod cream could result in severe local skin reactions. Following accidental ingestion, nausea, emesis, headache, myalgia and fever could occur after a single dose of 200 mg Imiquimod which corresponds to the content of approximately 16 sachets. The most clinically serious adverse event reported following multiple oral doses of ≥ 200 mg was hypotension which resolved following oral or intravenous fluid administration.

Store in a cool & dry place, protected from light. Store at 4°-25°C.

Flunarizine is indicated for

• Prophylaxis of classic (with aura) or common (without aura) migraine
• Symptomatic treatment of vestibular vertigo (due to a diagnosed functional disorder of the vestibular system).
• Peripheral Vascular Disease (PVD)
• Motion sickness
• Refractory epilepsy resistant to conventional antiepileptic therapy.

Miscellaneous prophylactic migraine preparations

Flunarizine is the difluorinated derivative of cinnarizine. It is a selective calcium channel antagonist. By reducing excessive transmembrane influx of calcium Flunarizine prevents cellular calcium overload. It does not interfere with normal cellular calcium homeostasis. Flunarizine also has some antihistaminic and sedative properties. It binds at an affinity of 99% to plasma protein.

Migraine Prophylaxis:

• Starting Dose: 10 mg at night in patients less than 65 years of age and 5 mg daily in patients older than 65 years. If, during this treatment depressive, extrapyramidal or other unacceptable symptoms occur, administration should be discontinued. If, after 2 months of this initial treatment, no significant improvement is observed, the patient should be considered a non-responder and administration should be discontinued.
• Maintenance Treatment: If a patient is responding satisfactorily and if a maintenance treatment is needed, the dose should be decreased to 5 days treatment at the same daily dose with two successive medicine free days every week. Even if the prophylactic maintenance treatment is successful and well tolerated, it should be interrupted after 6 months and it should be re-initiated only if the patient relapses.

Peripheral Vascular disease: 10 mg twice daily, up to 30 mg per day if required.

Vertigo & motion sickness: 10-20 mg daily for adults and 5 mg daily for children (> 40 kg).

Epileptic seizure: 15-20 mg daily in adults and 5 to 10 mg daily for children as an add-on therapy

Drowsiness and/or fatigue, as well as weight gain and/or increased appetite may occur. The following adverse experiences have been reported during chronic treatment with Flunarizine: depression, of which female patients with a history of depressive illness may be particularly at risk; extrapyramidal symptoms (such as bradykinesia, rigidity, akathisia, orofacial dyskinesia, tremor), of which elderly patients seem particularly at risk. Infrequently reported adverse reaction are: heartburn; nausea; gastralgia; insomnia; anxiety; galactorrhoea; dry mouth; muscle ache; skin rash.

Hypersensitivity to Flunarizine. Flunarizine is contra-indicated in patients with a history of depressive illness, or with pre-existing symptoms of Parkinson's disease or other extrapyramidal disorders.

Flunarizine may lead to drowsiness which is aggravated by the simultaneous intake of alcohol or other central nervous system depressants. Patients should be cautioned against driving motor vehicles or performing other potentially hazardous tasks where a loss of mental alertness may lead to accidents. Flunarizine is not suited for aborting a migraine attack. The possible occurrence of an attack is therefore no reason to increase the dose of Flunarizine. This treatment may give rise to extrapyramidal and depressive symptoms and reveal Parkinsonism, especially in predisposed patients such as the elderly. Flunarizine should therefore be used with caution in such patients.

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

Safety in pregnancy and lactation has not been established.

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

Flunarizine is indicated for

• Prophylaxis of classic (with aura) or common (without aura) migraine
• Symptomatic treatment of vestibular vertigo (due to a diagnosed functional disorder of the vestibular system).
• Peripheral Vascular Disease (PVD)
• Motion sickness
• Refractory epilepsy resistant to conventional antiepileptic therapy.

Miscellaneous prophylactic migraine preparations

Flunarizine is the difluorinated derivative of cinnarizine. It is a selective calcium channel antagonist. By reducing excessive transmembrane influx of calcium Flunarizine prevents cellular calcium overload. It does not interfere with normal cellular calcium homeostasis. Flunarizine also has some antihistaminic and sedative properties. It binds at an affinity of 99% to plasma protein.

Migraine Prophylaxis:

• Starting Dose: 10 mg at night in patients less than 65 years of age and 5 mg daily in patients older than 65 years. If, during this treatment depressive, extrapyramidal or other unacceptable symptoms occur, administration should be discontinued. If, after 2 months of this initial treatment, no significant improvement is observed, the patient should be considered a non-responder and administration should be discontinued.
• Maintenance Treatment: If a patient is responding satisfactorily and if a maintenance treatment is needed, the dose should be decreased to 5 days treatment at the same daily dose with two successive medicine free days every week. Even if the prophylactic maintenance treatment is successful and well tolerated, it should be interrupted after 6 months and it should be re-initiated only if the patient relapses.

Peripheral Vascular disease: 10 mg twice daily, up to 30 mg per day if required.

Vertigo & motion sickness: 10-20 mg daily for adults and 5 mg daily for children (> 40 kg).

Epileptic seizure: 15-20 mg daily in adults and 5 to 10 mg daily for children as an add-on therapy

Drowsiness and/or fatigue, as well as weight gain and/or increased appetite may occur. The following adverse experiences have been reported during chronic treatment with Flunarizine: depression, of which female patients with a history of depressive illness may be particularly at risk; extrapyramidal symptoms (such as bradykinesia, rigidity, akathisia, orofacial dyskinesia, tremor), of which elderly patients seem particularly at risk. Infrequently reported adverse reaction are: heartburn; nausea; gastralgia; insomnia; anxiety; galactorrhoea; dry mouth; muscle ache; skin rash.

Hypersensitivity to Flunarizine. Flunarizine is contra-indicated in patients with a history of depressive illness, or with pre-existing symptoms of Parkinson's disease or other extrapyramidal disorders.

Flunarizine may lead to drowsiness which is aggravated by the simultaneous intake of alcohol or other central nervous system depressants. Patients should be cautioned against driving motor vehicles or performing other potentially hazardous tasks where a loss of mental alertness may lead to accidents. Flunarizine is not suited for aborting a migraine attack. The possible occurrence of an attack is therefore no reason to increase the dose of Flunarizine. This treatment may give rise to extrapyramidal and depressive symptoms and reveal Parkinsonism, especially in predisposed patients such as the elderly. Flunarizine should therefore be used with caution in such patients.

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

Safety in pregnancy and lactation has not been established.

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

Flunarizine is indicated for

• Prophylaxis of classic (with aura) or common (without aura) migraine
• Symptomatic treatment of vestibular vertigo (due to a diagnosed functional disorder of the vestibular system).
• Peripheral Vascular Disease (PVD)
• Motion sickness
• Refractory epilepsy resistant to conventional antiepileptic therapy.

Miscellaneous prophylactic migraine preparations

Flunarizine is the difluorinated derivative of cinnarizine. It is a selective calcium channel antagonist. By reducing excessive transmembrane influx of calcium Flunarizine prevents cellular calcium overload. It does not interfere with normal cellular calcium homeostasis. Flunarizine also has some antihistaminic and sedative properties. It binds at an affinity of 99% to plasma protein.

Migraine Prophylaxis:

• Starting Dose: 10 mg at night in patients less than 65 years of age and 5 mg daily in patients older than 65 years. If, during this treatment depressive, extrapyramidal or other unacceptable symptoms occur, administration should be discontinued. If, after 2 months of this initial treatment, no significant improvement is observed, the patient should be considered a non-responder and administration should be discontinued.
• Maintenance Treatment: If a patient is responding satisfactorily and if a maintenance treatment is needed, the dose should be decreased to 5 days treatment at the same daily dose with two successive medicine free days every week. Even if the prophylactic maintenance treatment is successful and well tolerated, it should be interrupted after 6 months and it should be re-initiated only if the patient relapses.

Peripheral Vascular disease: 10 mg twice daily, up to 30 mg per day if required.

Vertigo & motion sickness: 10-20 mg daily for adults and 5 mg daily for children (> 40 kg).

Epileptic seizure: 15-20 mg daily in adults and 5 to 10 mg daily for children as an add-on therapy

Drowsiness and/or fatigue, as well as weight gain and/or increased appetite may occur. The following adverse experiences have been reported during chronic treatment with Flunarizine: depression, of which female patients with a history of depressive illness may be particularly at risk; extrapyramidal symptoms (such as bradykinesia, rigidity, akathisia, orofacial dyskinesia, tremor), of which elderly patients seem particularly at risk. Infrequently reported adverse reaction are: heartburn; nausea; gastralgia; insomnia; anxiety; galactorrhoea; dry mouth; muscle ache; skin rash.

Hypersensitivity to Flunarizine. Flunarizine is contra-indicated in patients with a history of depressive illness, or with pre-existing symptoms of Parkinson's disease or other extrapyramidal disorders.

Flunarizine may lead to drowsiness which is aggravated by the simultaneous intake of alcohol or other central nervous system depressants. Patients should be cautioned against driving motor vehicles or performing other potentially hazardous tasks where a loss of mental alertness may lead to accidents. Flunarizine is not suited for aborting a migraine attack. The possible occurrence of an attack is therefore no reason to increase the dose of Flunarizine. This treatment may give rise to extrapyramidal and depressive symptoms and reveal Parkinsonism, especially in predisposed patients such as the elderly. Flunarizine should therefore be used with caution in such patients.

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

Safety in pregnancy and lactation has not been established.

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

Other beta-lactam Antibiotics

Imipenem acts as an antimicrobial through the inhibition of cell wall synthesis of various gram-positive and gram-negative bacteria. This inhibition of cell wall synthesis in gram-negative bateria is attained by binding to pencillin binding proteins (PBPs). In E. coli and selected strains of P. aeruginosa, imipenem has shown to have the highest affinity to PBP-2, PBP-1a, and PBP-1b. This preferential binding to PBP-2 and PBP-1b results in the direct conversion of the individual cell to a spheroblast, which leads to rapid cell lysis and death without filament formation.

Cilastatin is a specific and reversible renal dehydropeptidase-I inhibitor. Since the antibiotic, imipenem, is hydrolyzed by dehydropeptidase-I, which resides in the brush border of the renal tubule, cilastatin is administered with imipenem to block the metabolism and thus the inactivation of imipenem so that antibacterial levels of imipenem can be attained in the urine. The drug also prevents the metabolism of leukotriene D4 to leukotriene E4 through the inhibition of leukotriene D4 dipeptidase.

The total daily dosage of Imipenem should be based on the type or severity of infection and given in equally divided doses based on consideration of degree of susceptibility of the pathogens, renal function and body-weight.

Imipenem & Cilastatin IV: Up to 500 mg dose should be given over 20 to 30 minutes; > 500 mg dose should be infused over 40 to 60 minutes. In patients who develop nausea during the infusion, the rate of infusion may be slowed.

Adult: Normal daily dose is 1-2 g administered in 3-4 divided doses. For the treatment of moderate infection, a 1 g b.i.d. dosage regimen may also be used. In infections due to less susceptible organisms, the daily dosage may be increased to a maximum of 4 g/day or 50 mg/kg/day, whichever is lower.

• Mild infection: 250 mg 6 hourly (1 gm/day)
• Moderate infection: 500 mg 8 hourly or 1 gm 12 hourly (1.5-2 gm/day)
• Severe infection with fully susceptible microorganism: 500 mg 6 hourly (2gm/day)
• Severe infection with less susceptible organisms (primarily some strains of P. aeruginosa): 1 gm 3-4 times daily (3-4 gm/day)

Paediatric Dosing Schedule:

• ≥ 3 months of age: the recommended dose for non-CNS infections is 15-25 mg/kg/dose administered every six hours. The maximum daily dose for treatment of infections with fully susceptible organisms is 2.0 g per day, and of infections with moderately susceptible organisms is 4.0 g/day. Higher doses (up to 90 mg/kg/day in older children) have been used in patients with cystic fibrosis.
• ≤3 months of age: Following dosage schedule is recommended for non-CNS infections:
• <1 week of age: 25 mg/kg every 12 hrs
• 1-4 weeks of age: 25 mg/kg every 8 hrs
• 4 weeks-3 months of age: 25 mg/kg every 6 hrs.

Imipenem is not recommended for the therapy of meningitis. If meningitis is suspected, an appropriate antibiotic should be used. Imipenem and cilastatin for injection is not recommended in pediatric patients <30 kg with impaired renal function, as no data are available.

Most common side effects with imipenem are nausea and vomiting. Other side effects reported with this drug are diarrhea, rash, thrombophlebitis, thrombocytosis, neutro-penia, eosinophilia and derangements of liver and renal functions. Use of imipenem is not recommended for patient with history of anaphylactic reaction with penicillin.

Contraindicated in patients who have demonstrated hypersensitivity to this product.

Caution when used in patients with known hypersensitivity to other β-lactams due to possibility of cross-sensitivity. CNS disorders such as epilepsy; renal, hepatic impairment; pregnancy, lactation.

Concurrent admin with probenecid may increase the half-life of cilastatin. Increased risk of generalised seizures when used concurrently with ganciclovir.

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

Lactation: Imipenem has been detected in human milk. If the use of Cispenam is deemed essential, the patient should stop nursing.

Dosage adjustment in renal impairment:

• CrCl >71: No changes.
• CrCl 41-70: Max 37.5 mg/kg/day or 3 g/day. (Range: 9.4 - 37.5 mg/kg/day) divided q6-8h.
• CrCl 21-40: Max 25 mg/kg/day or 2 g/day. (Range: 6.25 - 25 mg/kg/day) divided q6-12h.
• CrCl 6-20: Max 12.5 mg/kg/day (max dose 1 g/day). Range: 6.25 - 12.5 mg/kg/day) divided q12h. (Usual: 250mg q12h)
• Dialysis Hemodialysis: 125 - 500 mg q12h. (Max 12.5 mg/kg/day). Give dose after dialysis.
• Peritonial Dialysis: 125 - 250 mg q12h

In the case of overdosage, discontinue Imipenem/Cilastatin, treat symptomatically, and institute supportive measures as required. Imipenem/Cilastatin Sodium is hemodialyzable.

Other beta-lactam Antibiotics

Imipenem acts as an antimicrobial through the inhibition of cell wall synthesis of various gram-positive and gram-negative bacteria. This inhibition of cell wall synthesis in gram-negative bateria is attained by binding to pencillin binding proteins (PBPs). In E. coli and selected strains of P. aeruginosa, imipenem has shown to have the highest affinity to PBP-2, PBP-1a, and PBP-1b. This preferential binding to PBP-2 and PBP-1b results in the direct conversion of the individual cell to a spheroblast, which leads to rapid cell lysis and death without filament formation.

Cilastatin is a specific and reversible renal dehydropeptidase-I inhibitor. Since the antibiotic, imipenem, is hydrolyzed by dehydropeptidase-I, which resides in the brush border of the renal tubule, cilastatin is administered with imipenem to block the metabolism and thus the inactivation of imipenem so that antibacterial levels of imipenem can be attained in the urine. The drug also prevents the metabolism of leukotriene D4 to leukotriene E4 through the inhibition of leukotriene D4 dipeptidase.

The total daily dosage of Imipenem should be based on the type or severity of infection and given in equally divided doses based on consideration of degree of susceptibility of the pathogens, renal function and body-weight.

Imipenem & Cilastatin IV: Up to 500 mg dose should be given over 20 to 30 minutes; > 500 mg dose should be infused over 40 to 60 minutes. In patients who develop nausea during the infusion, the rate of infusion may be slowed.

Adult: Normal daily dose is 1-2 g administered in 3-4 divided doses. For the treatment of moderate infection, a 1 g b.i.d. dosage regimen may also be used. In infections due to less susceptible organisms, the daily dosage may be increased to a maximum of 4 g/day or 50 mg/kg/day, whichever is lower.

• Mild infection: 250 mg 6 hourly (1 gm/day)
• Moderate infection: 500 mg 8 hourly or 1 gm 12 hourly (1.5-2 gm/day)
• Severe infection with fully susceptible microorganism: 500 mg 6 hourly (2gm/day)
• Severe infection with less susceptible organisms (primarily some strains of P. aeruginosa): 1 gm 3-4 times daily (3-4 gm/day)

Paediatric Dosing Schedule:

• ≥ 3 months of age: the recommended dose for non-CNS infections is 15-25 mg/kg/dose administered every six hours. The maximum daily dose for treatment of infections with fully susceptible organisms is 2.0 g per day, and of infections with moderately susceptible organisms is 4.0 g/day. Higher doses (up to 90 mg/kg/day in older children) have been used in patients with cystic fibrosis.
• ≤3 months of age: Following dosage schedule is recommended for non-CNS infections:
• <1 week of age: 25 mg/kg every 12 hrs
• 1-4 weeks of age: 25 mg/kg every 8 hrs
• 4 weeks-3 months of age: 25 mg/kg every 6 hrs.

Imipenem is not recommended for the therapy of meningitis. If meningitis is suspected, an appropriate antibiotic should be used. Imipenem and cilastatin for injection is not recommended in pediatric patients <30 kg with impaired renal function, as no data are available.

Most common side effects with imipenem are nausea and vomiting. Other side effects reported with this drug are diarrhea, rash, thrombophlebitis, thrombocytosis, neutro-penia, eosinophilia and derangements of liver and renal functions. Use of imipenem is not recommended for patient with history of anaphylactic reaction with penicillin.

Contraindicated in patients who have demonstrated hypersensitivity to this product.

Caution when used in patients with known hypersensitivity to other β-lactams due to possibility of cross-sensitivity. CNS disorders such as epilepsy; renal, hepatic impairment; pregnancy, lactation.

Concurrent admin with probenecid may increase the half-life of cilastatin. Increased risk of generalised seizures when used concurrently with ganciclovir.

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

Lactation: Imipenem has been detected in human milk. If the use of Cispenam is deemed essential, the patient should stop nursing.

Dosage adjustment in renal impairment:

• CrCl >71: No changes.
• CrCl 41-70: Max 37.5 mg/kg/day or 3 g/day. (Range: 9.4 - 37.5 mg/kg/day) divided q6-8h.
• CrCl 21-40: Max 25 mg/kg/day or 2 g/day. (Range: 6.25 - 25 mg/kg/day) divided q6-12h.
• CrCl 6-20: Max 12.5 mg/kg/day (max dose 1 g/day). Range: 6.25 - 12.5 mg/kg/day) divided q12h. (Usual: 250mg q12h)
• Dialysis Hemodialysis: 125 - 500 mg q12h. (Max 12.5 mg/kg/day). Give dose after dialysis.
• Peritonial Dialysis: 125 - 250 mg q12h

In the case of overdosage, discontinue Imipenem/Cilastatin, treat symptomatically, and institute supportive measures as required. Imipenem/Cilastatin Sodium is hemodialyzable.