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Minoxidil is indicated in the treatment of androgenic alopecia in males and females and stabilisation of hair loss in patients with androgenic alopecia, and also of alopecia areata.

Other scalp preparations

Minoxidil stimulates hair growth by increasing oxygen, blood and nutrients supply to the hair follicle by widening blood vessels and inhibiting androgen hormone to affect hair follicles.

Following topical application, an average of about 1.4% of the total applied dose is absorbed from the normal intact scalp. Topical Minoxidil absorption is increased by increasing the  dose applied, increasing the frequency of dosing and decreasing the barrier function of the stratum corneum. Serum Minoxidil levels and systemic effects resulting from the administration of topical Minoxidil are governed by the drug’s absorption rate through the skin. Following cessation of topical dosing, approximately 95% of the systemically absorbed drug is eliminated within 4 days. Minoxidil and its metabolites are excreted principally in the urine.

Minoxidil topical solution is for external use only and should be applied when the hair and scalp are clean and dry. Apply 1 ml (7 sprays) of Minoxidil topical solution twice daily at 12-hour intervals to the scalp, beginning at the centre of the affected area and spreading the solution out to cover the entire affected area. The total daily application dose should not exceed 2 ml.

For the best results, Minoxidil topical solution should be allowed to remain on the scalp for about 4 hours before washing. The night-time application should be done 2-4 hours before going to bed to allow the solution to dry out. Minoxidil topical solution should not be massaged into the scalp, but applied lightly. A hair dryer should not be used to speed up the drying of the solution as it may decrease the effectiveness. Minoxidil topical solution should not be mixed with any hair oil. The drug should not be used more than two times a day, or be taken orally or applied to any other part of the body to avoid the risk of adverse effects and unwanted hair growth. More frequent use or longer application time have no effect on hair growth. In case of missing any daily applications of Minoxidil topical solution, the patient should continue with the next application.

Hands should be washed immediately if Minoxidil topical solution is applied with the fingertips. Clinical experience with Minoxidil indicates that twice-daily applications for 4 months or more may be required before there is evidence of hair growth. To arrest hair fall, Minoxidil topical solution should be used for not less than 45 days. Depending upon the severity of hair loss or type and extent of baldness, particular strength of Minoxidil topical solution may be selected.

Commonly encountered side effects in clinical trials with Minoxidil topical solution were minor dermatological reactions. Dermatitis or hypertrichosis may occur. These incidences may occur in 0.1–5% of patients.

Minoxidil topical solution is more likely to cause scalp irritation. If scalp irritation continues or worsen, use of Minoxidil topical solution should be stopped.

Minoxidil topical solution should not be used along with other topical agents known to alter the stratum corneum barrier such as tretinoin or dithranol, due to the enhanced absorption of Minoxidil. Although there is no clinical evidence, there exists the theoretical possibility of absorbed Minoxidil potentiating orthostatic hypotension caused by peripheral vasodilators.

Minoxidil topical solution should not be used during pregnancy and lactation.

Increased systemic absorption of Minoxidil may potentially occur if higher-than-recommended doses of Minoxidil are applied to larger surface areas of the body or areas other than the scalp. There are no known cases of Minoxidil overdosage resulting from topical administration of Minoxidil.

Signs and symptoms of Minoxidil overdosage would primarily be cardiovascular effects associated with sodium and water retention, and tachycardia. Fluid retention can be managed with appropriate diuretic therapy. Clinically significant tachycardia can be controlled by administration of a beta-adrenergic blocking agent.

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

Peppermint Oil is indicated in Irritable bowel syndrome (IBS), Functional dyspepsia, Abdominal pain and spasm, Abdominal distension/bloating

Anticholinergics (antimuscarinics)/ Anti-spasmodics, Herbal and Nutraceuticals

Peppermint Oil helps to relieve both the painful abdominal spasm and uncomfortable bloating of IBS. It has a relaxant, antispasmodic effect especially on the muscles of the large bowel or colon and in bowel spasm, particularly large-bowel spasm. It is carminative, antibacterial, mucolytic. Peppermint Oil helps to treat unpleasant sensations of fullness and bloating and facilitates the passing of bowel gases, so relieving accompanying cramp like pain.

Adults: 1 capsule 3 times daily with a glass of water. The dose may be increased to a maximum of 2 capsules 3 times daily or as directed by a physician.

Children (8 years and above): 1 capsule 3 times daily with a glass of water or a directed by a physician.

Contraindicated in patients with achlorhydria. Also contraindicated for infants due to the potential risk of spasm of the tongue or respiratory arrest.

Should not be taken with food or immediately after meals. Should be taken 30 to 60 minutes before meals. Must be swallowed whole, with a little liquid. Capsules must not be chewed or crushed.

Exacerbation of adverse effects if taken with alcohol; enteric-coated preparations containing peppermint oil should not be taken immediately with antacids.

No known restrictions.

Keep in a cool & dry place, away from direct sunlight. Keep out of reach of children.

Peppermint Oil is indicated in Irritable bowel syndrome (IBS), Functional dyspepsia, Abdominal pain and spasm, Abdominal distension/bloating

Anticholinergics (antimuscarinics)/ Anti-spasmodics, Herbal and Nutraceuticals

Peppermint Oil helps to relieve both the painful abdominal spasm and uncomfortable bloating of IBS. It has a relaxant, antispasmodic effect especially on the muscles of the large bowel or colon and in bowel spasm, particularly large-bowel spasm. It is carminative, antibacterial, mucolytic. Peppermint Oil helps to treat unpleasant sensations of fullness and bloating and facilitates the passing of bowel gases, so relieving accompanying cramp like pain.

Adults: 1 capsule 3 times daily with a glass of water. The dose may be increased to a maximum of 2 capsules 3 times daily or as directed by a physician.

Children (8 years and above): 1 capsule 3 times daily with a glass of water or a directed by a physician.

Contraindicated in patients with achlorhydria. Also contraindicated for infants due to the potential risk of spasm of the tongue or respiratory arrest.

Should not be taken with food or immediately after meals. Should be taken 30 to 60 minutes before meals. Must be swallowed whole, with a little liquid. Capsules must not be chewed or crushed.

Exacerbation of adverse effects if taken with alcohol; enteric-coated preparations containing peppermint oil should not be taken immediately with antacids.

No known restrictions.

Keep in a cool & dry place, away from direct sunlight. Keep out of reach of children.

This is indicated for the treatment and prevention of zinc and vitamin B deficiencies.

Specific mineral & vitamin combined preparations

Zinc is vital for many biological functions such as immunity enhancement, wound healing, digestion, reproduction, physical growth and mental development. Zinc supports normal growth and development during pregnancy, childhood, and adolescence. Zinc also has some antioxidant properties. Zinc is used to treat ADHD (Attention Deficit Hyper-activity Disorder) in children. In adult, due to zinc deficiency loss of appetite, poor sense of taste and smell, tendency towards depression, white marks on fingernails, frequent infections, low fertility, prostate problems, mental problems, poor wound healing, a poor immune system, diarrhoea, mental lethargy, rough skin and weight loss may occur.

B-Vitamins are needed to release energy from food. They play an important role in ensuring healthy brain and nerve function, healthy red blood cells formation in children & adults. They are specially needed for healthy growth and development of children. B-Vitamin deficiencies in adult cause profound fatigue and various types of neurologic manifestations, which may include weakness, poor balance, confusion, irritability, memory loss, nervousness, tingling of the limbs and loss of coordination. Additional symptoms of vitamin B deficiency are sleep disturbances, nausea, poor appetite, frequent infections, and skin lesions.

Syrup-

• Adults: 10 ml (2 teaspoonful) 2 to 3 times daily or as recommended by the physician.
• Children: 10 ml (2 teaspoonful) 1 to 3 times daily or as recommended by the physician.
• Infants: 5 ml (1 teaspoonful) 1 to 2 times daily or as recommended by the physician.

Tablet-

• Adults & Children over 30 kg: 1 to 2 tablets 2 to 3 times daily or as recommended by the physician.

This is generally well tolerated. However, a few side effects like nausea, vomiting, diarrhoea & stomach upset may occur. Side effects have been reported with specific vitamins but generally at levels substantially higher than recommended doses.

Vitamin B Complex & Zinc is contraindicated in patients with a known hypersensitivity to any of the ingredients of this product.

In acute renal failure, zinc accumulation may occur, so dosage adjustment is needed. This is not intended for the treatment of severe specific deficiencies.

Concomitant intake of tetracyclines and zinc may decrease the Gl absorption and serum levels of tetracyclines. Similarly concomitant administration of zinc and fluroquinolones may decrease the Gl absorption and serum  levels of some fluroquinolones. Coadministration of Niacin and HMG-CoA reductase inhibitors (eg. lovastatin) may result mayopathy and rhabdomyolysis. Pyridoxine reduces levodopa's effectiveness by increasing its peripheral metabolism. Co-administration of pyridoxine with phenytoin may decrease serum levels of phenytoin.

This is recommended in pregnancy and lactation.

In case of overdosage, initially epigastric pain, diarrhoea and vomiting can occur. In that case, one should seek emergency medical attention. Initially, an emetic should be given and then gastric lavage and general supportive measures should be employed.

Store in a cool & dry place, protected from light. Keep all medicines out of reach of children.

Zolmitriptan is indicated for the acute treatment of migraines with or without aura in adults.

5-HT Agonists

Migraines are likely due to local cranial vasodilatation and/or to the release of sensory neuropeptides through nerve endings in the trigeminal system. The therapeutic activity of Zolmitriptan for the treatment of migraine headache is thought to be due to the agonist effects at the 5-HT_1B/1D receptors on intracranial blood vessels and sensory nerves of the trigeminal system which results in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.

Tablet: The recommended starting dose of Zolmitriptan is 2.5 mg tablet. Maximum recommended single dose is 5 mg. If the migraine has not resolved by 2 hours after taking Zolmitriptan, or returns after a transient improvement, a second dose may be administered at least 2 hours after the first dose. The maximum daily dose is 10 mg in any 24-hours period.

Nasal Spray: Administer one dose of Zolmitriptan Nasal Spray 5 mg for the treatment of acute migraine. If the headache returns the dose may be repeated after 2 hours. The maximum daily dose should not exceed 10 mg in any 24-hour period. In controlled clinical trials, single doses of 5 mg zolmitriptan nasal spray were administered into one nostril and were effective for the treatment of acute migraines in adults. Individuals may vary in response to Zolmitriptan Nasal Spray. The pharmacokinetics of a 5 mg nasal spray dose is similar to the 5 mg oral formulations. Doses lower than 5 mg can only be achieved through the use of an oral formulation. The choice of dose, and route of administration should therefore be made on an individual basis. The effectiveness of a second dose has not been established in placebo-controlled trials. The safety of treating an average of more than four headaches in a 30 day period has not been established.

Most common adverse reactions were neck/throat/jaw pain or pressure, dizziness, paresthesia, asthenia, somnolence, warm/cold sensation, nausea, heaviness sensation, and dry mouth.

Contraindicated in patients with ischemic coronary artery disease, history of stroke, concurrent or recent use of a monoamine oxidase inhibitor and known hypersensitivity to Zolmitriptan.

There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration. Sensations of tightness, pain, and pressure may occur in the chest, throat, neck, and jaw after treatment with Zolmitriptan.

Pregnancy Category C. Zolmitriptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is not known whether Zolmitriptan is excreted in human milk. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: Not recommended for use in patients under 18 years of age.

Protect from light and moisture, store below 30°C. Keep the medicine out of the reach of children.

Vitamin B1, B6 & B12 is indicated for the treatment of vitamin B1, B6 & B12 deficiency syndrome. It is also indicated for the supportive treatment of neuritis & non-inflammatory diseases of the nerves, e.g.- Diabetic neuropathy, Peripheral neuralgin, Lumbago, Myalgia, Optic neuritis, Sciatica, Facial neuralgia, Intercostal neuralgia, Spinal pain.

Specific combined vitamin preparations

Vitamin B1 converts carbohydrates, fatty acids and amino acids into energy, promotes healthy nerves, improves mood, strengthens the heart. Vitamin B6 forms RBCs, helps cells to make proteins, manufactures neurotransmitters e.g. serotonin and releases stored forms of energy, helps to prevent CVS diseases and stroke, helps to lift depression and eases insomnia. Vitamin B12 is essential for cell replication and important for RBC production, prevents anemia, helps to prevent depression, reduces nerve pain, numbness, tingling and lowers the risk of heart diseases.

The vitamin ingredients are absorbed well in per oral reception. It is widely distributed to most tissues and appears in breast milk. Within the cell, thiamine is mostly present as diphosphate. Thiamine is not stored to any appreciable extent in the body and amounts in excess of the body’s requirements are excreted in the urine as unchanged thiamine or as metabolites. Pyridoxine, pyridoxal and pyridoxamine are readily absorbed from the GIT following oral administration and are converted to the active forms of pyridoxal phosphate an pyridoxamine phosphate. They are stored mainly in liver where there is oxidation to 4-pyridoxic acid and other inactive metabolites, which are excreted in urine. As the dose increases, proportionally greater amounts are excreted unchanged in the urine.

Tablet: 1-3 Tablets per day or as advised by the physician.

Injection:

• In severe (acute) cases: 1 injection daily until the acute symptoms subside or taken as advised by the physician.
• In mild cases: 1 injection 2-3 times per week. Ampoules are preferably injected intramuscularly.

Use in children: There is no information on the use of this drug in children.

Generally well tolerated but allergic reactions may be observed in few cases.

Vitamin B1, Vitamin B6 and Vitamin B12 is contraindicated in patients on levodopa therapy, and in patients with hypersensitivity to any of the ingredients of the preparation.

Cyanocobalamin should not be given in patients with subacute degeneration of the spinal cord. Cyanocobalamin is not suitable form of vitamin B12 for the treatment of optic neuropathies associated with raised plasma concentrations of cyanocobalamin.

No drug interaction has been reported yet.

Oral tablet form is recommended but due to the presence of benzyl alcohol, injection is not recommended during pregnancy & lactation.

No overdosage symptoms are to be expected in the recommended dosage. If there is known overdose then treatment is symptomatic & supportive.

Keep out of reach of children. Store in a cool (below 25°C temperature) and dry place, protected from light.

Drugs acting on the Uterus, Prostaglandin analogues

Misoprostol is extensively absorbed, and undergoes rapid de-esterification to its free acid, which is responsible for its clinical activity and, unlike the parent compound, is detectable in plasma. Maximum plasma concentrations of Misoprostol acid are diminished when the dose is taken with food and total availability of Misoprostol acid is reduced by use of concomitant antacid. Misoprostol has both antisecretory (inhibiting gastric acid secretion) and (in animals) mucosal protective properties. NSAIDs inhibit prostaglandin synthesis, and a deficiency of prostaglandins within the gastric mucosa may lead to diminishing bicarbonate and mucus secretion and may contribute to the mucosal damage caused by these agents. Misoprostol can increase bicarbonate and mucus production, but in man this has been shown at doses 200 meg and above that are also antisecretory. It is therefore not possible to tell whether the ability of Misoprostol to reduce the risk of gastric ulcer is the result of its antisecretory effect, its mucosal protective effect, or both.

Benign gastric and duodenal ulceration and NSAID associated ulceration: 800 mcg daily (in 2-4 divided doses) with breakfast or main meals and at bedtime; treatment should be continued for at least 4 weeks and may be continued for up to 8 weeks if required.

Prophylaxis of NSAID-induced gastric and duodenal ulcer: 200 mcg 2-4 times daily taken with NSAID. If this dose cannot be tolerated, a dose of 100 mcg can be used. Misoprostol should be taken for the duration of NSAID therapy as prescribed by the physician.

Induction of labor: Place 25 mcg in the posterior fornix of the vagina. Repeat after every 6 hours if necessary until the maximum dosage of 200 mcg total misoprostol is reached. Fetal heart rate and uterus contractions should be monitored. Alternatively, 100 mcg taken orally. If cervical ripening or active labor does not occur, repeated dose of 100-200 mcg of oral misoprostol is given every 4 hourly until labor is established (as evidenced by a Bishop score of 7 or more). Maximum number of dose is 6. Maternal vital signs, fetal heart rate and contractions should be monitored. Oxytocin can be started 4 hours after last dose of misoprostol. Physician should be notified for signs of fetal distress or tetanic uterine contractions. Oral misoprostol therapy should be monitored by Physician.

Prevention of postpartum hemorrhage: 600 mcg orally immediately following delivery.

Treatment of postpartum hemorrhage: 600 mcg orally or 1000 mcg per rectally.

Generally, Misoprostol is well tolerated. The most frequent adverse effects associated with Misoprostol therapy involve the GI tract such as diarrhea, abdominal pain, dyspepsia, flatulence, nausea, vomiting, rashes and dizziness. The incidence of diarrhea may be minimized by administering the drug after meal and at bedtime and by avoiding concomitant administration with a magnesium-containing or other laxative antacid.

Misoprostol is contraindicated to anyone with a history of allergy to prostaglandins and it is also contraindicated in pregnancy.

In case of prevention and treatment of NSAID induced gastric and duodenal ulcer: Misoprostol is contraindicated in women who are pregnant, and should not be used in women of child bearing potential unless the patient requires NSAID therapy. Women of child bearing potential should be told that they must not be pregnant when Misoprostol therapy is initiated and they must use an effective contraception method while taking misoprostol.

In case of induction of labor: The pregnancy should have completed 38 weeks gestation by reliable dating, or lung maturity as evidenced by a L/S >2.0 or a positive phosphotidyl glycerol test, or completed 36 weeks gestation with a maternal or fetal medical indication for induction of labor. Induction of labor is contraindicated in acute fetal distress, abruptio placenta, placenta previa or unexplained vaginal bleeding. The fetus should be in vertex presentation.

There is no evidence of clinically significant interaction between Misoprostol and cardiac, pulmonary, CNS drugs and NSAID's. The bioavailability of Misoprostol is decreased with high doses of antacid.

Because of the abortifacient property of the Misoprostol component, it is contraindicated in women who are pregnant. It should not be used in women of childbearing potential unless the patient requires nonsteroidal anti-inflammatory drug (NSAID) therapy and is at high risk of developing gastric or duodenal ulceration or for developing complications from gastric or duodenal ulcers associated with the use of the NSAID. In such patients, it may be prescribed if the patient:

• has had a negative serum pregnancy test within 2 weeks prior to beginning therapy.
• is capable of complying with effective contraceptive measures.
• has received both oral and written warnings of the hazards of Misoprostol, the risk of possible contraception failure, and the danger to other women of childbearing potential should the drug be taken by mistake.
• will begin it only on the second or third day of the next normal menstrual period.

Excretion of the active metabolite (Misoprostol acid) into milk is possible but has not been studied. Because of the potential for serious adverse reactions in nursing infants, it is not recommended for use by nursing mothers.

Use in children: Safety and effectiveness of Misoprostol in children below the age of 18 years have not been established.

The toxic dose of Misoprostol in human has not been determined. Clinical signs that may indicate an overdose are a sedation, tremor, convulsions, dyspnea, abdominal pain, diarrhea and fever. Symptoms should be treated with supportive therapy.

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

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

BPH/ Urinary retention/ Urinary incontinence

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

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

Renal or hepatic impairment:

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

Gender: No dose adjustment is necessary according to gender.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

BPH/ Urinary retention/ Urinary incontinence

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

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

Renal or hepatic impairment:

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

Gender: No dose adjustment is necessary according to gender.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Minerals in bone formation, Specific mineral preparations

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

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

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

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

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

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

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

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

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

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

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

Specific mineral & vitamin combined preparations

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

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

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

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

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

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

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

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

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

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

Minerals in bone formation, Specific mineral preparations

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

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

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

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

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

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

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

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

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

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

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

Specific mineral & vitamin combined preparations

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

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

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

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

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

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

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

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

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

Cough suppressant

Butamirate Citrate acts directly on the brain's cough center to suppress cough. Butamirate Citrate is safe and non-sedating which is neither chemically nor pharmacologically related to opium alkaloids. Butamirate Citrate is rapidly and completely absorbed after oral administration. Maximum concentration is reached within 9 hours with the sustained-release tablet. This is extremely protein-bound and plasma elimination half-life is about 13 hours. The active metabolites of Butamirate Citrate have also antitussive action.

Use in adult:

• Butamirate Citrate 50 mg tablet: 2-3 tablets daily.
• Butamirate Citrate syrup: 15 ml 4 times daily.

Use in children & adolescents:
Butamirate Citrate 50 mg tablet:

• Adolescent over 12 years old: 1-2 tablets daily.

Butamirate Citrate syrup:

• Children (3-6 yrs): 5 ml 3 times daily.
• Children (6-12 yrs): 10 ml 3 times daily.
• Adolescent: 15 ml 3 times daily.

Butamirate Citrate pediatric drops:

• Children ( 2 months- 1 yrs): 0.50 ml 4 times daily.
• Children (1-3 yrs): 0.75 ml 4 times daily.

Tolerance of Butamirate Citrate is good.Adverse reactions such as rash,nausea,diarrhoea and vertigo have been observed in a few rare cases,resolving after dose reduction or treatment withdrawal.

Hypersensitivity to the active ingredient.

Butamirate Citrate suppresses the cough reflex and therefore the concomitant use with expectorants should be avoided, since it may lead to mucus retention in the airways, which increases the risk of bronchospasm and respiratory infections. If the cough persists for more than 7 days (more than 3 days in children younger than12 years of age) doctor must be consulted.

Concomitant use with expectorants should be avoided.

Butamirate Citrate should not be used during the first trimester of pregnancy. During the remainder of pregnancy, it can be used if indicated by a physician but with caution. As a general rule, for safety reasons, in the absence of data on elimination of the active substance in breast milk, the benefits of Butamirate Citrate administration during breast feeding should be carefully weighed against the risks.

Accidental overdose with Butamirate Citrate can cause the following symptoms: drowsiness, nausea, vomiting, diarrhoea, loss of balance and hypotension. Standard emergency procedures should be followed: activated charcoal, saline laxatives and standard cardio-respiratory resuscitation.

Keep away from light and moisture, store below 30°C. Keep all the medicines out of the reach of children.

Adjunct anti-epileptic drugs, Benzodiazepine hypnotics

Clonazepam exhibits pharmacological properties which are common to benzodiazepines and include anticonvulsive, sedative, muscle relaxing and anxiolytic effects. The central actions of benzodiazepines are mediated through an enhancement of the GABAergic neurotransmission at inhibitory synapses. In the presence of benzodiazepines the affinity of the GABA receptor for the neurotransmitter is enhanced through positive allosteric modulation resulting in an increased action of released GABA on the postsynaptic transmembrane chloride ion flux.

There are also animal data showing an effect of clonazepam on serotonin. Animal data and electroencephalographic investigations in man have shown that clonazepam rapidly suppresses many types of paroxysmal activity including the spike and wave discharge in absences seizures (petit mal), slow spike wave, generalized spike wave, spikes with temporal or other locations as well as irregular spikes and waves. Generalized EEG abnormalities are more regularly suppressed than focal abnormalities. According to these findings clonazepam has beneficial effects in generalized and focal epilepsies.

Oral:

• Adults: The initial dose for adults with seizure disorders should not exceed 1.5 mg/day divided into three doses. Dosage may be increased in increments of 0.5 to 1 mg every 3 days until seizures are adequately controlled or until side effects preclude any further increase. Maintenance dosage must be individualized for each patient depending upon response. Maximum recommended daily dose is 20 mg.

• The initial dose for adults with panic disorder is 0.25 mg given in two divided dose. An increase to the target dose for most patients of 1 mg/day may be made after 3 days.
• Pediatric Patients: In order to minimize drowsiness, the initial dose for infants and children (up to 10 years of age or 30 kg of body weight) should be between 0.01 and 0.03 mg/kg/day but not to exceed 0.05 mg/kg/day given in two or three divided doses.

Injection:

• Infants and children: half of a vial (0.5 mg) by slow IV injection or by IV infusion.

• Adults: 1 vial (1 mg) by slow IV injection or by IV infusion. This dose can be repeated as required (1-4 mg are usually sufficient to reverse the status). In adults, the rate of injection must not exceed 0.25 - 0.5 mg per minute (0.5-1.0 ml of the prepared solution) and a total dose of 10 mg should not be exceeded.

The most frequently occurring side effects of Clonazepam are referable to CNS depression. Experience in treatment of seizures has shown that drowsiness has occurred in approximately 50% of patients and ataxia in approximately 30%. In some cases, these may diminish with time; behavior problems have been noted in approximately 25% of patients. Abnormal eye movements, aphonia, coma, tremor, vertigo, confusion, depression, amnesia, hallucinations, hysteria, increased libido, insomnia, psychosis & palpitations may also occur.

It should not be used in patients with a history of hypersensitivity to benzodiazepines, nor in patients with clinical or biochemical evidence of significant liver disease. It may be used in patients with open angle glaucoma who are receiving appropriate therapy but is contraindicated in acute narrow angle glaucoma.

When used in patients in whom several different types of seizure disorders coexist, Clonazepam may increase the incidence or precipitate the onset of generalized tonic-clonic seizures. This may require the addition of appropriate anticonvulsants or an increase in their dosages. The concomitant use of valproic acid and Clonazepam may produce absence status.

Clonazepam does not appear to alter the pharmacokinetics of phenytoin, carbamazepine or phenobarbital. The effect of Clonazepam on the metabolism of other drugs has not been investigated.

Pregnancy: From preclinical studies it cannot be excluded that clonazepam possesses the possibility of producing congenital malformations. From epidemiological evaluations there is evidence that anticonvulsant drugs act as teratogens. However, it is difficult to determine from published epidemiological reports which drug or combination of drugs is responsible for defects in the newborn. The possibility also exists that other factors e.g. genetic factors or the epileptic condition itself may be more important than drug therapy in leading to birth defects. Under these circumstances, the drug should only be administered to pregnant women if the potential benefits outweigh the risk to the foetus. During pregnancy, Clonazepam may be administered only if there is a compelling indication. Administration of high doses in the last trimester of pregnancy or during labour can cause irregularities in the heartbeat of the unborn child and hypothermia, hypotonia, mild respiratory depression and poor feeding in the neonate. It should be borne in mind that both pregnancy itself and abrupt discontinuation of the medication can cause exacerbation of epilepsy. Withdrawal symptoms in newborn infants have occasionally been reported with benzodiazepines.

Nursing Mothers: Although the active ingredient of Clonazepam has been found to pass into the maternal milk in small amounts only, mothers undergoing treatment with this drug should not breastfeed. If there is a compelling indication for Clonazepam, breastfeeding should be discontinued.

Pediatric Use: In infants and small children Rivotril may cause increased production of saliva and bronchial secretion. Therefore special attention must be paid to maintaining patency of the airways. 

Geriatric Use: Benzodiazepine pharmacologic effects appear to be greater in elderly patients than in younger patients even at similar plasma benzodiazepine concentrations, possibly because of age-related changes in drug–receptor interactions, post-receptor mechanisms and organ function.

Renal Impairment: Renal impairment does not affect the pharmacokinetics of clonazepam. Based on pharmacokinetic criteria, no dose adjustment is required in patients with renal impairment.

Hepatic Impairment: Plasma protein binding of clonazepam in cirrhotic patients is significantly different from that in healthy subjects (free fraction 17.1±1.0% vs 13.9±0.2%). Although the influence of hepatic impairment on clonazepam pharmacokinetics has not been further investigated, experience with another closely related nitrobenzodiazepine (nitrazepam) indicates that clearance of unbound clonazepam might be reduced in liver cirrhosis.

Symptoms: Benzodiazepines commonly cause drowsiness, ataxia, dysarthria and nystagmus. Overdose of Clonazepam is seldom life-threatening if the drug is taken alone, but may lead to areflexia, apnoea, hypotension, cardiorespiratory depression and coma. Coma, if it occurs, usually lasts a few hours but it may be more protracted and cyclical, particularly in elderly patients. Increased frequency of seizures may occur in patients at supratherapeutic plasma concentrations. Benzodiazepine respiratory depressant effects are more serious in patients with respiratory disease. Benzodiazepines increase the effects of other central nervous system depressants, including alcohol.

Treatment: Monitor the patient’s vital signs and institute supportive measures as indicated by the patient’s clinical state. In particular, patients may require symptomatic treatment for cardiorespiratory effects or central nervous system effects. Further absorption should be prevented using an appropriate method e.g. treatment within 1-2 hours with activated charcoal. If activated charcoal is used airway protection is imperative for drowsy patients. In case of mixed ingestion gastric lavage may be considered, however not as a routine measure. If CNS depression is severe consider the use of flumazenil, a benzodiazepine antagonist. This should only be administered under closely monitored conditions. It has a short half-life (about an hour), therefore patients administered flumazenil will require monitoring after its effects have worn off. Flumazenil is to be used with extreme caution in the presence of drugs that reduce seizure threshold (e.g. tricyclic antidepressants). Refer to the prescribing information for flumazenil, for further information on the correct use of this drug.

Slow intravenous injection: The contents of the vial must be diluted with 1 ml of water for injection prior to administration so as to avoid local irritation of the veins. The injection solution should be prepared immediately before use. IV injection should be administered slowly with continuous monitoring of EEG, respiration and blood pressure.

Intravenous infusion: Clonazepam (the vial) can be diluted for infusion in a ratio of 1 vial (1 mg) to at least 85 ml diluting media. The diluting media can be any of the following: sodium chloride 0.9%; sodium chloride 0.45% + glucose 2.5%; glucose 5% or glucose 10%. These mixtures are stable for 24 hours at room temperature. Infusion bags other than PVC should be used for infusing Clonazepam. If PVC infusion bags are used then the mixture should be infused immediately or within 4 hours. The infusion time should not exceed 8 hours. Do not prepare Clonazepam infusions using sodium bicarbonate solution, as precipitation of the solution may occur.

Intramuscular injection: The IM route should be used only in exceptional cases or if IV administration is not feasible.

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

Adjunct anti-epileptic drugs, Benzodiazepine hypnotics

Clonazepam exhibits pharmacological properties which are common to benzodiazepines and include anticonvulsive, sedative, muscle relaxing and anxiolytic effects. The central actions of benzodiazepines are mediated through an enhancement of the GABAergic neurotransmission at inhibitory synapses. In the presence of benzodiazepines the affinity of the GABA receptor for the neurotransmitter is enhanced through positive allosteric modulation resulting in an increased action of released GABA on the postsynaptic transmembrane chloride ion flux.

There are also animal data showing an effect of clonazepam on serotonin. Animal data and electroencephalographic investigations in man have shown that clonazepam rapidly suppresses many types of paroxysmal activity including the spike and wave discharge in absences seizures (petit mal), slow spike wave, generalized spike wave, spikes with temporal or other locations as well as irregular spikes and waves. Generalized EEG abnormalities are more regularly suppressed than focal abnormalities. According to these findings clonazepam has beneficial effects in generalized and focal epilepsies.

Oral:

• Adults: The initial dose for adults with seizure disorders should not exceed 1.5 mg/day divided into three doses. Dosage may be increased in increments of 0.5 to 1 mg every 3 days until seizures are adequately controlled or until side effects preclude any further increase. Maintenance dosage must be individualized for each patient depending upon response. Maximum recommended daily dose is 20 mg.

• The initial dose for adults with panic disorder is 0.25 mg given in two divided dose. An increase to the target dose for most patients of 1 mg/day may be made after 3 days.
• Pediatric Patients: In order to minimize drowsiness, the initial dose for infants and children (up to 10 years of age or 30 kg of body weight) should be between 0.01 and 0.03 mg/kg/day but not to exceed 0.05 mg/kg/day given in two or three divided doses.

Injection:

• Infants and children: half of a vial (0.5 mg) by slow IV injection or by IV infusion.

• Adults: 1 vial (1 mg) by slow IV injection or by IV infusion. This dose can be repeated as required (1-4 mg are usually sufficient to reverse the status). In adults, the rate of injection must not exceed 0.25 - 0.5 mg per minute (0.5-1.0 ml of the prepared solution) and a total dose of 10 mg should not be exceeded.

The most frequently occurring side effects of Clonazepam are referable to CNS depression. Experience in treatment of seizures has shown that drowsiness has occurred in approximately 50% of patients and ataxia in approximately 30%. In some cases, these may diminish with time; behavior problems have been noted in approximately 25% of patients. Abnormal eye movements, aphonia, coma, tremor, vertigo, confusion, depression, amnesia, hallucinations, hysteria, increased libido, insomnia, psychosis & palpitations may also occur.

It should not be used in patients with a history of hypersensitivity to benzodiazepines, nor in patients with clinical or biochemical evidence of significant liver disease. It may be used in patients with open angle glaucoma who are receiving appropriate therapy but is contraindicated in acute narrow angle glaucoma.

When used in patients in whom several different types of seizure disorders coexist, Clonazepam may increase the incidence or precipitate the onset of generalized tonic-clonic seizures. This may require the addition of appropriate anticonvulsants or an increase in their dosages. The concomitant use of valproic acid and Clonazepam may produce absence status.

Clonazepam does not appear to alter the pharmacokinetics of phenytoin, carbamazepine or phenobarbital. The effect of Clonazepam on the metabolism of other drugs has not been investigated.

Pregnancy: From preclinical studies it cannot be excluded that clonazepam possesses the possibility of producing congenital malformations. From epidemiological evaluations there is evidence that anticonvulsant drugs act as teratogens. However, it is difficult to determine from published epidemiological reports which drug or combination of drugs is responsible for defects in the newborn. The possibility also exists that other factors e.g. genetic factors or the epileptic condition itself may be more important than drug therapy in leading to birth defects. Under these circumstances, the drug should only be administered to pregnant women if the potential benefits outweigh the risk to the foetus. During pregnancy, Clonazepam may be administered only if there is a compelling indication. Administration of high doses in the last trimester of pregnancy or during labour can cause irregularities in the heartbeat of the unborn child and hypothermia, hypotonia, mild respiratory depression and poor feeding in the neonate. It should be borne in mind that both pregnancy itself and abrupt discontinuation of the medication can cause exacerbation of epilepsy. Withdrawal symptoms in newborn infants have occasionally been reported with benzodiazepines.

Nursing Mothers: Although the active ingredient of Clonazepam has been found to pass into the maternal milk in small amounts only, mothers undergoing treatment with this drug should not breastfeed. If there is a compelling indication for Clonazepam, breastfeeding should be discontinued.

Pediatric Use: In infants and small children Rivotril may cause increased production of saliva and bronchial secretion. Therefore special attention must be paid to maintaining patency of the airways. 

Geriatric Use: Benzodiazepine pharmacologic effects appear to be greater in elderly patients than in younger patients even at similar plasma benzodiazepine concentrations, possibly because of age-related changes in drug–receptor interactions, post-receptor mechanisms and organ function.

Renal Impairment: Renal impairment does not affect the pharmacokinetics of clonazepam. Based on pharmacokinetic criteria, no dose adjustment is required in patients with renal impairment.

Hepatic Impairment: Plasma protein binding of clonazepam in cirrhotic patients is significantly different from that in healthy subjects (free fraction 17.1±1.0% vs 13.9±0.2%). Although the influence of hepatic impairment on clonazepam pharmacokinetics has not been further investigated, experience with another closely related nitrobenzodiazepine (nitrazepam) indicates that clearance of unbound clonazepam might be reduced in liver cirrhosis.

Symptoms: Benzodiazepines commonly cause drowsiness, ataxia, dysarthria and nystagmus. Overdose of Clonazepam is seldom life-threatening if the drug is taken alone, but may lead to areflexia, apnoea, hypotension, cardiorespiratory depression and coma. Coma, if it occurs, usually lasts a few hours but it may be more protracted and cyclical, particularly in elderly patients. Increased frequency of seizures may occur in patients at supratherapeutic plasma concentrations. Benzodiazepine respiratory depressant effects are more serious in patients with respiratory disease. Benzodiazepines increase the effects of other central nervous system depressants, including alcohol.

Treatment: Monitor the patient’s vital signs and institute supportive measures as indicated by the patient’s clinical state. In particular, patients may require symptomatic treatment for cardiorespiratory effects or central nervous system effects. Further absorption should be prevented using an appropriate method e.g. treatment within 1-2 hours with activated charcoal. If activated charcoal is used airway protection is imperative for drowsy patients. In case of mixed ingestion gastric lavage may be considered, however not as a routine measure. If CNS depression is severe consider the use of flumazenil, a benzodiazepine antagonist. This should only be administered under closely monitored conditions. It has a short half-life (about an hour), therefore patients administered flumazenil will require monitoring after its effects have worn off. Flumazenil is to be used with extreme caution in the presence of drugs that reduce seizure threshold (e.g. tricyclic antidepressants). Refer to the prescribing information for flumazenil, for further information on the correct use of this drug.

Slow intravenous injection: The contents of the vial must be diluted with 1 ml of water for injection prior to administration so as to avoid local irritation of the veins. The injection solution should be prepared immediately before use. IV injection should be administered slowly with continuous monitoring of EEG, respiration and blood pressure.

Intravenous infusion: Clonazepam (the vial) can be diluted for infusion in a ratio of 1 vial (1 mg) to at least 85 ml diluting media. The diluting media can be any of the following: sodium chloride 0.9%; sodium chloride 0.45% + glucose 2.5%; glucose 5% or glucose 10%. These mixtures are stable for 24 hours at room temperature. Infusion bags other than PVC should be used for infusing Clonazepam. If PVC infusion bags are used then the mixture should be infused immediately or within 4 hours. The infusion time should not exceed 8 hours. Do not prepare Clonazepam infusions using sodium bicarbonate solution, as precipitation of the solution may occur.

Intramuscular injection: The IM route should be used only in exceptional cases or if IV administration is not feasible.

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

Adjunct anti-epileptic drugs, Benzodiazepine hypnotics

Clonazepam exhibits pharmacological properties which are common to benzodiazepines and include anticonvulsive, sedative, muscle relaxing and anxiolytic effects. The central actions of benzodiazepines are mediated through an enhancement of the GABAergic neurotransmission at inhibitory synapses. In the presence of benzodiazepines the affinity of the GABA receptor for the neurotransmitter is enhanced through positive allosteric modulation resulting in an increased action of released GABA on the postsynaptic transmembrane chloride ion flux.

There are also animal data showing an effect of clonazepam on serotonin. Animal data and electroencephalographic investigations in man have shown that clonazepam rapidly suppresses many types of paroxysmal activity including the spike and wave discharge in absences seizures (petit mal), slow spike wave, generalized spike wave, spikes with temporal or other locations as well as irregular spikes and waves. Generalized EEG abnormalities are more regularly suppressed than focal abnormalities. According to these findings clonazepam has beneficial effects in generalized and focal epilepsies.

Oral:

• Adults: The initial dose for adults with seizure disorders should not exceed 1.5 mg/day divided into three doses. Dosage may be increased in increments of 0.5 to 1 mg every 3 days until seizures are adequately controlled or until side effects preclude any further increase. Maintenance dosage must be individualized for each patient depending upon response. Maximum recommended daily dose is 20 mg.

• The initial dose for adults with panic disorder is 0.25 mg given in two divided dose. An increase to the target dose for most patients of 1 mg/day may be made after 3 days.
• Pediatric Patients: In order to minimize drowsiness, the initial dose for infants and children (up to 10 years of age or 30 kg of body weight) should be between 0.01 and 0.03 mg/kg/day but not to exceed 0.05 mg/kg/day given in two or three divided doses.

Injection:

• Infants and children: half of a vial (0.5 mg) by slow IV injection or by IV infusion.

• Adults: 1 vial (1 mg) by slow IV injection or by IV infusion. This dose can be repeated as required (1-4 mg are usually sufficient to reverse the status). In adults, the rate of injection must not exceed 0.25 - 0.5 mg per minute (0.5-1.0 ml of the prepared solution) and a total dose of 10 mg should not be exceeded.

The most frequently occurring side effects of Clonazepam are referable to CNS depression. Experience in treatment of seizures has shown that drowsiness has occurred in approximately 50% of patients and ataxia in approximately 30%. In some cases, these may diminish with time; behavior problems have been noted in approximately 25% of patients. Abnormal eye movements, aphonia, coma, tremor, vertigo, confusion, depression, amnesia, hallucinations, hysteria, increased libido, insomnia, psychosis & palpitations may also occur.

It should not be used in patients with a history of hypersensitivity to benzodiazepines, nor in patients with clinical or biochemical evidence of significant liver disease. It may be used in patients with open angle glaucoma who are receiving appropriate therapy but is contraindicated in acute narrow angle glaucoma.

When used in patients in whom several different types of seizure disorders coexist, Clonazepam may increase the incidence or precipitate the onset of generalized tonic-clonic seizures. This may require the addition of appropriate anticonvulsants or an increase in their dosages. The concomitant use of valproic acid and Clonazepam may produce absence status.

Clonazepam does not appear to alter the pharmacokinetics of phenytoin, carbamazepine or phenobarbital. The effect of Clonazepam on the metabolism of other drugs has not been investigated.

Pregnancy: From preclinical studies it cannot be excluded that clonazepam possesses the possibility of producing congenital malformations. From epidemiological evaluations there is evidence that anticonvulsant drugs act as teratogens. However, it is difficult to determine from published epidemiological reports which drug or combination of drugs is responsible for defects in the newborn. The possibility also exists that other factors e.g. genetic factors or the epileptic condition itself may be more important than drug therapy in leading to birth defects. Under these circumstances, the drug should only be administered to pregnant women if the potential benefits outweigh the risk to the foetus. During pregnancy, Clonazepam may be administered only if there is a compelling indication. Administration of high doses in the last trimester of pregnancy or during labour can cause irregularities in the heartbeat of the unborn child and hypothermia, hypotonia, mild respiratory depression and poor feeding in the neonate. It should be borne in mind that both pregnancy itself and abrupt discontinuation of the medication can cause exacerbation of epilepsy. Withdrawal symptoms in newborn infants have occasionally been reported with benzodiazepines.

Nursing Mothers: Although the active ingredient of Clonazepam has been found to pass into the maternal milk in small amounts only, mothers undergoing treatment with this drug should not breastfeed. If there is a compelling indication for Clonazepam, breastfeeding should be discontinued.

Pediatric Use: In infants and small children Rivotril may cause increased production of saliva and bronchial secretion. Therefore special attention must be paid to maintaining patency of the airways. 

Geriatric Use: Benzodiazepine pharmacologic effects appear to be greater in elderly patients than in younger patients even at similar plasma benzodiazepine concentrations, possibly because of age-related changes in drug–receptor interactions, post-receptor mechanisms and organ function.

Renal Impairment: Renal impairment does not affect the pharmacokinetics of clonazepam. Based on pharmacokinetic criteria, no dose adjustment is required in patients with renal impairment.

Hepatic Impairment: Plasma protein binding of clonazepam in cirrhotic patients is significantly different from that in healthy subjects (free fraction 17.1±1.0% vs 13.9±0.2%). Although the influence of hepatic impairment on clonazepam pharmacokinetics has not been further investigated, experience with another closely related nitrobenzodiazepine (nitrazepam) indicates that clearance of unbound clonazepam might be reduced in liver cirrhosis.

Symptoms: Benzodiazepines commonly cause drowsiness, ataxia, dysarthria and nystagmus. Overdose of Clonazepam is seldom life-threatening if the drug is taken alone, but may lead to areflexia, apnoea, hypotension, cardiorespiratory depression and coma. Coma, if it occurs, usually lasts a few hours but it may be more protracted and cyclical, particularly in elderly patients. Increased frequency of seizures may occur in patients at supratherapeutic plasma concentrations. Benzodiazepine respiratory depressant effects are more serious in patients with respiratory disease. Benzodiazepines increase the effects of other central nervous system depressants, including alcohol.

Treatment: Monitor the patient’s vital signs and institute supportive measures as indicated by the patient’s clinical state. In particular, patients may require symptomatic treatment for cardiorespiratory effects or central nervous system effects. Further absorption should be prevented using an appropriate method e.g. treatment within 1-2 hours with activated charcoal. If activated charcoal is used airway protection is imperative for drowsy patients. In case of mixed ingestion gastric lavage may be considered, however not as a routine measure. If CNS depression is severe consider the use of flumazenil, a benzodiazepine antagonist. This should only be administered under closely monitored conditions. It has a short half-life (about an hour), therefore patients administered flumazenil will require monitoring after its effects have worn off. Flumazenil is to be used with extreme caution in the presence of drugs that reduce seizure threshold (e.g. tricyclic antidepressants). Refer to the prescribing information for flumazenil, for further information on the correct use of this drug.

Slow intravenous injection: The contents of the vial must be diluted with 1 ml of water for injection prior to administration so as to avoid local irritation of the veins. The injection solution should be prepared immediately before use. IV injection should be administered slowly with continuous monitoring of EEG, respiration and blood pressure.

Intravenous infusion: Clonazepam (the vial) can be diluted for infusion in a ratio of 1 vial (1 mg) to at least 85 ml diluting media. The diluting media can be any of the following: sodium chloride 0.9%; sodium chloride 0.45% + glucose 2.5%; glucose 5% or glucose 10%. These mixtures are stable for 24 hours at room temperature. Infusion bags other than PVC should be used for infusing Clonazepam. If PVC infusion bags are used then the mixture should be infused immediately or within 4 hours. The infusion time should not exceed 8 hours. Do not prepare Clonazepam infusions using sodium bicarbonate solution, as precipitation of the solution may occur.

Intramuscular injection: The IM route should be used only in exceptional cases or if IV administration is not feasible.

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

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

BPH/ Urinary retention/ Urinary incontinence

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

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

Renal or hepatic impairment:

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

Gender: No dose adjustment is necessary according to gender.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

BPH/ Urinary retention/ Urinary incontinence

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

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

Renal or hepatic impairment:

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

Gender: No dose adjustment is necessary according to gender.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

BPH/ Urinary retention/ Urinary incontinence

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

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

Renal or hepatic impairment:

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

Gender: No dose adjustment is necessary according to gender.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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