Etoricoxib film coated tablets

ETOSPEEDTM- 90

Each film coated tablet contains:

Etoricoxib 90 mg

Tablets, 90 mg

Therapeutic indication

ETOSPEED is indicated in adults and adolescents 16 years of age and older for the symptomatic relief of osteoarthritis (OA), rheumatoid arthritis (RA), ankylosing spondylitis, and the pain and signs of inflammation associated with acute gouty arthritis. ETOSPEED is indicated in adults and adolescents 16 years of age and older for the short-term treatment of moderate pain associated with dental surgery. The decision to prescribe a selective COX-2 inhibitor should be based on an assessment of the individual patient's overall risks.

Posology and method of administration

Posology

As the cardiovascular risks of etoricoxib may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used. The patient's need for symptomatic relief and response to therapy should be re-evaluated periodically, especially in patients with osteoarthritis.

Osteoarthritis

The recommended dose is 30 mg once daily. In some patients with insufficient relief from symptoms, an increased dose of 60 mg once daily may increase efficacy. In the absence of an increase in therapeutic benefit, other therapeutic options should be considered.

Rheumatoid arthritis

The recommended dose is 60 mg once daily. In some patients with insufficient relief from symptoms, an increased dose of 90 mg once daily may increase efficacy. Once the patient is clinically stabilised, down-titration to a 60 mg once daily dose may be appropriate. In the absence of an increase in therapeutic benefit, other therapeutic options should be considered.

Ankylosing spondylitis

The recommended dose is 60 mg once daily. In some patients with insufficient relief from symptoms, an increased dose of 90 mg once daily may increase efficacy. Once the patient is clinically stabilised, down-titration to a 60 mg once daily dose may be appropriate. In the absence of an increase in therapeutic benefit, other therapeutic options should be considered.

Acute pain conditions

For acute pain conditions, etoricoxib should be used only for the acute symptomatic period.

Acute gouty arthritis

The recommended dose is 120 mg once daily. In clinical trials for acute gouty arthritis, etoricoxib was given for 8 days.

Postoperative dental surgery pain

The recommended dose is 90 mg once daily, limited to a maximum of 3 days. Some patients may require other postoperative analgesia in addition to ETOSPEED during the three-day treatment period. Doses greater than those recommended for each indication have either not demonstrated additional efficacy or have not been studied. Therefore:

The dose for OA should not exceed 60 mg daily.

The dose for RA and ankylosing spondylitis should not exceed 90 mg daily.

The dose for acute gout should not exceed 120 mg daily, limited to a maximum of 8 days’ treatment.

The dose for postoperative acute dental surgery pain should not exceed 90 mg daily, limited to a maximum of 3 days.

Special populations

Elderly patients

No dosage adjustment is necessary for elderly patients. As with other drugs, caution should be exercised in elderly patients.

Patients with hepatic impairment

Regardless of indication, in patients with mild hepatic dysfunction (Child-Pugh score 5-6) a dose of 60 mg once daily should not be exceeded. In patients with moderate hepatic dysfunction (Child-Pugh score 7-9), regardless of indication, the dose of 30 mg once daily should not be exceeded. Clinical experience is limited particularly in patients with moderate hepatic dysfunction and caution is advised. There is no clinical experience in patients with severe hepatic dysfunction (Child-Pugh score ≥10); therefore, its use is contraindicated in these patients.

Patients with renal impairment

No dosage adjustment is necessary for patients with creatinine clearance ≥ 30 mL/min. The use of etoricoxib in patients with creatinine clearance < 30 mL/min is contra-indicated.

Paediatric population

Etoricoxib is contra-indicated in children and adolescents under 16 years of age.

Method of administration

ETOSPEED is administered orally and may be taken with or without food. The onset of the effect of the medicinal product may be faster when ETOSPEED is administered without food. This should be considered when rapid symptomatic relief is needed.

4.3 Contraindications

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

• Active peptic ulceration or active gastro-intestinal (GI) bleeding.

• Patients who, after taking acetylsalicylic acid or NSAIDs including COX-2 (cyclooxygenase-2) inhibitors, experience bronchospasm, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria, or allergic-type reactions.

• Pregnancy and lactation.

• Severe hepatic dysfunction (serum albumin < 25 g/L or Child-Pugh score ≥10).

• Estimated renal creatinine clearance < 30 mL/min.

• Children and adolescents under 16 years of age.

• Inflammatory bowel disease.

• Congestive heart failure (NYHA II-IV).

• Patients with hypertension whose blood pressure is persistently elevated above 140/90 mmHg and has not been adequately controlled.

• Established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease.

4.4 Special warnings and precautions for use

Gastrointestinal effects

Upper gastrointestinal complications [perforations, ulcers or bleedings (PUBs)], some of them resulting in fatal outcome, have occurred in patients treated with etoricoxib. Caution is advised with treatment of patients most at risk of developing a gastrointestinal complication with NSAIDs; the elderly, patients using any other NSAID or acetylsalicylic acid concomitantly or patients with a prior history of gastrointestinal disease, such as ulceration and GI bleeding.

There is a further increase in the risk of gastrointestinal adverse effects (gastrointestinal ulceration or other gastrointestinal complications) when etoricoxib is taken concomitantly with acetylsalicylic acid (even at low doses). A significant difference in GI safety between selective COX-2 inhibitors + acetylsalicylic acid vs. NSAIDs + acetylsalicylic acid has not been demonstrated in long-term clinical trials.

Cardiovascular effects

Clinical trials suggest that the selective COX-2 inhibitor class of drugs may be associated with a risk of thrombotic events (especially myocardial infarction (MI) and stroke), relative to placebo and some NSAIDs. As the cardiovascular risks of etoricoxib may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used. The patient's need for symptomatic relief and response to therapy should be re-evaluated periodically, especially in patients with osteoarthritis. Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking) should only be treated with etoricoxib after careful consideration.

COX-2 selective inhibitors are not a substitute for acetylsalicylic acid for prophylaxis of cardiovascular thromboembolic diseases because of their lack of antiplatelet effect. Therefore, antiplatelet therapies should not be discontinued.

Renal effects

Renal prostaglandins may play a compensatory role in the maintenance of renal perfusion. Therefore, under conditions of compromised renal perfusion, administration of etoricoxib may cause a reduction in prostaglandin formation and, secondarily, in renal blood flow, and thereby impair renal function. Patients at greatest risk of this response are those with pre-existing significantly impaired renal function, uncompensated heart failure, or cirrhosis. Monitoring of renal function in such patients should be considered.

Fluid retention, oedema and hypertension

As with other medicinal products known to inhibit prostaglandin synthesis, fluid retention, oedema and hypertension have been observed in patients taking etoricoxib. All Nonsteroidal Anti-inflammatory Drugs (NSAIDs), including etoricoxib, can be associated with new onset or recurrent congestive heart failure. For information regarding a dose related response for etoricoxib. Caution should be exercised in patients with a history of cardiac failure, left ventricular dysfunction, or hypertension and in patients with pre-existing oedema from any other reason. If there is clinical evidence of deterioration in the condition of these patients, appropriate measures including discontinuation of etoricoxib should be taken.

Etoricoxib may be associated with more frequent and severe hypertension than some other NSAIDs and selective COX2 inhibitors, particularly at high doses. Therefore, hypertension should be controlled before treatment with etoricoxib and special attention should be paid to blood pressure monitoring during treatment with etoricoxib. Blood pressure should be monitored within two weeks after initiation of treatment and periodically thereafter. If blood pressure rises significantly, alternative treatment should be considered.

Hepatic effects

Elevations of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) (approximately three or more times the upper limit of normal) have been reported in approximately 1 % of patients in clinical trials treated for up to one year with etoricoxib 30, 60 and 90 mg daily.

Any patients with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver function test has occurred, should be monitored. If signs of hepatic insufficiency occur, or if persistently abnormal liver function tests (three times the upper limit of normal) are detected, etoricoxib should be discontinued.

General

If during treatment, patients deteriorate in any of the organ system functions described above, appropriate measures should be taken and discontinuation of etoricoxib therapy should be considered. Medically appropriate supervision should be maintained when using etoricoxib in the elderly and in patients with renal, hepatic, or cardiac dysfunction.

Caution should be used when initiating treatment with etoricoxib in patients with dehydration. It is advisable to rehydrate patients prior to starting therapy with etoricoxib.

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs and some selective COX-2 inhibitors during post-marketing surveillance. Patients appear to be at highest risk for these reactions early in the course of therapy with the onset of the reaction occurring in the majority of cases within the first month of treatment. Serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been reported in patients receiving etoricoxib. Some selective COX-2 inhibitors have been associated with an increased risk of skin reactions in patients with a history of any drug allergy. Etoricoxib should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Etoricoxib may mask fever and other signs of inflammation.

Caution should be exercised when co-administering etoricoxib with warfarin or other oral anticoagulants.

The use of etoricoxib, as with any medicinal product known to inhibit cyclooxygenase / prostaglandin synthesis, is not recommended in women attempting to conceive.

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacodynamics interactions

Oral anticoagulants: In subjects stabilised on chronic warfarin therapy, the administration of etoricoxib 120 mg daily was associated with an approximate 13 % increase in prothrombin time International Normalised Ratio (INR). Therefore, patients receiving oral anticoagulants should be closely monitored for their prothrombin time INR, particularly in the first few days when therapy with etoricoxib is initiated or the dose of etoricoxib is changed.

Diuretics, ACE inhibitors and Angiotensin II Antagonists: NSAIDs may reduce the effect of diuretics and other antihypertensive drugs. In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with compromised renal function) the co-administration of an ACE inhibitor or Angiotensin II antagonist and agents that inhibit cyclo-oxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. These interactions should be considered in patients taking etoricoxib concomitantly with ACE inhibitors or angiotensin II antagonists. Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy, and periodically thereafter.

Acetylsalicylic Acid: In a study in healthy subjects, at steady state, etoricoxib 120 mg once daily had no effect on the anti-platelet activity of acetylsalicylic acid (81 mg once daily). Etoricoxib can be used concomitantly with acetylsalicylic acid at doses used for cardiovascular prophylaxis (low-dose acetylsalicylic acid). However, concomitant administration of low dose acetylsalicylic acid with etoricoxib may result in an increased rate of GI ulceration or other complications compared to use of etoricoxib alone. Concomitant administration of etoricoxib with doses of acetylsalicylic acid above those for cardiovascular prophylaxis or with other NSAIDs is not recommended.

Cyclosporin and tacrolimus: Although this interaction has not been studied with etoricoxib, coadministration of cyclosporin or tacrolimus with any NSAID may increase the nephrotoxic effect of cyclosporin or tacrolimus. Renal function should be monitored when etoricoxib and either of these drugs is used in combination.

Pharmacokinetic interactions

The effect of etoricoxib on the pharmacokinetics of other drugs

Lithium: NSAIDs decrease lithium renal excretion and therefore increase lithium plasma levels. If necessary, monitor blood lithium closely and adjust the lithium dosage while the combination is being taken and when the NSAID is withdrawn.

Methotrexate: Two studies investigated the effects of etoricoxib 60, 90 or 120 mg administered once daily for seven days in patients receiving once-weekly methotrexate doses of 7.5 to 20 mg for rheumatoid arthritis. Etoricoxib at 60 and 90 mg had no effect on methotrexate plasma concentrations or renal clearance. In one study, etoricoxib 120 mg had no effect, but in the other study, etoricoxib 120 mg increased methotrexate plasma concentrations by 28 % and reduced renal clearance of methotrexate by 13 %. Adequate monitoring for methotrexate-related toxicity is recommended when etoricoxib and methotrexate are administered concomitantly.

Oral contraceptives: Etoricoxib 60 mg given concomitantly with an oral contraceptive containing 35 micrograms ethinyl estradiol (EE) and 0.5 to 1 mg norethindrone for 21 days increased the steady state AUC0-24hr of EE by 37 %. Etoricoxib 120 mg given with the same oral contraceptive concomitantly or separated by 12 hours, increased the steady state

AUC0-24hr of EE by 50 to 60 %. This increase in EE concentration should be considered when selecting an oral contraceptive for use with etoricoxib. An increase in EE exposure can increase the incidence of adverse events associated with oral contraceptives (e.g., venous thrombo-embolic events in women at risk).

Hormone Replacement Therapy (HRT): Administration of etoricoxib 120 mg with hormone replacement therapy consisting of conjugated estrogens (0.625 mg premarin) for 28 days, increased the mean steady state AUC0-24hr of unconjugated estrone (41 %), equilin (76 %), and 17-β-estradiol (22 %). The effect of the recommended chronic doses of etoricoxib (30, 60, and 90 mg) has not been studied. The effects of etoricoxib 120 mg on the exposure (AUC0-24hr) to these estrogenic components of PREMARIN were less than half of those observed when PREMARIN was administered alone and the dose was increased from 0.625 to 1.25 mg. The clinical significance of these increases is unknown, and higher doses of PREMARIN were not studied in combination with etoricoxib. These increases in estrogenic concentration should be taken into consideration when selecting post-menopausal hormone therapy for use with etoricoxib because the increase in oestrogen exposure might increase the risk of adverse events associated with HRT.

Prednisone/prednisolone: In drug-interaction studies, etoricoxib did not have clinically important effects on the pharmacokinetics of prednisone/prednisolone.

Digoxin: Etoricoxib 120 mg administered once daily for 10 days to healthy volunteers did not alter the steady-state plasma AUC0-24hr or renal elimination of digoxin. There was an increase in digoxin Cmax (approximately 33 %). This increase is not generally important for most patients. However, patients at high risk of digoxin toxicity should be monitored for this when etoricoxib and digoxin are administered concomitantly.

Effect of etoricoxib on drugs metabolised by sulfotransferases

Etoricoxib is an inhibitor of human sulfotransferase activity, particularly SULT1E1, and has been shown to increase the serum concentrations of ethinyl estradiol. While knowledge about effects of multiple sulfotransferases is presently limited and the clinical consequences for many drugs are still being examined, it may be prudent to exercise care when administering etoricoxib concurrently with other drugs primarily metabolised by human sulfotransferases (e.g., oral salbutamol and minoxidil).

Effect of etoricoxib on drugs metabolised by CYP isoenzymes

Based on in vitro studies, etoricoxib is not expected to inhibit cytochromes P450 (CYP) 1A2, 2C9, 2C19, 2D6, 2E1 or 3A4. In a study in healthy subjects, daily administration of etoricoxib 120 mg did not alter hepatic CYP3A4 activity as assessed by the erythromycin breath test.

Effects of other drugs on the pharmacokinetics of etoricoxib

The main pathway of etoricoxib metabolism is dependent on CYP enzymes. CYP3A4 appears to contribute to the metabolism of etoricoxib in vivo. In vitro studies indicate that CYP2D6, CYP2C9, CYP1A2 and CYP2C19 also can catalyse the main metabolic pathway, but their quantitative roles have not been studied in vivo.

Ketoconazole: Ketoconazole, a potent inhibitor of CYP3A4, dosed at 400 mg once a day for 11 days to healthy volunteers, did not have any clinically important effect on the single-dose pharmacokinetics of 60 mg etoricoxib (43 % increase in AUC).

Voriconazole and Miconazole: Co-administration of either oral voriconazole or topical miconazole oral gel, strong CYP3A4 inhibitors, with etoricoxib caused a slight increase in exposure to etoricoxib, but is not considered to be clinically meaningful based on published data.

Rifampicin: Co-administration of etoricoxib with rifampicin, a potent inducer of CYP enzymes, produced a 65 % decrease in etoricoxib plasma concentrations. This interaction may result in recurrence of symptoms when etoricoxib is co-administered with rifampicin. While this information may suggest an increase in dose, doses of etoricoxib greater than those listed for each indication have not been studied in combination with rifampicin and are therefore not recommended.

Antacids: Antacids do not affect the pharmacokinetics of etoricoxib to a clinically relevant extent.

4.6 Fertility, Pregnancy and Lactation

Pregnancy

No clinical data on exposed pregnancies are available for etoricoxib. Studies in animals have shown reproductive toxicity. The potential for human risk in pregnancy is unknown. Etoricoxib, as with other medicinal products inhibiting prostaglandin synthesis, may cause uterine inertia and premature closure of the ductus arteriosus during the last trimester. Etoricoxib is contraindicated in pregnancy. If a woman becomes pregnant during treatment, etoricoxib must be discontinued.

Breast-feeding

It is not known whether etoricoxib is excreted in human milk. Etoricoxib is excreted in the milk of lactating rats. Women who use etoricoxib must not breast feed.

Fertility

The use of etoricoxib, as with any drug substance known to inhibit COX-2, is not recommended in women attempting to conceive.

4.7 Effects on ability to drive and use machines

Patients who experience dizziness, vertigo or somnolence while taking etoricoxib should refrain from driving or operating machinery.

4.8 Undesirable effects

Summary of the safety profile

In clinical trials, etoricoxib was evaluated for safety in 9,295 individuals, including 6,757 patients with OA, RA, chronic low back pain or ankylosing spondylitis (approximately 600 patients with OA or RA were treated for one year or longer).

In clinical studies, the undesirable effects profile was similar in patients with OA or RA treated with etoricoxib for one year or longer.

In a clinical study for acute gouty arthritis, patients were treated with etoricoxib 120 mg once daily for eight days. The adverse experience profile in this study was generally similar to that reported in the combined OA, RA, and chronic low back pain studies.

In a cardiovascular safety outcomes programme of pooled data from three active comparator-controlled trials, 17, 412 patients with OA or RA were treated with etoricoxib (60 mg or 90 mg) for a mean duration of approximately 18 months. The safety data and details from this programme.

In clinical studies for acute postoperative dental pain following surgery including 614 patients treated with etoricoxib (90 mg or 120 mg), the adverse experience profile in these studies was generally similar to that reported in the combined OA, RA, and chronic low back pain studies.

Tabulated list of adverse reactions

The following undesirable effects were reported at an incidence greater than placebo in clinical trials in patients with OA, RA, chronic low back pain or ankylosing spondylitis treated with etoricoxib 30 mg, 60 mg or 90 mg up to the recommended dose for up to 12 weeks; instudies for up to 3½ years; in short term acute pain studies for up to 7 days; or in post-marketing experience (see Table 1):

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

In clinical studies, administration of single doses of etoricoxib up to 500 mg and multiple doses up to 150 mg/day for 21 days did not result in significant toxicity. There have been reports of acute overdosage with etoricoxib, although adverse experiences were not reported in the majority of cases. The most frequently observed adverse experiences were consistent with the safety profile for etoricoxib (e.g. gastrointestinal events, cardiorenal events). In the event of overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the GI tract, employ clinical monitoring, and institute supportive therapy, if required.

Etoricoxib is not dialysable by haemodialysis; it is not known whether etoricoxib is dialysable by peritoneal dialysis.

Pharmacodynamic properties

Pharmacotherapeutic group: Anti-inflammatory and anti-rheumatic products, non-steroids, coxibs, ATC code: M01 AH05

Mechanism of Action

Etoricoxib is an oral, selective cyclo-oxygenase-2 (COX-2) inhibitor within the clinical dose range.

Across clinical pharmacology studies, ETOSPEED produced dose-dependent inhibition of COX-2 without inhibition of COX-1 at doses up to 150 mg daily. Etoricoxib did not inhibit gastric prostaglandin synthesis and had no effect on platelet Function.

Cyclooxygenase is responsible for generation of prostaglandins. Two isoforms, COX-1 and COX-2, have been identified. COX-2 is the isoform of the enzyme that has been shown to be induced by pro-inflammatory stimuli and has been postulated to be primarily responsible for the synthesis of prostanoid mediators of pain, inflammation, and fever. COX-2 is also involved in ovulation, implantation and closure of the ductus arteriosus, regulation of renal function, and central nervous system functions (fever induction, pain perception and cognitive function). It may also play a role in ulcer healing. COX-2 has been identified in tissue around gastric ulcers in man but its relevance to ulcer healing has not been established.

Clinical efficacy and safety

Efficacy

In patients with osteoarthritis (OA), etoricoxib 60 mg once daily provided significant improvements in pain and patient assessments of disease status. These beneficial effects were observed as early as the second day of therapy and maintained for up to 52 weeks. Studies with etoricoxib 30 mg once daily demonstrated efficacy superior to placebo over a 12-week treatment period (using similar assessments as the above studies). In a dose ranging study, etoricoxib 60 mg demonstrated significantly greater improvement than 30 mg for all 3 primary endpoints over 6 weeks of treatment. The 30 mg dose has not been studied in osteoarthritis of hands.

In patients with rheumatoid arthritis (RA), etoricoxib 60 mg and 90 mg once daily both provided significant improvements in pain, inflammation, and mobility. In studies evaluating the 60 mg and 90 mg dose, these beneficial effects were maintained over the 12-week treatment periods. In a study evaluating the 60 mg dose compared to the 90 mg dose, etoricoxib 60 mg once daily and 90 mg once daily were both more effective than placebo. The 90 mg dose was superior to the 60 mg dose for Patient Global Assessment of Pain (0-100 mm visual analogue scale), with an average improvement of -2.71 mm (95 % CI: -4.98 mm, -0.45 mm).

In patients experiencing attacks of acute gouty arthritis, etoricoxib 120 mg once daily over an eight-day treatment period, relieved moderate to extreme joint pain and inflammation comparable to indomethacin 50 mg three times daily. Pain relief was observed as early as four hours after initiation of treatment.

In patients with ankylosing spondylitis, etoricoxib 90 mg once daily provided significant improvements in spine pain, inflammation, stiffness and function. The clinical benefit of etoricoxib was observed as early as the second day of therapy after initiation of treatment and was maintained throughout the 52-week treatment period. In a second study evaluating the 60 mg dose compared to the 90 mg dose, etoricoxib 60 mg daily and 90 mg daily demonstrated similar efficacy compared to naproxen 1,000 mg daily. Among inadequate responders to 60 mg daily for 6 weeks, dose escalation to 90 mg daily improved spinal pain intensity score (0-100 mm visual analogue scale) compared to continuing on 60 mg daily, with an average improvement of -2.70 mm (95 % CI: -4.88 mm, -0.52 mm).

In a clinical study evaluating postoperative dental pain, etoricoxib 90 mg was administered once daily for up to three days. In the subgroup of patients with moderate pain at baseline, etoricoxib 90 mg demonstrated a similar analgesic effect to that of ibuprofen 600 mg (16.11 vs. 16.39; P = 0.722), and greater than that of paracetamol/codeine 600 mg/60 mg (11.00; P < 0.001) and placebo (6.84; P < 0.001) as measured by total pain relief over the first 6 hours (TOPAR6). The proportion of patients reporting rescue medication usage within the first 24 hours of dosing was 40.8 % for etoricoxib 90 mg, 25.5 % for ibuprofen 600 mg Q6h, and 46.7 % for paracetamol/codeine 600 mg/60 mg Q6h compared to 76.2 % for placebo. In this study, the median onset of action (perceptible pain relief) of 90 mg etoricoxib was 28 minutes’ after dosing.

Safety

Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) Programme. The MEDAL Programme was a prospectively designed Cardiovascular (CV) Safety Outcomes Programme of pooled data from three randomized, double-blind active comparator-controlled trials, the MEDAL study, EDGE II and EDGE.

The MEDAL Study, was an endpoint driven CV Outcomes study in 17,804 OA and 5,700 RA patients treated with etoricoxib 60 (OA) or 90 mg (OA and RA) or diclofenac 150 mg daily for a mean period of 20.3 months (maximum of 42.3 months, median 21.3 months). In this trial, only serious adverse events and discontinuations due to any adverse events were recorded.

The EDGE and EDGE II studies compared the gastrointestinal tolerability of etoricoxib versus diclofenac. The EDGE study included 7,111 OA patients treated with a dose of etoricoxib 90 mg daily (1.5 times the dose recommended for OA) or diclofenac 150 mg daily for a mean period of 9.1 months (maximum 16.6 months, median 11.4 months). The EDGE study included 4,086 RA patients treated with etoricoxib 90 mg daily or diclofenac 150 mg daily for a mean period of 19.2 months (maximum 33.1 months, median 24 months).

In the pooled MEDAL Programme, 34,701 patients with OA or RA were treated for a mean duration of 17.9 months (maximum 42.3 months, median 16.3 months) with approximately 12,800 patients receiving treatment for more than 24 months. Patients enrolled in the Programme had a wide range of cardiovascular and gastrointestinal risk factors at baseline. Patients with a recent history of myocardial infarction, coronary artery bypass grafting or percutaneous coronary intervention within 6 months preceding enrolment were excluded. Use of gastro-protective agents and low dose aspirin were permitted in the studies.

Overall Safety:

There was no significant difference between etoricoxib and diclofenac in the rate of cardiovascular thrombotic events. Cardiorenal adverse events were observed more frequently with etoricoxib than with diclofenac, and this effect was dose-dependent (see specific results below). Gastrointestinal and hepatic adverse events were observed significantly more frequently with diclofenac than etoricoxib. The incidence of adverse experiences in EDGE and EDGE II and of adverse experiences considered serious or resulting in discontinuation in the MEDAL study was higher with etoricoxib than diclofenac.

Pharmacokinetic properties

Absorption

Orally administered etoricoxib is well absorbed. The absolute bioavailability is approximately 100 %. Following 120 mg once-daily dosing to steady state, the peak plasma concentration (geometric mean Cmax = 3.6 µg/mL) was observed at approximately 1 hour (Tmax) after administration to fasted adults. The geometric mean area under the curve (AUC0-24hr) was 37.8 µg•hr/mL. The pharmacokinetics of etoricoxib are linear across the clinical dose range. Dosing with food (a high-fat meal) had no effect on the extent of absorption of etoricoxib after administration of a 120-mg dose. The rate of absorption was affected, resulting in a 36 % decrease in Cmax and an increase in Tmax by 2 hours. These data are not considered clinically significant. In clinical trials, etoricoxib was administered without regard to food intake.

Distribution

Etoricoxib is approximately 92 % bound to human plasma protein over the range of concentrations of 0.05 to 5 µg/mL. The volume of distribution at steady state (Vdss) was approximately 120 L in humans. Etoricoxib crosses the placenta in rats and rabbits, and the blood-brain barrier in rats.

Biotransformation

Etoricoxib is extensively metabolised with < 1 % of a dose recovered in urine as the parent drug. The major route of metabolism to form the 6'-hydroxymethyl derivative is catalysed by CYP enzymes. CYP3A4 appears to contribute to the metabolism of etoricoxib in vivo. In vitro studies indicate that CYP2D6, CYP2C9, CYP1A2 and CYP2C19 also can catalyse the main metabolic pathway, but their quantitative roles in vivo have not been studied. Five metabolites have been identified in man. The principal metabolite is the 6'-carboxylic acid derivative of etoricoxib formed by further oxidation of the 6'-hydroxymethyl derivative. These principal metabolites either demonstrate no measurable activity or are only weakly active as COX-2 inhibitors. None of these metabolites inhibit COX-1.

Elimination

Following administration of a single 25-mg radio-labelled intravenous dose of etoricoxib to healthy subjects, 70 % of radioactivity was recovered in urine and 20 % in faeces, mostly as metabolites. Less than 2 % was recovered as unchanged drug. Elimination of etoricoxib occurs almost exclusively through metabolism followed by renal excretion. Steady state concentrations of etoricoxib are reached within seven days of once daily administration of 120 mg, with an accumulation ratio of approximately 2, corresponding to a half-life of approximately 22 hours. The plasma clearance after a 25-mg intravenous dose is estimated to be approximately 50 mL/min.

Characteristics in patients

Elderly patients: Pharmacokinetics in the elderly (65 years of age and older) are similar to those in the young.

Gender: The pharmacokinetics of etoricoxib are similar between men and women.

Hepatic impairment: Patients with mild hepatic dysfunction (Child-Pugh score 5-6) administered etoricoxib 60 mg once daily had an approximately 16 % higher mean AUC as compared to healthy subjects given the same regimen. Patients with moderate hepatic dysfunction (Child-Pugh score 7-9) administered etoricoxib 60 mg every other day had similar mean AUC to the healthy subjects given etoricoxib 60 mg once daily; etoricoxib 30 mg once daily has not been studied in this population. There are no clinical or pharmacokinetic data in patients with severe hepatic dysfunction (Child-Pugh score ≥ 10).

Renal impairment: The pharmacokinetics of a single dose of etoricoxib 120 mg in patients with moderate to severe renal insufficiency and patients with end-stage renal disease on haemodialysis were not significantly different from those in healthy subjects. Haemodialysis contributed negligibly to elimination (dialysis clearance approximately 50 mL/min).

Paediatric patients: The pharmacokinetics of etoricoxib in paediatric patients (< 12 years old) have not been studied. In a pharmacokinetic study (n = 16) conducted in adolescents (aged 12 to 17) the pharmacokinetics in adolescents weighing 40 to 60 kg given etoricoxib 60 mg once daily and adolescents > 60 kg given etoricoxib 90 mg once daily were similar to the pharmacokinetics in adults given etoricoxib 90 mg once daily. Safety and effectiveness of etoricoxib in paediatric patients have not been established.

Preclinical safety data

In preclinical studies, etoricoxib has been demonstrated not to be genotoxic. Etoricoxib was not carcinogenic in mice. Rats developed hepatocellular and thyroid follicular cell adenomas at > 2-times the daily human dose [90 mg] based on systemic exposure when dosed daily for approximately two years. Hepatocellular and thyroid follicular cell adenomas observed in rats are considered to be a consequence of rat-specific mechanism related to hepatic CYP enzyme induction. Etoricoxib has not been shown to cause hepatic CYP3A enzyme induction in humans.

In the rat, gastrointestinal toxicity of etoricoxib increased with dose and exposure time. In the 14-week toxicity study etoricoxib caused gastrointestinal ulcers at exposures greater than those seen in man at the therapeutic dose. In the 53- and 106-week toxicity study, gastrointestinal ulcers were also seen at exposures comparable to those seen in man at the therapeutic dose. In dogs, renal and gastrointestinal abnormalities were seen at high exposures.

Etoricoxib was not teratogenic in reproductive toxicity studies conducted in rats at 15 mg/kg/day (this represents approximately 1.5 times the daily human dose [90 mg] based on systemic exposure). In rabbits, a treatment related increase in cardiovascular malformations was observed at exposure levels below the clinical exposure at the daily human dose (90 mg). However, no treatment-related external or skeletal foetal malformations were observed. In rats and rabbits, there was a dose dependent increase in post implantation loss at exposures greater than or equal to 1.5 times the human exposure.

Etoricoxib is excreted in the milk of lactating rats at concentrations approximately two-fold those in plasma. There was a decrease in pup body weight following exposure of pups to milk from dams administered etoricoxib during lactation.

Incompatibilities

Not applicable

Shelf life

Refer on the pack.

Packaging information

10 Blister strips of 10 tablets in each strip.

Storage and handling instructions

Store below 30°C. Protect from light. Do not freeze.

Keep out of reach of children.

• Ensure the prescribed dose of ETOSPEED 90 is taken as directed.

• Not to exceed the stated recommended daily dose.

• If pregnant or breast-feeding, ask a health professional before use.

• Ask the patient to report any adverse events.

S (-) Metoprolol Succinate Prolonged-Release Tablets

KIMET XL®-12.5

Each prolonged-release film-coated tablet contains:

S (-) Metoprolol Succinate 11.875 mg

equivalent to S (-) Metoprolol Tartrate 12.50 mg

Colour: Titanium Dioxide IP

KIMET XL®-25

Each prolonged-release film-coated tablet contains:

S (-) Metoprolol Succinate 23.75 mg

equivalent to S (-) Metoprolol Tartrate 25 mg

Colour: Titanium Dioxide IP

KIMET XL®-50

Each prolonged-release film-coated tablet contains

S (-) Metoprolol Succinate 47.50 mg

equivalent to S (-) Metoprolol Tartrate 50 mg

Colour: Titanium Dioxide IP

Tablets, 12.5 mg, 25 mg, 50 mg

4.1 Therapeutic indication

KIMET XL® tablets are indicated for the treatment of hypertension and angina pectoris.

KIMET XL® tablets are also used for the treatment of functional heart disorders, migraine prophylaxis, cardiac arrhythmias, prevention of cardiac death and re-infarction after the acute phase of myocardial infarction stable symptomatic CHF.

4.2 Posology and method of administration

One KIMET XL® tablet daily treatment is preferably taken in the morning. The dosage of KIMET XL® tablets should be individualized.

Hypertension: The usual initial dosage of KIMET XL® is 12.5 to 50 mg daily in a single dose alone or combined with other antihypertensive agents. A further reduction in blood pressure may be achieved if S (-) Metoprolol is used in conjunction with an antihypertensive diuretic or other hypotensive agent.

Angina Pectoris: KIMET XL® 25-50 mg twice or three times daily. In general, a significant improvement in exercise tolerance and reduction of anginal attacks may be expected with a dose of 25-50 mg twice daily.

Cardiac Arrhythmias: KIMET XL® dosage of 25 mg two or three times daily is usually sufficient. If necessary, the dose can be increased up to 150 mg per day and administered in divided doses.

Myocardial infarction: Early intervention: 25 mg every 6 hours for 48 hours, preferably within 12 hours of the onset of chest pain. Maintenance: The usual maintenance dose of KIMET XL® is 100 mg daily given in divided doses. The treatment should be continued for at least 3 months.

Prophylaxis of migraine: KIMET XL® dosage of 50-100 mg daily, given in divided doses (morning and evening).

Stable heart failure, function class II and III: A recommended initial dosage of KIMET XL® for the first two weeks is 12.5 mg once daily. In patients with more severe heart failure, the starting dose is 6.25mg once daily. After two weeks, the dosage can be doubled every second week upto the dosage tolerated by the patient. The target dose for long-term treatment is 100 mg once daily.

4.3 Contraindications

Hypersensitivity to the active substances, to related derivatives or to any of the excipients. KIMET XL® is contraindicated in

• Severe asthma or history of severe bronchospasm.
• Atrioventricular block of second or third degree.
• Uncontrolled heart failure.
• Clinically relevant sinus bradycardia.
• Sick-sinus syndrome.
• Severe peripheral arterial disease.
• Cardiogenic shock.
• Hypotension.
• Untreated phaeochromocytoma.
• Metabolic acidosis.

KIMET XL® is also contraindicated when myocardial infarction is complicated by significant bradycardia, first-degree heart block, systolic hypotension (less than 100 mmHg) and/or severe heart failure.

4.4 Special warnings and precautions for use

Special warnings

Cardiac Failure: In hypertensive and angina patients who have congestive heart failure controlled by digitalis and diuretics, KIMET XL® should be administered cautiously as β blockade carries the potential hazard of further depressing myocardial contractility and precipitating more severe failure.

In Patients without a History of Cardiac Failure: Continued depression of the myocardium with β-blocking agents over a period of time can, in some cases, lead to cardiac failure.

Ischemic Heart Disease: Following abrupt cessation of therapy with certain β-blocking agents, exacerbations of angina pectoris and, in some cases, myocardial infarction has occurred. When discontinuing chronically administered KIMET XL®, particularly in patients with ischemic heart disease, the dosage should be gradually reduced over a period of 1-2 weeks and the patient should be carefully monitored.

Bronchospastic Diseases: Patients with bronchospastic diseases should, in general, not receive β blockers, including KIMET XL®. Because of its relative β1 selectivity, however, KIMET XL may be used with caution in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment. Since β1 selectivity is not absolute, a β2-stimulating agent should be administered concomitantly, and the lowest possible dose of KIMET XL® should be used. In these circumstances it would be prudent initially to administer KIMET XL® in smaller doses three times daily, instead of larger doses two times daily, to avoid the higher plasma levels associated with the longer dosing interval.

Major Surgery: Chronically administered β-blocking therapy should not be routinely withdrawn prior to major surgery.

Diabetes and Hypoglycemia: β blockers may mask tachycardia occurring with hypoglycemia.

Pheochromocytoma: If KIMET XL® is used in the setting of pheochromocytoma, it should be given in combination with an alpha blocker, and only after the alpha blocker has been initiated. Administration of β blockers alone in the setting of pheochromocytoma has been associated with a paradoxical increase in blood pressure due to the attenuation of β-mediated vasodilatation in skeletal muscle.

Thyrotoxicosis: β-adrenergic blockade may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of β blockade, which might precipitate a thyroid storm.

Bradycardia: KIMET XL® produces a decrease in sinus heart rate in most patients. Acute myocardial infarction (particularly inferior infarction) may in itself produce significant lowering of the sinus rate. If the sinus rate decreases to <40 beats/min, particularly if associated with evidence of lowered cardiac output, atropine (0.25-0.5 mg) should be administered intravenously.

AV Block: KIMET XL® slows AV conduction and may produce significant first- (P-R interval≥0.26 sec), second-, or third-degree heart block. If heart block occurs, KIMET XL® should be discontinued and atropine (0.25-0.5 mg) should be administered intravenously.

Hypotension: If hypotension (systolic blood pressure ≤90 mmHg) occurs, KIMET XL® should be discontinued, and the hemodynamic status of the patient and the extent of myocardial damage carefully assessed.

Bronchospastic Diseases: Patients with bronchospastic diseases should, in general, not receive β blockers, including KIMET XL. Because of its relative β1 selectivity, KIMET XL® may be used with extreme caution in patients with bronchospastic disease.

Precautions

KIMET XL® should be used with caution in patients with impaired hepatic function.

KIMET XL® should be taken regularly and continuously as directed. It should not be discontinued without consulting the physician. Abrupt interruption of the medication is to be avoided. Sudden withdrawal of β blockade is hazardous, especially in high risk patients, and may aggravate chronic heart failure as well as increase the risk of myocardial infarction and sudden death. Any withdrawal of the product should therefore, if possible, be made gradually over at least two weeks where the dose is reduced by half in each step, down to the final dose when a 25 mg tablet is reduced to half a tablet. The final dose should be given for at least four days before discontinuation.

It is advisable (1) to avoid operating automobiles and machinery or engaging in other tasks requiring alertness until the patient’s response to therapy with KIMET XL® has been determined; (2) to contact the physician if any difficulty in breathing occurs; (3) to inform the physician or dentist before any type of surgery that he or she is taking KIMET XL®.

Concomitant use of KIMET XL® with catecholamine-depleting drugs or digitalis glycosides can increase the risk of bradycardia and hypotension.

Risk of Anaphylactic Reaction: While taking β blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenges, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.

General Anesthetics: Some inhalation anesthetics may enhance the cardio-depressant effect of β blockers.

CYP2D6 Inhibitors: Potent inhibitors of the CYP2D6 enzyme may increase the plasma concentration of KIMET XL®. Caution should therefore be exercised when co-administering potent CYP2D6 inhibitors with KIMET XL®.

Clonidine: If a patient is treated with clonidine and KIMET XL® concurrently, and clonidine treatment is to be discontinued, KIMET XL® should be stopped several days before clonidine is withdrawn.

4.5 Drugs interactions

The effects of S (-) Metoprolol and other antihypertensive drugs on blood pressure are usually additive, and care should be taken to avoid hypotension. However, combinations of antihypertensive drugs may often be used with the benefit to improve the control of hypertension.

As beta-blockers may affect peripheral circulation, care should be exercised when drugs with similar activity, e.g. ergotamine are given concurrently.

Care should also be exercised when beta-blockers are given in combination with sympathetic ganglion-blocking agents, other beta-blockers (also in the form of eye drops), or MAO inhibitors.

Prazosin

The acute postural hypotension that can follow the first dose of prazosin may be increased in patients already taking a beta-blocker.

Clonidine

If combination treatment with clonidine is to be discontinued S (-) Metoprolol should be withdrawn several days before clonidine. This is because the hypertension that can follow withdrawal of clonidine may be increased in patients receiving concurrent beta-blocker treatment.

Calcium channel blockers

Calcium channel blockers such as verapamil and diltiazem may potentiate the depressant effects of beta-blockers on blood pressure, heart rate, cardiac contractility and atrioventricular conduction. A calcium channel blocker of the verapamil (phenylalkylamine) type should not be given intravenously to patients receiving S (-) Metoprolol because there is a risk of cardiac arrest in this situation. Patients taking an oral calcium channel blocker of the verapamil type in combination with S (-) Metoprolol should be closely monitored.

CYP2D6 inhibitors

Potent inhibitors of this enzyme may increase the plasma concentration of S (-) Metoprolol (see section 5.2). Caution should therefore be exercised when co-administering potent CYP2D6 inhibitors with metoprolol. Known clinically significant potent inhibitors of CYP2D6 are antidepressants such as fluoxetine, paroxetine or bupropion, antipsychotics such as thioridazine, antiarrhythmics such as propafenone, antiretrovirals such as ritonavir, antihistamines such as diphenhydramine, antimalarials such as hydroxychloroquine or quinidine, antifungals such as terbinafine and medications for stomach ulcers such as cimetidine.

Class I anti-arrhythmic drugs and amiodarone

Amiodarone, propafenone, and other class I anti-arrhythmic agents such as quinidine and disopyramide may potentiate the effects of beta-blockers on heart rate and atrioventricular conduction.

Nitroglycerin

Nitroglycerin may enhance the hypotensive effect of metoprolol.

Digitalis glycosides

Concurrent use of digitalis glycosides may result in excessive bradycardia and/or increase in atrioventricular conduction time.

Sympathomimetics

S (-) Metoprolol will antagonise the beta1 effects of sympathomimetic agents but should have little influence on the bronchodilator effects of beta2-agonists at normal therapeutic doses.

Insulin and oral hypoglycaemic drugs

In diabetic patients who use insulin, beta-blocker treatment may be associated with increased or prolonged hypoglycaemia. Beta-blockers may also antagonize the hypoglycaemic effects of sulfonylureas. The risk of either effect is less with a beta1-selective drug such as S (-) Metoprolol than with a non-selective beta-blocker. However, diabetic patients receiving S (-) Metoprolol should be monitored to ensure that diabetes control is maintained.

Non-steroidal anti-inflammatory drugs

Concurrent treatment with non-steroidal anti-inflammatory drugs such as indomethacin may decrease the antihypertensive effect of metoprolol.

Lignocaine

S (-) Metoprolol may impair the elimination of lignocaine.

General anaesthetics

Some inhalation anaesthetics may enhance the cardio-depressant effect of beta-blockers.

Hepatic enzyme inducers/inhibitors

Enzyme-inducing agents (e.g. rifampicin) may reduce plasma concentrations of metoprolol, whereas enzyme inhibitors (e.g. cimetidine) may increase plasma concentrations.

Alcohol

During concomitant ingestion of alcohol and metoprolol, the concentration of blood alcohol may reach higher levels and may decrease more slowly.

4.6 Use in special populations

S(-)Metoprolol should not be used in pregnancy or lactation unless it is considered that the benefit outweighs the possible risk to the fetus/infant.

If S(-)Metoprolol is used during pregnancy and lactation special attention should be paid to the fetus, neonate and breastfed infant for undesirable effects of the drug's beta-blocking action (e.g. bradycardia, hypoglycemia). The lowest possible dose should be used, and treatment should be discontinued at least 2 to 3 days before delivery to avoid increased uterine contractility and the effects of beta-blockade in the newborn baby.

Pregnancy

Beta-blockers reduce placental perfusion which may result in intrauterine fetal death, and immature and premature deliveries.

S(-)Metoprolol has, however, been used in pregnancy-associated hypertension under close supervision after 20 weeks gestation. Although the drug crosses the placental barrier and is present in cord blood no evidence of fetal abnormalities has been reported. Animal experiments have shown neither teratogenic potential nor other adverse events on the embryo and/or fetus relevant to the safety assessment of the product.

Breast-feeding

The amount of S(-)Metoprolol ingested via breast milk seems to be negligible with regard to its beta-blocking effects if the mother is treated in doses within the therapeutic range.

4.7 Effects on ability to drive and use machines

As with all beta-blockers, S(-)Metoprolol may affect patients' ability to drive and operate machinery. Patients should be warned accordingly.

4.8 Undesirable effects

Adverse reactions have been ranked under headings of frequency using the following convention: very common (≥ 1/10); common (≥ 1/100 to <1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known.

Post-marketing experience

The following adverse reactions have been reported during post-approval use of S(-)Metoprolol: a confusional state, an increase in blood triglycerides and a decrease in high-density lipoprotein (HDL). Because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

4.9 Overdose

Symptoms

In more severe cases an overdosage of S(-)Metoprolol may lead to severe hypotension, sinus bradycardia, atrioventricular block, heart failure, cardiogenic shock, cardiac arrest, bronchospasm, impairment of consciousness, coma, convulsions, nausea, vomiting, cyanosis, hypoglycaemia and occasionally hyperkalaemia.

Management

Patients should be admitted to hospital and, generally, should be managed in an intensive care setting, with continuous monitoring of cardiac function, blood gases, and blood biochemistry. Emergency supportive measures such as artificial ventilation or cardiac pacing should be instituted if appropriate. Even apparently well patients who have taken a small overdose should be closely observed for signs of poisoning for at least 4 hours. In the event of a potentially life-threatening oral overdose, use induction of vomiting or gastric lavage (if within 4 hours after ingestion of metoprolol) and/or activated charcoal to remove the drug from the gastrointestinal tract. S (-) Metoprolol cannot be effectively removed by haemodialysis.

Atropine may be given intravenously to control significant bradycardia. Intravenous beta-agonists such as prenalterol or isoprenaline should be used to treat bradycardia and hypotension; very high doses may be needed to overcome the beta blockade. Dopamine, dobutamine or noradrenaline may be given to maintain blood pressure. Glucagon has positive inotropic and chronotropic effects on the heart that are independent of beta-adrenergic receptors and has proved effective in the treatment of resistant hypotension and heart failure associated with beta-blocker overdose.

5.1 Mechanism of Action

S(-)Metoprolol has a relatively greater blocking effect on beta1-receptors (i.e. those mediating adrenergic stimulation of heart rate and contractility and release of free fatty acids from fat stores) than on beta2-receptors which are chiefly involved in broncho and vasodilation. It has no membrane-stabilizing effect nor partial agonist (intrinsic sympathomimetic) activity.

The stimulant effect of catecholamines on the heart is reduced or inhibited by S(-)Metoprolol. This leads to a decrease in heart rate, cardiac contractility, and cardiac output.

5.2 Pharmacodynamic properties

S (-) Metoprolol is a selective β1 adrenergic receptor blocker. It has a preferential effect on β1 receptors, chiefly located in the cardiac muscle. This preferential effect is however not absolute, and at higher doses, S (-) Metoprolol also inhibits β2 receptors which are abundantly present in the bronchial and vascular musculature. S (-) Metoprolol has no intrinsic sympathomimetic activity and membrane-stabilizing activity is detectable only at plasma concentrations much greater than required for β-blockade.

The antihypertensive effects of β blocking agents may be attributed to

i) Competitive antagonism of catecholamines at peripheral (cardiac) adrenergic neuron sites, leading to decreased cardiac output; ii) A central effect leading to reduced sympathetic outflow to the periphery; and iii) Suppression of renin activity.

S (-) Metoprolol has been shown to be an effective antihypertensive agent when used alone or as concomitant therapy with thiazide-type diuretics, at doses of 100-400 mg daily.

In addition, S (-) Metoprolol reduces the oxygen requirements of the heart at any given level of effort by blocking catecholamine-induced increases in heart rate, velocity and extent of myocardial contraction, and in blood pressure, thus making it useful in the long-term management of angina pectoris.

S (-) Metoprolol administered two or four times daily, has been shown to be an effective anti-anginal agent, reducing the number of angina attacks and increasing exercise tolerance.

5.3 Pharmacokinetic properties

Absorption

S (-) Metoprolol is well absorbed after oral administration, peak plasma concentrations occurring 1.5 - 2 hours after dosing. The bioavailability of a single dose is approximately 50%, increasing to approximately 70% during repeated administration. The bioavailability also increases if S (-) Metoprolol is given with food.

Distribution

Approximately 10% of S (-) Metoprolol in plasma is protein bound. S (-) Metoprolol crosses the placenta and is found in breast milk.

S (-) Metoprolol is extensively metabolized by enzymes of the cytochrome P450 system in the liver. The oxidative metabolism of S (-) Metoprolol is under genetic control with a major contribution of the polymorphic cytochrome P450 isoform 2D6 (CYP2D6). There are marked ethnic differences in the prevalence of the poor metabolizers (PM) phenotype. Approximately 7% of Caucasians and less than 1% of Orientals are PMs.

CYP2D6 poor metabolizers exhibit several-fold higher plasma concentrations of S (-) Metoprolol than extensive metabolizers with normal CYP2D6 activity. None of the metabolites of S (-) Metoprolol contribute significantly to its beta-blocking effect.

Elimination

Elimination is mainly by hepatic metabolism and the average elimination half-life is 3.5 hours (range 1 to 9 hours). Rates of metabolism vary between individuals, with poor metabolizers (approximately 10%) showing higher plasma concentrations and slower elimination than extensive metabolizers. Within individuals, however, plasma concentrations are stable and reproducible.

6.1 Animal Toxicology or Pharmacology

Long-term studies in animals have been conducted to evaluate the carcinogenic potential of metoprolol tartrate. In 2-year studies in rats at three oral dosage levels of up to 800 mg/kg/day (41 times, on a mg/m2 basis, the daily dose of 200 mg for a 60 kg patient), there was no increase in the development of spontaneously occurring benign or malignant neoplasms of any type. The only histologic changes that appeared to be drug-related were an increased incidence of generally mild focal accumulation of foamy macrophages in pulmonary alveoli and a slight increase in biliary hyperplasia. In a 21-month study in Swiss albino mice at three oral dosage levels of up to 750 mg/kg/day (18 times, on a mg/m2 basis, the daily dose of 200 mg for a 60-kg patient), benign lung tumors (small adenomas) occurred more frequently in female mice receiving the highest dose than in untreated control animals. There was no increase in malignant or total (benign plus malignant) lung tumors, nor in the overall incidence of tumors or malignant tumors. This 21­month study was repeated in CD-1 mice, and no statistically or biologically significant differences were observed between treated and control mice of either sex for any type of tumor. All genotoxicity tests performed on metoprolol tartrate (a dominant lethal study in mice, chromosome studies in somatic cells, a Salmonella/mammalian-microsome mutagenicity test, and a nucleus anomaly test in somatic interphase nuclei) and metoprolol succinate (a Salmonella/mammalian-microsome mutagenicity test) were negative. No evidence of impaired fertility due to metoprolol tartrate was observed in a study performed in rats at doses up to 22 times, on a mg/m2 basis, the daily dose of 200 mg in a 60-kg patient.

S(-)Metoprolol, is a beta 1-selective (cardioselective) adrenoceptor-blocking agent, for oral administration, available as prolonged-release tablets. Metoprolol succinate prolonged-release tablet has been formulated to provide a controlled and predictable release of S(-)Metoprolol for once-daily administration.

The tablets contain 11.875, 23.75, and 47.5 mg of S(-)Metoprolol succinate equivalent to 12.5, 25, and 50 mg of S(-)Metoprolol tartrate respectively. Its chemical name is (2S)-1-[4-(2-methoxyethyl)phenoxy]-3-(propan-2-ylamino)propan-2-ol. Its structural formula is: C15H25NO3

8.1 Incompatibilities

None

8.2 Shelf-life

24 Months

8.3 Packaging information

Strip of 10 tablets

8.4 Storage and handing instructions

The medical product does not require any special storage conditions

Heart failure patients should be advised if they experience signs or symptoms of worsening heart failure such as weight gain or increasing shortness of breath.

Advise patients if a dose is missed, the patient should take only the next scheduled dose (without doubling it). Patients should not interrupt or discontinue metoprolol succinate extended-release capsules without consulting the physician.

Advise patients

(1) to avoid operating automobiles and machinery or engaging in other tasks requiring alertness until the patient’s response to therapy with metoprolol succinate extended-release capsules has been determined;

(2) to contact the physician if any difficulty in breathing occurs;

(3) to inform the physician or dentist before any type of surgery that he or she is taking metoprolol succinate extended-release capsules.

Advise patients who are breastfeeding to monitor the infant for bradycardia, dry mouth, skin or eyes, and diarrhea or constipation.

Lafutidine Tablets

(brand name- LAFAXID-10 tablet)

Each film-coated tablet contains:

Lafutidine 10 mg.

Excipients q. s

Colour: Titanium Dioxide I P

Film coated tablets

Lafutidine 10 mg

4.1 Therapeutic Indication

For the treatment of:

1. gastric ulcers, duodenal ulcers and stromal ulcers.
2. gastric mucosal lesions (erosion, hemorrhage, redness or edema) associated with acute gastritis and acute exacerbation of chronic gastritis.

4.2 Posology And Method of Administration

• Gastric ulcers, duodenal ulcers and stromal ulcers For Adults- 1 tablet two times daily, one after breakfast and one after evening meal or before sleeping. Dose must be adjusted according to patients age and symptoms.
• Gastric mucosal lesions (erosion, hemorrhage, redness or edema) associated with acute gastritis and acute exacerbation of chronic gastritis. For Adults-1 tablet once daily, after evening meal or before sleeping. Dose must be adjusted according to patients age and symptoms.

4.3 Contraindications

Patients with a history of drug hypersensitivity to any of the ingredients in the product.

4.4 Warning and Precautions

Lafutidine should be administered with care in patients with a history of drug hypersensitivity, impaired hepatic function, impaired renal function and patients on dialysis.

Use in the Elderly

Normally, because physiological function is deteriorated in the elderly, it is advisable to take such measures as a reduction in the dose and a prolongation of the administration interval under careful supervision.

4.5 Drug Interactions

Not known

4.6 Special populations

Pregnancy and Lactation

The safety of Lafutidine in pregnant women has not been established. Therefore, the administration of Lafutidine to pregnant women or women who may possibly be pregnant should be strictly limited to occasions where the therapeutic benefits outweigh the possible risks associated with the treatment. Animal studies (in rats) have shown that lafutidine is excreted in breast milk. Therefore, the mothers should be advised to discontinue breast feeding during treatment.

Pediatric use

This lafutidine drug can be used in children

4.7 Effects on ability to drive and use machines

The effects of the medicinal product on the ability to drive and use machines have not been studied.

4.8 Undesirable Effects

Constipation, diarrhea, drug rash, nausea or vomiting and dizziness are the adverse reactions observed during clinical trials. Other adverse effects of unknown frequency include abnormal changes in laboratory tests, hypersensitivity reactions (itching, redness of the skin, skin rash)

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via

email to: medico@zuventus.com

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9: Overdose

No data on overdosage with Lafutidine tablet is available.

5.1 Mechanism of Action /5.2 Pharmacodynamic Properties

Lafutidine inhibits acid secretion via histamine H2-receptor blockade. It also possesses a cytoprotective efficacy, which comprises mucin biosynthesis, stimulation of gastric blood flow and promotion of epithelial restitution of damaged mucosa, mediated through capsaicin-sensitive sensory neurons and endogenous calcitonin gene-related peptide (CGRP). It increases the endothelial production of prostacyclin, which inhibits neutrophil activation and reduces inflammation. It also affects gastrointestinal functions by regulating gastrointestinal motility closely relate to changes in the plasma levels of somatostatin, CGRP and secretin.

5.3 Pharmacokinetic properties

When 10mg of lafutidine is orally administered to normal adult males in fasting conditions, peak plasma concentration of 265.15±49.84 ng/ml is achieved at 0.95±0.24 hours. Lafutidine is metabolized primarily in the liver. In vitro studies showed that lafutidine is mainly metabolized by CYP3A4 and partially metabolized by CYP2D6. Hydroxylated and sulfonyl lafutidine are the major metabolites. Most of the drug is excreted in bile while approximately 20% of the given dosage is excreted in urine. The plasma half-life is 1.92 ± 0.94 hours. Among the elderly, there was no difference in pharmacokinetics parameters between those with normal renal function and those with deteriorating renal function. In dialytic patients when administered without hemodialysis, the Cmax, AUC and the T1/2 values were 336±40 ng/ml, 2278±306 ng･hr/mL and 6.71±0.30 hours respectively while those after hemodialysis were 226±36 ng/ml, 853±128 ng･hr/mL and 4.57±0.2 hours respectively.

6.1 Animal Toxicology or Pharmacology

No known animal toxicology data

Lafutidine is a second-generation histamine receptor antagonist (H2-RA) possessing an antisecretory effect as well as gastro-protective activity against several necrotizing agents independent of its antisecretory action.

Molecular Formula: C₂₂H₂₉N₃O₄S

Chemical name: 2-(Furfurylsulfinyl)-N-[4-[4-(piperidinomethyl)-2-pyridyl]oxy-(Z)-2-butenyl]acetamide Molecular weight: 431.56 Structural formula:

8.1 Incompatibilities

Not applicable

8.2 Shelf Life

Refer on the pack.

8.3 Packaging Information

3 composite blister strips of 3 x 10 tablets each.

8.4 Storage and Handling Instructions

Store in a cool dry place.

Keep out of reach of children.

• Take Lafutidine before going to bed if you are taking this medicine once a day. It is very effective in controlling stomach acid that is released when you are asleep.
• If you are also taking other medications to treat acidity (e.g., antacid), take them 2 hours before or after taking Lafutidine.
• Avoid taking soft drinks, citrus fruits like orange and lemon, which can irritate the stomach and increase acid secretion.
• Inform your doctor if you do not feel better after taking Lafutidine for 2 weeks as you may be suffering from some other problems.
• Inform your doctor if you have ever been diagnosed with kidney disease as dose of your medicine may need to be adjusted.
• Do not stop taking the medication without talking to your doctor.

Paracetamol, Phenylephrine Hydrochloride & Chlorpheniramine Maleate Oral Drops

Each ml contains :

Paracetamol IP 125 mg

Phenylephrine Hydrochloride IP 2.5 mg

Chlorpheniramine Maleate IP 1 mg

Excipients q.s.

In a flavoured syrup base

1 ml = Approx. 25 Drops

Syrup, Paracetamol 125 mg, Phenylephrine Hydrochloride 2.5 mg, and Chlorpheniramine Maleate 1 mg

4.1 Therapeutic indication

For symptomatic treatment of common cold and flu-like syndrome.

4.2 Posology and method of administration

4.3 Contraindications

• Hypersensitivity to any of the ingredients of the formulation.

• Avoid in patients with cardiovascular disease, high blood pressure, diabetes mellitus, closed angle glaucoma, hyperthyroidism, prostatic enlargement and phaeochromocytoma.

• Taking a monoamine oxidase inhibitor (MAOI), (certain drugs for depression, psychiatric or Parkinson’s disease), or for 2 weeks after stopping the MAOI drug.

• Patients with peripheral or mesenteric vascular thrombosis, because ischemia may be increased and the area of infarction extended with the use of phenylephrine.

• Premature or full-term neonates.

• Patients with hepatocellular insufficiency and in patients with hepatic failure or active liver disease as the formulation contains Paracetamol.

4.4 Special warnings and precautions for use

Especially in infants and small children, antihistamines in overdosage may cause hallucinations, convulsions and death. Antihistamines may diminish mental alertness. In young children, they may produce excitation.

• General: this product should be used with caution in patients with a history of narrow-angle glaucoma, gastrointestinal obstruction, or urinary bladder neck obstruction (enlarged prostate), a breathing problem such as emphysema or chronic bronchitis.

• Because of its sympathomimetic component, this product should be used with caution in patients with diabetes, hypertension, heart disease, or thyroid disease.

• Care is advised in the administration of paracetamol to patients with alcohol dependency, and severe renal or severe hepatic impairment. The hazards of overdose are greater in those with non-cirrhotic alcoholic liver disease. Do not exceed the recommended dose.

• If symptoms persist consult your doctor.

• Keep out of the reach and sight of children.

• Do not take with any other paracetamol-containing products.

• Immediate medical advice should be sought in the event of an overdose, even if you feel well, because of the risk of delayed, serious liver damage.

4.5 Drugs interactions

• Avoid using with any other drug containing acetaminophen. (prescription or nonprescription).

• Avoid use if you are now taking monoamine oxidase inhibitor (MAOI) (drugs for depression, psychiatric, or emotional conditions, or Parkinson's disease), or for 2 weeks after stopping the MAOI drug.

• Anticoagulants - the effect of warfarin and other coumarins may be enhanced by prolonged regular use of paracetamol with increased risk of bleeding. Occasional doses have no significant effect.

• Metoclopramide, Domperidone – may increase speed of absorption of paracetamol.

• Colestyramine – may reduce absorption if given within one hour of paracetamol.

• Imatinib - restriction or avoidance of concomitant regular paracetamol use should be taken with imatinib.

4.6 Use in special populations

Pregnancy

Pregnancy category C. It is not known whether this product can cause fetal harm when administered to a pregnant woman. This product should be given to pregnant woman only if clearly needed.

Labor and Delivery

Use of sympathomimetic amines during late pregnancy or during labor may cause fetal anoxia and bradycardia by increasing contractibility of the uterus and decreasing uterine blood flow.

Nursing Mothers

Because of the higher risk of intolerance of antihistamines in infants in general, and in newborns in particular, this product is contraindicated in nursing mothers.

Pediatrics

The use of antihistamines is not recommended in newborns and infants. This age group may be at a higher risk than others because of an increased susceptibility to anticholinergic effects such as CNS excitation, and an increased tendency toward convulsion. In older children, antihistamines may cause a paradoxical reaction characterized by hyperexcitability. Very young children may be more sensitive to the effects of sympathomimetics.

Geriatrics

The elderly (60 years or older) may be more susceptible to the vasopressor effects of sympathomimetics. Confusion, hallucinations, seizures and CNS depression may be more likely to occur in geriatric patients taking sympathomimetics. Antihistamines may cause confusion, dizziness, sedation, hypotension, hyperexcitability, and anticholinergic side effects such as dryness of the mouth and urinary retention in geriatric patients. If these symptoms occur and continue, or are severe, medication should probably be discontinued.

4.7 Effects on the ability to drive and use machines

Maxtra P Oral Drops may decrease alertness, affect your vision or make you feel sleepy and dizzy. Do not drive if these symptoms occur.

4.8 Undesirable effects

Phenylephrine may cause restlessness, anxiety, nervousness, weakness, dizziness, precordial pain or discomfort, tremor, respiratory distress, pallor or blanching of the skin, or a pilomotor response. Overdosage of phenylephrine may cause hypertension, headache, seizures, cerebral hemorrhage, palpitation, paresthesia, or vomiting. Phenylephrine can cause severe peripheral and visceral vasoconstriction, reduced blood flow to vital organs, decreased renal perfusion, and probably reduced urine output and metabolic acidosis. Severe vasoconstrictive effects may be most likely to occur in hypovolemic patients. Phenylephrine can cause severe bradycardia and decreased cardiac output.

The adverse effects of Paracetamol include allergic dermatitis, angioedema, drug-induced hepatitis, hepatitis, leukopenia, maculopapular rash, fixed drug eruption, neutropenic disorder, thrombocytopenic disorder, urticaria, vomiting, diarrhea, constipation, nausea, dyspepsia, and fatigue and chest pain. Most common adverse effects of Chlorpheniramine are drowsiness and thick bronchial secretions. Other side effects include abdominal pain with cramps, allergic reactions, anorexia, blurred vision, dizziness, dry nose, dry throat, excitement, headache disorder, hyperhidrosis, impaired cognition, nervousness, nightmares, skin photosensitivity, skin rash etc.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

Initiate general symptomatic and supportive measures in all cases of overdosages where necessary

5.1 Mechanism of Action / Pharmacodynamic properties

Phenylephrine is sympathomimetic post-synaptic α1–adrenergic receptor agonist with low cardioselective beta receptor affinity and minimal central nervous stimulant activity. It is a recognised decongestant and acts by vasoconstriction to reduce oedema and nasal swelling.

Chlorphenamine is a potent antihistamine (H1-antagonist).

Antihistamines diminish or abolish the actions of histamine in the body by competitive reversible blockade of histamine H1-receptor sites on tissues. Chlorphenamine also has anticholinergic activity. Antihistamines act to prevent the release of histamine, prostaglandins and leukotrienes and have been shown to prevent the migration of inflammatory mediators. The actions of chlorphenamine include inhibition of histamine on smooth muscle, capillary permeability and hence reduction of oedema and wheal in hypersensitivity reactions such as allergy and anaphylaxis.

Paracetamol may act predominantly by inhibiting prostaglandin synthesis in the central nervous system (CNS) and to a lesser extent, through a peripheral action by blocking pain-impulse generation.

The peripheral action may also be due to inhibition of prostaglandin synthesis or to inhibition of the synthesis or actions of other substances that sensitise pain receptors to mechanical or chemical stimulation.

Antipyretic – paracetamol probably produces antipyresis by acting centrally on the hypothalamic heat-regulation centre to produce peripheral vasodilation resulting in increased blood flow through the skin, sweating and heat loss. The central action probably involves inhibition of prostaglandin synthesis in the hypothalamus.

5.2 Pharmacokinetic properties

Paracetamol is readily absorbed from the gastro-intestinal tract with peak plasma concentrations occurring about 30 minutes to 2 hours after ingestion. It is metabolised in the liver and excreted in the urine mainly as the glucuronide and sulfate conjugates. Less than 5% is excreted as unchanged paracetamol. The elimination half-life varies from about 1 to 4 hours. Plasma-protein binding is negligible at usual therapeutic concentrations but increases with increasing concentrations. A minor hydroxylated metabolite which is usually produced in very small amounts by mixed-function oxidases in the liver and which is usually detoxified by conjugation with liver glutathione may accumulate following paracetamol overdosage and cause liver damage.

Phenylephrine is absorbed from the gastrointestinal tract, but has reduced bioavailability by the oral route due to first-pass metabolism. It retains activity as a nasal decongestant when given orally, the drug distributing through the systemic circulation to the vascular bed of the nasal mucosa. When taken by mouth as a nasal decongestant phenylephrine is usually given at intervals of 4-6 hours

Chlorphenamine is well absorbed from the gastro-intestinal tract, following oral administration. The effects develop within 30 minutes, are maximal within 1 to 2 hours and last 4 to 6 hours. The plasma half-life has been estimated to be 12 to 15 hours. Chlorphenamine is metabolised to the monodesmethyl and didesmethyl derivatives. About 22% of an oral dose is excreted unchanged in the urine.

6.1 Animal Toxicology or Pharmacology

No studies have been performed to evaluate the carcinogenic or mutagenic potential of this product.

Maxtra-P drop is a combination of anti-allergic chlorpheniramine maleate, analgesic/antipyretic paracetamol, and decongestant phenylephrine hydrochloride

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

A bottle of 15 ml.

8.4 Storage and handling instructions

Store at a temperature not exceeding 25°C. Protect from light.

Keep out of reach of children.

• It may cause dizziness and sleepiness. Don't drive or do anything that requires mental focus until you know how it affects you.

• Avoid consuming alcohol when taking this medicine as it may cause excessive drowsiness.

• Maxtra P drop is not recommended in severe cardiovascular disease, tachycardia, hypertension as well as other disorders like diabetes mellitus, thyrotoxicosis, prostatic enlargement & glaucoma.

• Do not take it with any other medicine containing paracetamol (drugs for pain/fever or cough-and-cold) without asking your doctor first.

• Inform your doctor if you are pregnant, planning to conceive or breastfeeding.

Phenylephrine Hydrochloride, Chlorpheniramine Maleate & Paracetamol Syrup

Each 5 ml contains :

Paracetamol IP 125 mg

Phenylephrine Hydrochloride IP 5 mg

Chlorpheniramine Maleate IP 1 mg

Excipients q.s.

Colour : Sunset Yellow FCF

In a mentholated flavoured syrup base

Syrup, Paracetamol 125 mg, Phenylephrine Hydrochloride 5 mg, and Chlorpheniramine Maleate 1 mg

4.1 Therapeutic indication

For symptomatic treatment of common cold and flu-like syndrome.

4.2 Posology and method of administration

4.3 Contraindications

• Hypersensitivity to any of the ingredients of the formulation.

• Avoid in patients with cardiovascular disease, high blood pressure, diabetes mellitus, closed angle glaucoma, hyperthyroidism, prostatic enlargement and phaeochromocytoma.

• Taking a monoamine oxidase inhibitor (MAOI), (certain drugs for depression, psychiatric or Parkinson’s disease), or for 2 weeks after stopping the MAOI drug.

• Patients with peripheral or mesenteric vascular thrombosis, because ischemia may be increased and the area of infarction extended with the use of phenylephrine

• Premature or full-term neonates

• Patients with hepatocellular insufficiency and in patients with hepatic failure or active liver disease as the formulation contains Paracetamol.

4.4 Special warnings and precautions for use

Especially in infants and small children, antihistamines in overdosage may cause hallucinations, convulsions and death. Antihistamines may diminish mental alertness. In young children, they may produce excitation.

• General: this product should be used with caution in patients with a history of narrow-angle glaucoma, gastrointestinal obstruction, or urinary bladder neck obstruction (enlarged prostate), a breathing problem such as emphysema or chronic bronchitis.

• Because of its sympathomimetic component, this product should be used with caution in patients with diabetes, hypertension, heart disease, or thyroid disease.

• Care is advised in the administration of paracetamol to patients with alcohol dependency, and severe renal or severe hepatic impairment. The hazards of overdose are greater in those with non-cirrhotic alcoholic liver disease. Do not exceed the recommended dose

• If symptoms persist consult your doctor,

• Keep out of the reach and sight of children

• Do not take with any other paracetamol-containing products.

• Immediate medical advice should be sought in the event of an overdose, even if you feel well, because of the risk of delayed, serious liver damage.

4.5 Drugs interactions

• Avoid using with any other drug containing acetaminophen. (prescription or nonprescription).

• Avoid use if you are now taking monoamine oxidase inhibitor (MAOI) (drugs for depression, psychiatric, or emotional conditions, or Parkinson's disease), or for 2 weeks after stopping the MAOI drug.

• Anticoagulants - the effect of warfarin and other coumarins may be enhanced by prolonged regular use of paracetamol with increased risk of bleeding. Occasional doses have no significant effect.

• Metoclopramide, Domperidone – may increase speed of absorption of paracetamol.

• Colestyramine – may reduce absorption if given within one hour of paracetamol.

• Imatinib - restriction or avoidance of concomitant regular paracetamol use should be taken with imatinib.

4.6 Use in special populations

Pregnancy

Pregnancy category C. It is not known whether this product can cause fetal harm when administered to a pregnant woman. This product should be given to pregnant woman only if clearly needed.

Labor and Delivery

Use of sympathomimetic amines during late pregnancy or during labor may cause fetal anoxia and bradycardia by increasing contractibility of the uterus and decreasing uterine blood flow

Nursing Mothers

Because of the higher risk of intolerance of antihistamines in infants in general, and in newborns in particular, this product is contraindicated in nursing mothers.

Pediatrics

The use of antihistamines is not recommended in newborns and infants. This age group may be at a higher risk than others because of an increased susceptibility to anticholinergic effects such as CNS excitation, and an increased tendency toward convulsion. In older children, antihistamines may cause a paradoxical reaction characterized by hyperexcitability. Very young children may be more sensitive to the effects of sympathomimetics.

Geriatrics

The elderly (60 years or older) may be more susceptible to the vasopressor effects of sympathomimetics. Confusion, hallucinations, seizures and CNS depression may be more likely to occur in geriatric patients taking sympathomimetics. Antihistamines may cause confusion, dizziness, sedation, hypotension, hyperexcitability, and anticholinergic side effects such as dryness of the mouth and urinary retention in geriatric patients. If these symptoms occur and continue, or are severe, medication should probably be discontinued.

4.7 Effects on the ability to drive and use machines

Maxtra P Syrup may decrease alertness, affect your vision or make you feel sleepy and dizzy. Do not drive if these symptoms occur

4.8 Undesirable effects

Phenylephrine may cause restlessness, anxiety, nervousness, weakness, dizziness, precordial pain or discomfort, tremor, respiratory distress, pallor or blanching of the skin, or a pilomotor response. Overdosage of phenylephrine may cause hypertension, headache, seizures, cerebral hemorrhage, palpitation, paresthesia, or vomiting. Phenylephrine can cause severe peripheral and visceral vasoconstriction, reduced blood flow to vital organs, decreased renal perfusion, and probably reduced urine output and metabolic acidosis. Severe vasoconstrictive effects may be most likely to occur in hypovolemic patients. Phenylephrine can cause severe bradycardia and decreased cardiac output

The adverse effects of Paracetamol include allergic dermatitis, angioedema, drug-induced hepatitis, hepatitis, leukopenia, maculopapular rash, fixed drug eruption, neutropenic disorder, thrombocytopenic disorder, urticaria, vomiting, diarrhea, constipation, nausea, dyspepsia, and fatigue and chest pain. Most common adverse effects of Chlorpheniramine are drowsiness and thick bronchial secretions. Other side effects include abdominal pain with cramps, allergic reactions, anorexia, blurred vision, dizziness, dry nose, dry throat, excitement, headache disorder, hyperhidrosis, impaired cognition, nervousness, nightmares, skin photosensitivity, skin rash etc.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

Initiate general symptomatic and supportive measures in all cases of overdosages where necessary.

5.1 Mechanism of Action / Pharmacodynamic properties

Phenylephrine is sympathomimetic post-synaptic α1–adrenergic receptor agonist with low cardioselective beta receptor affinity and minimal central nervous stimulant activity. It is a recognised decongestant and acts by vasoconstriction to reduce oedema and nasal swelling. Chlorphenamine is a potent antihistamine (H1-antagonist). Antihistamines diminish or abolish the actions of histamine in the body by competitive reversible blockade of histamine H1-receptor sites on tissues. Chlorphenamine also has anticholinergic activity. Antihistamines act to prevent the release of histamine, prostaglandins and leukotrienes and have been shown to prevent the migration of inflammatory mediators. The actions of chlorphenamine include inhibition of histamine on smooth muscle, capillary permeability and hence reduction of oedema and wheal in hypersensitivity reactions such as allergy and anaphylaxis. Paracetamol may act predominantly by inhibiting prostaglandin synthesis in the central nervous system (CNS) and to a lesser extent, through a peripheral action by blocking pain-impulse generation. The peripheral action may also be due to inhibition of prostaglandin synthesis or to inhibition of the synthesis or actions of other substances that sensitise pain receptors to mechanical or chemical stimulation. Antipyretic – paracetamol probably produces antipyresis by acting centrally on the hypothalamic heat-regulation centre to produce peripheral vasodilation resulting in increased blood flow through the skin, sweating and heat loss. The central action probably involves inhibition of prostaglandin synthesis in the hypothalamus.

5.2 Pharmacokinetic properties

Paracetamol is readily absorbed from the gastro-intestinal tract with peak plasma concentrations occurring about 30 minutes to 2 hours after ingestion. It is metabolised in the liver and excreted in the urine mainly as the glucuronide and sulfate conjugates. Less than 5% is excreted as unchanged paracetamol. The elimination half-life varies from about 1 to 4 hours. Plasma-protein binding is negligible at usual therapeutic concentrations but increases with increasing concentrations. A minor hydroxylated metabolite which is usually produced in very small amounts by mixed-function oxidases in the liver and which is usually detoxified by conjugation with liver glutathione may accumulate following paracetamol overdosage and cause liver damage. Phenylephrine is absorbed from the gastrointestinal tract, but has reduced bioavailability by the oral route due to first-pass metabolism. It retains activity as a nasal decongestant when given orally, the drug distributing through the systemic circulation to the vascular bed of the nasal mucosa. When taken by mouth as a nasal decongestant phenylephrine is usually given at intervals of 4-6 hours. Chlorphenamine is well absorbed from the gastro-intestinal tract, following oral administration. The effects develop within 30 minutes, are maximal within 1 to 2 hours and last 4 to 6 hours. The plasma half-life has been estimated to be 12 to 15 hours. Chlorphenamine is metabolised to the monodesmethyl and didesmethyl derivatives. About 22% of an oral dose is excreted unchanged in the urine.

6.1 Animal Toxicology or Pharmacology

No studies have been performed to evaluate the carcinogenic or mutagenic potential of this product.

Maxtra-P syrup is a combination of anti-allergic chlorpheniramine maleate, analgesic/antipyretic paracetamol, and decongestant phenylephrine hydrochloride.

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

A bottle of 60 ml.

8.4 Storage and handling instructions

Store at a temperature not exceeding 25°C. Protect from light.

Keep out of reach of children.

• It may cause dizziness and sleepiness. Don't drive or do anything that requires mental focus until you know how it affects you.

• Avoid consuming alcohol when taking this medicine as it may cause excessive drowsiness.

• Maxtra P Syrup is not recommended in severe cardiovascular disease, tachycardia, hypertension as well as other disorders like diabetes mellitus, thyrotoxicosis, prostatic enlargement & glaucoma.

• Do not take it with any other medicine containing paracetamol (drugs for pain/fever or cough-and-cold) without asking your doctor first.

• Inform your doctor if you are pregnant, planning to conceive or breastfeeding.

Paracetamol, Phenylephrine Hydrochloride & Chlorpheniramine Maleate Tablets

Each uncoated tablet contains :

Paracetamol IP 500 mg

Phenylephrine Hydrochloride IP 10 mg

Chlorpheniramine Maleate IP 4 mg

Excipient q.s.

Tablets, Paracetamol 500 mg, Phenylephrine Hydrochloride 10 mg and Chlorpheniramine Maleate 4 mg

4.1 Therapeutic indication

For symptomatic treatment of common cold and flu-like syndrome.

4.2 Posology and method of administration

Adults and children 12 years of age and older : Take 1 tablet every 4 to 6 hours.

4.3 Contraindications

• Hypersensitivity to any of the ingredients of the formulation.

• Avoid in patients with cardiovascular disease, high blood pressure, diabetes mellitus, closed angle glaucoma, hyperthyroidism, prostatic enlargement and phaeochromocytoma.

• Taking a monoamine oxidase inhibitor (MAOI), (certain drugs for depression, psychiatric or Parkinson’s disease), or for 2 weeks after stopping the MAOI drug.

• Patients with peripheral or mesenteric vascular thrombosis, because ischemia may be increased and the area of infarction extended with the use of Phenylephrine.

• Premature or full-term neonates.

• Patients with hepatocellular insufficiency and in patients with hepatic failure or active liver disease as the formulation contains Paracetamol.

4.4 Special warnings and precautions for use

Especially in infants and small children, antihistamines in overdosage may cause hallucinations, convulsions and death. Antihistamines may diminish mental alertness. In young children, they may produce excitation.

• General : This product should be used with caution in patients with a history of narrow-angle glaucoma, gastrointestinal obstruction, or urinary bladder neck obstruction (enlarged prostate), a breathing problem such as emphysema or chronic bronchitis.

• Because of its sympathomimetic component, this product should be used with caution in patients with diabetes, hypertension, heart disease, or thyroid disease.

• Care is advised in the administration of Paracetamol to patients with alcohol dependency and severe renal or severe hepatic impairment. The hazards of overdose are greater in those with noncirrhotic alcoholic liver disease. Do not exceed the recommended dose.

• If symptoms persist consult your doctor.

• Keep out of the reach and sight of children.

• Do not take with any other Paracetamol-containing products.

• Immediate medical advice should be sought in the event of an overdose, even if you feel well, because of the risk of delayed, serious liver damage.

4.5 Drugs interactions

• Avoid using with any other drug containing Acetaminophen.

• Avoid use if you are now taking monoamine oxidase inhibitor (MAOI) (drugs for depression, psychiatric, or emotional conditions, or Parkinson's disease), or for 2 weeks after stopping the MAOI drug.

• Anticoagulants : the effect of Warfarin and other coumarins may be enhanced by prolonged regular use of Paracetamol with increased risk of bleeding. Occasional doses have no significant effect.

• Metoclopramide, Domperidone : may increase speed of absorption of Paracetamol.

• Colestyramine : May reduce absorption if given within one hour of Paracetamol.

• Imatinib : restriction or avoidance of concomitant regular Paracetamol use should be taken with Imatinib.

4.6 Use in special populations

Pregnancy

Pregnancy category C. It is not known whether this product can cause fetal harm when administered to a pregnant woman. This product should be given to pregnant woman only if clearly needed.

Labor and delivery

Use of sympathomimetic amines during late pregnancy or during labor may cause fetal anoxia and bradycardia by increasing contractibility of the uterus and decreasing uterine blood flow

Nursing mothers

Because of the higher risk of intolerance of antihistamines in infants in general, and in new-borns in particular, this product is contraindicated in nursing mothers

Pediatrics

The use of antihistamines is not recommended in new-borns and infants. This age group may be at a higher risk than others because of an increased susceptibility to anticholinergic effects such as CNS excitation, and an increased tendency toward convulsion. In older children, antihistamines may cause a paradoxical reaction characterized by hyperexcitability. Very young children may be more sensitive to the effects of sympathomimetics.

Geriatrics

The elderly (60 years or older) may be more susceptible to the vasopressor effects of sympathomimetics. Confusion, hallucinations, seizures and CNS depression may be more likely to occur in geriatric patients taking sympathomimetics. Antihistamines may cause confusion, dizziness, sedation, hypotension, hyperexcitability, and anticholinergic side effects such as dryness of the mouth and urinary retention in geriatric patients. If these symptoms occur and continue, or are severe, medication should probably be discontinued.

4.7 Effects on the ability to drive and use machines

Maxtra P Tablet may decrease alertness, affect your vision or make you feel sleepy and dizzy. Do not drive if these symptoms occur.

4.8 Undesirable effects

Phenylephrine may cause restlessness, anxiety, nervousness, weakness, dizziness, precordial pain or discomfort, tremor, respiratory distress, pallor or blanching of the skin, or a pilomotor response. Over dosage of Phenylephrine may cause hypertension, headache, seizures, cerebral hemorrhage, palpitation, paresthesia, or vomiting. Phenylephrine can cause severe peripheral and visceral vasoconstriction, reduced blood flow to vital organs, decreased renal perfusion, and probably reduced urine output and metabolic acidosis. Severe vasoconstrictive effects may be most likely to occur in hypovolemic patients. Phenylephrine can cause severe bradycardia and decreased cardiac output

The adverse effects of Paracetamol include allergic dermatitis, angioedema, drug-induced hepatitis, hepatitis, leukopenia, maculopapular rash, fixed drug eruption, neutropenic disorder, thrombocytopenic disorder, urticaria, vomiting, diarrhea, constipation, nausea, dyspepsia, and fatigue and chest pain.

Most common adverse effects of Chlorpheniramine are drowsiness and thick bronchial secretions. Other side effects include abdominal pain with cramps, allergic reactions, anorexia, blurred vision, dizziness, dry nose, dry throat, excitement, headache disorder, hyperhidrosis, impaired cognition, nervousness, nightmares, skin photosensitivity, skin rash etc.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to : medico@zuventus.com

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

Initiate general symptomatic and supportive measures in all cases of over dosages where necessary.

5.1 Mechanism of action / pharmacodynamic properties

Phenylephrine is sympathomimetic post-synaptic α1–adrenergic receptor agonist with low cardioselective beta receptor affinity and minimal central nervous stimulant activity. It is a recognised decongestant and acts by vasoconstriction to reduce oedema and nasal swelling.

Chlorpheniramine is a potent antihistamine (H1-antagonist).

Antihistamines diminish or abolish the actions of histamine in the body by competitive reversible blockade of histamine H1-receptor sites on tissues. Chlorpheniramine also has anticholinergic activity. Antihistamines act to prevent the release of histamine, prostaglandins and leukotrienes and have been shown to prevent the migration of inflammatory mediators. The actions of Chlorpheniramine include inhibition of histamine on smooth muscle, capillary permeability and hence reduction of oedema and wheal in hypersensitivity reactions such as allergy and anaphylaxis. Paracetamol may act predominantly by inhibiting prostaglandin synthesis in the central nervous system (CNS) and to a lesser extent, through a peripheral action by blocking pain-impulse generation. The peripheral action may also be due to inhibition of prostaglandin synthesis or to inhibition of the synthesis or actions of other substances that sensitise pain receptors to mechanical or chemical stimulation.

Antipyretic : Paracetamol probably produces antipyresis by acting centrally on the hypothalamic heat-regulation centre to produce peripheral vasodilation resulting in increased blood flow through the skin, sweating and heat loss. The central action probably involves inhibition of prostaglandin synthesis in the hypothalamus.

5.2 Pharmacokinetic properties

Paracetamol is readily absorbed from the gastro-intestinal tract with peak plasma concentrations occurring about 30 minutes to 2 hours after ingestion. It is metabolised in the liver and excreted in the urine mainly as the glucuronide and sulfate conjugates. Less than 5% is excreted as unchanged Paracetamol. The elimination half-life varies from about 1 to 4 hours. Plasma-protein binding is negligible at usual therapeutic concentrations but increases with increasing concentrations.

A minor hydroxylated metabolite which is usually produced in very small amounts by mixed-function oxidases in the liver and which is usually detoxified by conjugation with liver glutathione may accumulate following Paracetamol over dosage and cause liver damage.

Phenylephrine is absorbed from the gastrointestinal tract, but has reduced bioavailability by the oral route due to first-pass metabolism. It retains activity as a nasal decongestant when given orally, the drug distributing through the systemic circulation to the vascular bed of the nasal mucosa. When taken by mouth as a nasal decongestant Phenylephrine is usually given at intervals of 4 - 6 hours. Chlorpheniramine is well absorbed from the gastro-intestinal tract, following oral administration. The effects develop within 30 minutes, are maximal within 1 to 2 hours and last 4 to 6 hours. The plasma half-life has been estimated to be 12 to 15 hours. Chlorpheniramine is metabolised to the monodesmethyl and didesmethyl derivatives. About 22% of an oral dose is excreted unchanged in the urine.

6.1 Animal toxicology or pharmacology

No studies have been performed to evaluate the carcinogenic or mutagenic potential of this product.

Maxtra P tablet is a combination of anti-allergic Chlorpheniramine Maleate, analgesic/antipyretic Paracetamol and decongestant Phenylephrine Hydrochloride.

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

PVC/PVDC-Alu blister strip of 10 tablets.

8.4 Storage and handling instructions

Store below 30°C. Protect from moisture.

Keep out of reach of children.

• It may cause dizziness and sleepiness. Don't drive or do anything that requires mental focus until you know how it affects you.

• Avoid consuming alcohol when taking this medicine as it may cause excessive drowsiness.

• Do not take it with any other medicine containing Paracetamol (drugs for pain / fever or cough-and-cold) without asking your doctor first.

• Inform your doctor if you are pregnant, planning to conceive or breastfeeding.

Mefenamic Acid & Paracetamol Suspension

Each 5 ml contains :

Mefenamic Acid IP 50 mg

Paracetamol IP 125 mg

Excipients q.s.

Colour : Sunset Yellow FCF

In a flavoured syrupy base

Suspension, Mefenamic Acid & Paracetamol Suspension (50 mg + 125 mg)

4.1 Therapeutic indication

Mefast P Suspension is indicated for fever and pain.

4.2 Posology and method of administration

Mefast P Suspension should be taken preferably with or after food. The recommended dosage in children is given up to three times daily, usually not to exceed one week.

4.3 Contraindications

• Patients with known hypersensitivity to mefenamic acid, paracetamol or to any of the excipients

• Patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients

• For the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery

• In patients with acute active ulceration or chronic inflammation of either the upper or lower gastrointestinal tract

• In patients with pre-existing renal disease

• In severe hepatic impairment

4.4 Special warnings and precautions for use

Mefast P Suspension should be used cautiously during following conditions:

• Cardiovascular Thrombotic Effects: shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal.

• Hypertension

• Congestive Heart Failure

• Renal and hepatic impairment

• Asthma

• Monitor blood counts and liver function during long-term therapy

• Drowsiness may affect ability to perform skilled tasks

• Elderly, advanced renal disease

4.5 Drugs interactions

Paracetamol

• Anticoagulant drugs (warfarin) - dosage may require reduction if paracetamol and anticoagulants are taken for a prolonged period of time.

• Paracetamol absorption is increased by substances that increase gastric emptying, e.g. metoclopramide.

• Paracetamol absorption is decreased by substances that decrease gastric emptying, e.g. propantheline, antidepressants with anticholinergic properties, and narcotic analgesics.

• Paracetamol may increase chloramphenicol concentrations

• The risk of paracetamol toxicity may be increased in patients receiving other potentially hepatotoxic drugs or drugs that induce liver microsomal enzymes such as alcohol and anticonvulsant agents

• Paracetamol excretion may be affected and plasma concentrations altered when given with probenecid

• Cholestyramine reduces the absorption of paracetamol if given within 1 hour.

• Antivirals: Regular use of paracetamol possibly reduces metabolism of Zidovudine (increased risk of neutropenia).

Mefenamic Acid

• Mefenamic Acid enhances activity of oral anticoagulants but rarely significant.

• Increased cyclosporine, lithium toxicity and convulsions reported with ciprofloxacin.

• Absorption is increased by Magnesium Hydroxide antacids.

4.6 Use in special populations

Pregnancy Category C

There are no adequate or well controlled studies in pregnant women. Mefenamic acid should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Although paracetamol have shown no ill effects in human pregnancy, the combination should not be used in late pregnancy, as with other NSAIDs, mefenamic acid may cause premature closure of the ductus arteriosus.

Labour and Delivery

In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of mefenamic acid on labour and delivery in pregnant women are unknown.

Nursing Mothers

Trace amounts of mefenamic acid may be present in breast milk and transmitted to the nursing infant. Because of the potential for serious adverse reactions in nursing infants from mefenamic acid, 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.

Geriatric use

Clinical studies of combination did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. As with other NSAIDs, caution should be exercised in treating the elderly (65 years and older). This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

4.7 Effects on ability to drive and use machines

Patients should be cautioned against engaging in activities requiring complete mental alertness, and motor coordination such as operating machinery until their response to Mefast P Suspension is known.

4.8 Undesirable effects

Fixed Drug Eruption (FDE) has been associated with Paracetamol use.

Difficulty in breathing or swallowing, swelling of the face, lips, tongue or throat, severe itching of the skin with a red rash or raised lumps, blistering of the mouth, eyes, or genital region, patchy areas of rash, peeling skin or any of the following reactions:

• Severe or worsening diarrhoea

• Passing blood in stools (faeces/motions)

• Passing black tarry stools

• Vomiting any blood or dark particles that look like coffee grounds

Abdominal pain, dyspepsia, constipation, diarrhea, nausea, GI ulcers, oedema, bronchospasm, headache, drowsiness, insomnia, visual disturbances, CHF, hypertension, tachycardia, syncope, urticaria, rash, thrombocytopenia, aplastic anemia, agranulocytosis, tinnitus, elevated liver enzymes, abnormal renal function. Potentially Fatal: Autoimmune hemolytic anemia; convulsions (overdosage).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

Symptoms following acute NSAIDs, overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose. Patients should be managed by symptomatic and supportive care following a NSAID overdose. There are no specific antidotes. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose (5 to 10 times the usual dose). In addition, administration of oral methionine or intravenous N-acetylcysteine (NAC) which may have a beneficial effect up to at least 48 hours after the over-dose may be required. Administration of intravenous NAC is most beneficial when initiated within 8 hours of overdose ingestion. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

5.1 Mechanism of action

Mefenamic acid binds the prostaglandin synthetase receptors COX-1 and COX-2, inhibiting the action of prostaglandin synthetase. As these receptors have a role as a major mediator of inflammation and/or a role for prostanoid signaling in activity-dependent plasticity, the symptoms of pain are temporarily reduced. Paracetamol act primarily in the CNS, increasing the pain threshold by inhibiting both isoforms of cyclooxygenase, COX-1, COX-2, and COX-3 enzymes involved in prostaglandin (PG) synthesis. The antipyretic properties of acetaminophen are likely due to direct effects on the heat-regulating centres of the hypothalamus resulting in peripheral vasodilation, sweating and hence heat dissipation.

5.2 Pharmacodynamic properties

Mefenamic acid belongs to the family of drugs called fenamates, which are aspirin-like drugs that are derivatives of N-phenylanthranilic acid. In tests of anti-inflammatory activity, mefenamic acid is about half as potent as phenylbutazone. Mefenamic acid has antipyretic and analgesic properties and displays a central as well as a peripheral action. Mefenamic acid appears to owe these properties to its capacity to inhibit cyclo-oxygenase (COX).

Paracetamol is a widely used analgesic and antipyretic drug that is used for the relief of fever, headaches, and other minor aches and pains. It is a major ingredient in numerous cold and flu medications and many prescription analgesics. It is extremely safe in standard doses, but because of its wide availability, deliberate or accidental overdoses are not uncommon. Paracetamol, unlike other common analgesics such as aspirin and ibuprofen, has no anti-inflammatory properties or effects on platelet function, and it is not a member of the class of drugs known as non-steroidal anti-inflammatory drugs or NSAIDs. At therapeutic doses Paracetamol does not irritate the lining of the stomach nor affect blood coagulation, kidney function, or the fetal ductus arteriosus (as NSAIDs can). Like NSAIDs and unlike opioid analgesics, Paracetamol does not cause euphoria or alter mood in any way. Paracetamol and NSAIDs have the benefit of being completely free of problems with addiction, dependence, tolerance and withdrawal.

5.3 Pharmacokinetic properties

Mefenamic acid is absorbed from the gastrointestinal tract. Peak plasma concentrations occur about 2 to 4 hours after ingestion. The plasma elimination half-life is reported to be about 2 to 4 hours. Mefenamic acid is more than 90% bound to plasma proteins. It is distributed into breast milk. Mefenamic acid is metabolised by the cytochrome P450 isoenzyme CYP2C9 to 3-hydroxymethyl Mefenamic acid, which may then be oxidised to 3- carboxymefenamic acid. Over 50% of a dose may be recovered in the urine, as unchanged drug or, mainly, as conjugates of Mefenamic acid and its metabolites.

Paracetamol is readily absorbed from the gastrointestinal tract with peak plasma concentrations occurring about 10 to 60 minutes after oral doses. Paracetamol is distributed into most body tissues. It crosses the placenta and is present in breast milk. Plasma-protein binding is negligible at usual therapeutic concentrations but increases with increasing concentrations. The elimination half-life of paracetamol varies from about 1 to 3 hours. Paracetamol is metabolised mainly in the liver and excreted in the urine mainly as the glucuronide and sulfate conjugates. Less than 5% is excreted as unchanged paracetamol. A minor hydroxylated metabolite (Nacetyl-p-benzoquinoneimine), is usually produced in very small amounts by cytochrome P450 isoenzymes (mainly CYP2E1 and CYP3A4) in the liver and kidney. It is usually detoxified by conjugation with glutathione but may accumulate after paracetamol over dosage and cause tissue damage.

6.1 Animal toxicology or pharmacology

No known animal toxicology data

Mefenamic acid (2-(2,3-dimethylphenyl) aminobenzoic acid) is a non-steroidal antiinflammatory drug with a molecular formula of and molecular weight of 241.285 g/mol. Paracetamol (N-(4-hydroxyphenyl) acetamide) is an analgesic with a molecular formula of C8H9NO2 and molecular weight of 151.17 g/mol.

8.1 Incompatibilities

Not applicable

8.2 Shelf life

Refer on the pack.

8.3 Packaging information

A bottle of 60 ml.

8.4 Storage and handling instructions

Store below 30°C. Protect from light. Do not freeze.

Keep out of reach of children.

• Ensure the prescribed dose of Mefast P Suspension is taken as directed.

• Not to exceed the stated recommended daily dose.

• Shake Mefast P suspension well before use each time.

• If pregnant or breast-feeding, ask a health professional before use. Instruct pregnant women not to take Mefast P Suspension especially in the last 3 months of pregnancy as it may cause harm to the foetus and during labour (delivery) because it may delay the labour and increases risk of bleeding.

• Not to use with any other drug containing paracetamol (prescription or over-the-counter - OTC). Users to ask a doctor or pharmacist, if they are not sure about presence of paracetamol in the drug taken for other illnesses.

• Ask the patient to report any adverse events.

Montelukast Sodium & Levocetirizine Dihydrochloride Tablets [10 mg + 5 mg]

Each uncoated bilayered tablet contains :

Montelukast Sodium

Equivalent to Montelukast 10 mg

Levocetirizine Dihydrochloride USP 5 mg

Excipients q.s.

Tablet, Montelukast Sodium & Levocetirizine Dihydrochloride Tablets [10 mg + 5 mg]

4.1 Therapeutic indication

For the treatment of allergic rhinitis in adults only.

4.2 Posology and method of administration

4.3 Contraindications

• Patients who are hypersensitive to any of the component of the product.
• Patients with severe renal impairment at less than 10 ml/min creatinine clearance.
• Patients undergoing haemodialysis.

4.4 Warning and precautions

Montelukast

Acute Asthma

Montelukast is not indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus. Patients should be advised to have appropriate rescue medication available. Therapy with Montelukast can be continued during acute exacerbations of asthma. While the dose of inhaled corticosteroid may be reduced gradually under medical supervision, Montelukast should not be abruptly substituted for inhaled or oral corticosteroids. There are no data demonstrating that oral corticosteroids can be reduced when Montelukast is given concomitantly. Patients who have exacerbations of asthma after exercise should have available for rescue a short-acting inhaled beta2- agonist.

Concomitant corticosteroid use

While the dose of inhaled corticosteroid may be reduced gradually under medical supervision, Montelukast should not be abruptly substituted for inhaled or oral corticosteroids

Aspirin sensitivity

Patients with known Aspirin sensitivity should continue avoidance of Aspirin or nonsteroidal anti-inflammatory agents while taking Montelukast. Although Montelukast is effective in improving airway function in asthmatics with documented aspirin sensitivity, it has not been shown to truncate bronchoconstrictor response to aspirin and other nonsteroidal anti-inflammatory drugs in Aspirin-sensitive asthmatic patients.

Eosinophilic conditions

Patients on therapy with Montelukast may present with systemic eosinophilia sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition, which is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction of oral corticosteroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal association between, Montelukast and these underlying conditions has not been established.

Neuropsychiatric events

Neuropsychiatric events have been reported in adult, adolescent, and pediatric patients taking Montelukast. Post-marketing reports with Montelukast use include agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, obsessive-compulsive symptoms, dream abnormalities, hallucinations, insomnia, irritability, memory impairment, restlessness, somnambulism, suicidal thinking and behavior (including suicide), and tremor. The clinical details of some post-marketing reports involving Montelukast appear consistent with a drug-induced effect. Patients and prescribers should be alert for neuropsychiatric events. Patients should be instructed to notify their prescriber if these changes occur. Prescribers should carefully evaluate the risks and benefits of continuing treatment with Montelukastif such events occur

Phenylketonuria

Phenylketonuric patients should be informed about the presence of Phenylalanine (a component of Aspartame) in this product.

Levocetirizine

Somnolence

In clinical trials the occurrence of somnolence, fatigue, and asthenia has been reported in some patients under therapy with Levocetirizine. Patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness, and motor coordination such as operating machinery or driving a motor vehicle after ingestion of Levocetirizine. Concurrent use of Levocetirizine with alcohol or other central nervous system depressants should be avoided because additional reductions in alertness and additional impairment of central nervous system performance may occur.

Urinary retention

Urinary retention has been reported post marketing with Levocetirizine. Levocetirizine should be used with caution in patients with predisposing factors of urinary retention (e.g. spinal cord lesion, prostatic hyperplasia) as Levocetirizine may increase the risk of urinary retention. Discontinue Levocetirizine if urinary retention occurs.

4.5 Drug interactions

Montelukast

Montelukast may be administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma. In drug-interaction studies, the recommended clinical dose of Montelukast did not have clinically important effects on the pharmacokinetics of the following drugs : Theophylline, Prednisone, Prednisolone, Oral contraceptives (Norethindrone 1 mg / Ethinyl estradiol 35 mcg), Terfenadine, Digoxin and Warfarin, Gemfibrozil, Itraconazole, Thyroid hormones, Sedative hypnotics, Non-steroidal antiinflammatory agents, Benzodiazepines, Decongestants and CYP450 enzyme inducers. The area under the plasma concentration curve (AUC) for Montelukast was decreased approximately 40% in subjects with co-administration of phenobarbital. Since Montelukast is metabolised by CYP 3A4, caution should be exercised, particularly in children, when Montelukast is co-administered with inducers of CYP3A4, such as phenytoin, phenobarbital and rifampicin. Although additional specific interaction studies were not performed, Montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants.

In vitro studies have shown that Montelukast is a potent inhibitor of CYP 2C8. However, data from a clinical drug-drug interaction study involving Montelukast and rosiglitazone (a probe substrate representative of medicinal products primarily metabolised by CYP 2C8) demonstrated that Montelukast does not inhibit CYP 2C8 in vivo. Therefore, Montelukast is not anticipated to markedly alter the metabolism of medicinal products metabolised by this enzyme (e.g., Paclitaxel, Rosiglitazone and Repaglinide.)

In vitro studies have shown that Montelukast is a substrate of CYP 2C8, and to a less significant extent, of 2C9, and 3A4. In a clinical drug-drug interaction study involving Montelukast and gemfibrozil (an inhibitor of both CYP 2C8 and 2C9) gemfibrozil increased the systemic exposure of Montelukast by 4.4-fold. No routine dosage adjustment of Montelukast is required upon co-administration with Gemfibrozil or other potent inhibitors of CYP2C8, but the Physician should be aware of the potential for an increase in adverse reactions. Based on in vitro data, clinically important drug interactions with less potent inhibitors of CYP 2C8 (e.g., trimethoprim) are not anticipated. Co-administration of Montelukast with Itraconazole, a strong inhibitor of CYP 3A4, resulted in no significant increase in the systemic exposure of Montelukast.

Levocetirizine

In vitro data on metabolite interaction indicate that Levocetirizine is unlikely to produce, or be subject to metabolic interactions. Levocetirizine at concentrations well above Cmax level achieved within the therapeutic dose ranges is not an inhibitor of CYP isoenzymes 1A2, 2C9, 2C19, 2A1, 2D6, 2E1, and 3A4, and is not an inducer of UGT1A or CYP isoenzymes 1A2, 2C9 and 3A4.

No in vivo drug-drug interaction studies have been performed with Levocetirizine. Drug interaction studies have been performed with racemic Cetirizine.

Antipyrine, Azithromycin, Cimetidine, Erythromycin, Ketoconazole, Theophylline, and Pseudoephedrine

Pharmacokinetic interaction studies performed with racemic Cetirizine demonstrated that Cetirizine did not interact with Antipyrine, Pseudoephedrine, Erythromycin, Glipizide and Diazepam, Azithromycin, Ketoconazole and Cimetidine. There was a small decrease (~16%) in the clearance of Cetirizine caused by a 400 mg dose of Theophylline. It is possible that higher Theophylline doses could have a greater effect. The extent of absorption of Levocetirizine is not reduced with food although the rate of absorption is decreased.

Ritonavir

Ritonavir increased the plasma AUC of Cetirizine by about 42% accompanied by an increase in half-life (53%) and a decrease in clearance (29%) of Cetirizine. The disposition of ritonavir was not altered by concomitant Cetirizine administration. In sensitive patients the simultaneous administration of Cetirizine or Levocetirizine and alcohol or other CNS depressants may have effects on the central nervous system, although it has been shown that the racemate Cetirizine does not potentiate the effect of Alcohol.

4.6 Special populations

Pregnancy

There are no adequate and well controlled studies of either Montelukast or Levocetirizine in pregnant women.

Hence this combination should not be used during pregnancy

Lactation

Since Levocetirizine is excreted in breast-milk the combination is not recommended during lactation.

4.7 Effects on ability to drive and use machines

Patients should be cautioned against engaging in activities requiring complete mental alertness, and motor coordination such as operating machinery until their response to Nukast Tablets is known.

4.8 Undesirable effects

There is no data available on undesirable effects of this combination. However, side effects have been reported with individual molecules.

Montelukast

The most common adverse reactions (incidence ≥ 5% and greater than placebo; listed in descending order of frequency) in controlled clinical trials were: upper respiratory infection, fever, headache, pharyngitis, cough, abdominal pain, diarrhoea, otitis media, influenza, rhinorrhea, sinusitis, otitis.

Montelukast has been evaluated in 280 paediatric patients 2 to 14 years of age in a 2-week, multicentre, double-blind, placebo-controlled, parallel-group safety study. Montelukast administered once daily in the evening had a safety profile similar to that of placebo. In this study, the following events occurred with a frequency ≥ 2% and at an incidence greater than placebo : headache, otitis media, pharyngitis, and upper respiratory infection. The safety in patients 2 to 14 years of age with perennial allergic rhinitis is supported by the safety in patients 2 to 14 years of age with seasonal allergic rhinitis. The safety in patients 6 to 23 months of age is supported by data from pharmacokinetic and safety and efficacy studies in asthma in this pediatric population and from adult pharmacokinetic studies. The following adverse reactions have been reported in post-marketing use :

Blood and lymphatic system disorders : Increased bleeding tendency. Immune system disorders : Hypersensitivity reactions including Anaphylaxis, Hepatic eosinophilic infiltration.

Psychaitric disorders :

Agitation including aggressive behaviour or hostility, Anxiousness, Depression, Disorientation, Dream abnormalities, Hallucinations, Insomnia, Irritability, Restlessness, Somnambulism, Suicidal thinking and behaviour (including suicide), Tremor.

Nervous system disorder : Drowsiness, Paresthesia / hypoesthesia, Seizure. Respiratory, Thoracic and mediastinal disorder, Epistaxis.

Cardiac disorders : Palpitations.

Gastro-intestinal disorders : Diarrhoea, Dry mouth, Dyspepsia, Nausea, Vomiting.

Hepatobiliary disorders : Elevated levels of serum transminases (ALT, AST), Rare cases of cholestatic hepatitis, Hepatocellular liver injury and mixed-pattern liver injury have been reported in patients treated with Montelukast.

Most of these occurred in combination with other confounding factors, such as use of other medications, or when Montelukast was administered to patients who had underlying potential for liver disease, such as alcohol use or other forms of hepatitis

Skin and subcutaneous tissue disorders : Angioedema, Bruising, Urticaria, Pruritus, Rash, Erythema nodosum.

Musculoskeletal and connective tissue disorders : Arthralgia, Myalgia including muscle cramps.

General disorders and administration site conditions : Asthenia/fatigue, Malaise, Oedema. Patients with asthma on therapy with Montelukast may present with systemic eosinophilia. Sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction of oral corticosteroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients

Levocetirizine

Use of Levocetirizine has been associated with somnolence, fatigue, nasopharyngitis, dry mouth and pharyngitis in subjects 12 years of age and older. Further uncommon incidences of adverse reactions like asthenia, abdominal pain, syncope and weight- increase were observed. Adverse reactions reported in ≥ 2% of paediatric subjects aged 1 - 6 years exposed to Levocetirizine 1.25 mg twice daily in a 2-week placebo-controlled clinical trial were pyrexia, diarrhoea, vomiting and otitis media while in paediatric subjects 6 - 12 years of age exposed to Levocetirizine 5 mg once daily in placebo-controlled clinical trials 4 and 6 weeks in duration were pyrexia, cough, somnolence, epistaxis. In paediatric subjects 6 months to 11 months receiving 1.25 mg Levocetirizine once daily in a 2-week placebo controlled double blind safety trial the common side effects (≥ 3% subjects) were diarrhoea and constipation. In addition to the adverse reactions reported during clinical studies and listed above very rare cases of the following adverse drug reactions have been reported in post-marketing experience :

Immune system disorders : Hypersensitivity including anaphylaxis.

Psychiatric disorders : Aggression, Agitation, Hallucination, Depression.

Nervous System disorders : Convulsion.

Eyes disorders : Visual disturbances.

Cardiac disorders : Palpitations, tachycardia.

Respiratory,

Thoracic, and mediastinal disorders : Dyspnoea.

Gastrointestinal disorders : Nausea, Vomiting.

Hepatobiliary disorders : Hepatitis.

Skin and subcutaneous tissue disorders : Angioneurotic edema, Fixed drug eruption, Pruritus, Rash urticaria.

Musculoskeletal, connective tissues, and bone disorders : Myalgia.

Investigations : Weight Increased, Abnormal liver functions tests.

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via

email to : medico@zuventus.com

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

There is no data reported on the overdosage of this combination. In case of overdosage the stomach should be emptied by aspiration and gastric lavage if the patient reports immediately.

Treatment should be symptomatic and supportive.

5.1 Mechanism of action / pharmacodynamic properties

Montelukast The cysteinyl leukotrienes (LTC4, LTD4, LTE4) are potent inflammatory eicosanoids released from various cells including mast cells and eosinophils. These important pro-asthmatic mediators bind to cysteinyl leukotriene (CysLT) receptors. The CysLT type-1 (CysLT1) receptor is found in the human airway (including airway smooth muscle cells and airway macrophages) and on other pro-inflammatory cells (including eosinophils and certain myeloid stem cells). CysLTs have been correlated with the pathophysiology of asthma and allergic rhinitis. In allergic rhinitis, CysLTs are released from the nasal mucosa after allergen exposure during both early- and late-phase reactions and are associated with symptoms of allergic rhinitis. Intranasal challenge with CysLTs has been shown to increase nasal airway resistance and symptoms of nasal obstruction. Montelukast is an orally active compound that binds with high affinity and selectivity to the CysLT1 receptor. Montelukast inhibits physiologic actions of LTD4 at the CysLT1 receptor without any agonist activity. Levocetirizine Pharmacodynamic studies in healthy volunteers demonstrate that, at half the dose Levocetirizine has comparable activity to Cetirizine, both in the skin and in the nose. Pharmacokinetic / pharmacodynamic relationship 5 mg Levocetirizine provide a similar pattern of inhibition of histamine-induced wheal and flare than 10 mg Cetirizine. As for Cetirizine, the action on histamine-induced skin reactions was out of phase with the plasma concentrations. ECGs did not show relevant effects of Levocetirizine on QT interval.

5.2 Pharmacokinetic properties

Montelukast

Absorption

Montelukast is rapidly absorbed following oral administration. For the 5 mg tablet, the Cmax is achieved in 2 hours after administration in adults in the fasted state. The mean oral bioavailability is 73% and is decreased to 63% by a standard meal.

Distribution

Montelukast is more than 99% bound to plasma proteins. The steady-state volume of distribution of Montelukast averages 8 - 11 liters.

Metabolism

Montelukast is extensively metabolized. In studies with therapeutic doses, plasma concentrations of metabolites of Montelukast are undetectable at steady state in adults and children. In vitro studies using human liver microsomes indicate that cytochrome P450 3A4, 2A6 and 2C9 are involved in the metabolism of Montelukast. Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of Montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6.

Elimination

The plasma clearance of Montelukast averages 45 ml/min in healthy adults. Following an oral dose of radiolabeled Montelukast, 86% of the radioactivity was recovered in 5-day faecal collections and < 0.2% was recovered in urine. Coupled with estimates of Montelukast oral bioavailability, this indicates that Montelukast and its metabolites are excreted almost exclusively via the bile.

Levocetirizine

The pharmacokinetics of Levocetirizine are linear, dose- and time-independent with low inter-subject variability.

Absorption

Levocetirizine is rapidly and extensively absorbed following oral administration. Peak plasma concentrations are achieved 0.9 h after dosing. Steady state is achieved after two days. Peak concentrations are typically 270 ng/ml and 308 ng/ml following a single and a repeated 5 mg o.d. dose, respectively. The extent of absorption is dose-independent and is not altered by food, but the peak concentration is reduced and delayed.

Distribution

Levocetirizine is 90% bound to plasma proteins. The distribution of Levocetirizine is restrictive, as the volume of distribution is 0.4 l/kg.

Metabolism

Metabolic pathways include aromatic oxidation, N- and O- dealkylation and taurine conjugation. Dealkylation pathways are primarily mediated by CYP 3A4 while aromatic oxidation involved multiple and/or unidentified CYP isoforms. Levocetirizine had no effect on the activities of CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 at concentrations well above peak concentrations achieved following a 5 mg oral dose. Due to its low metabolism and absence of metabolic inhibition potential, the interaction of Levocetirizine with other substances, or vice-versa, is unlikely.

Elimination

The plasma half-life in adults is 7.9 ± 1.9 hours. The mean apparent total body clearance is 0.63 ml/min/kg. The major route of excretion of Levocetirizine and metabolites is via urine, accounting for a mean of 85.4% of the dose. Excretion via feces accounts for only 12.9% of the dose. Levocetirizine is excreted both by glomerular filtration and active tubular secretion.

6.1 Animal toxicology or pharmacology

No known animal toxicology data.

Montelukast selectively antagonizes leukotriene D4 (LTD4) at the cysteinyl leukotriene receptor, CysLT1, in the human airway thereby preventing airway edema, bronchoconstriction, enhanced secretion of thick, viscous mucus and nasal congestion. It is a safe and effective treatment for patients with allergic rhinitis and allergic asthma. Levocetirizine is the R-enantiomer and the active form of cetirizine. It is an orally active, potent, selective and long acting H1-histamine receptor antagonist with no anticholinergic activity. It blocks the binding of histamine to H1 receptors thus preventing its systemic effects, such as vasodilation, edema, mucous secretion, and smooth muscle contraction. This results in providing relief from the symptoms of allergic rhinitis and asthma including sneezing, itching, rhinorrhea, dyspnea, bronchial hypersensitivity and mucus accumulation. It has been demonstrated by recent studies that the treatment of Allergic rhinitis and asthma with concomitant administration of an anti-leukotriene (Montelukast) and an antihistamine (Levocetirizine), shows significantly better symptom relief and additional improvement in quality of life when compared with each agent given alone.

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

24 Months

8.3 Packaging information

1 x 10 Tablets

8.4 Storage and handing instructions

Store protected from light and moisture at a temperature not exceeding 30°C.

KEEP AWAY FROM THE REACH OF CHILDREN.

Do not take Nukast if you

• Are allergic to Montelukast, Levocetirizine or any of the other ingredients of this medicine.
• If you suffer from severe kidney failure (severe renal failure with creatinine clearance below 10 ml/min). Talk to your doctor or pharmacist before taking Nukast
• If your asthma or breathing gets worse, tell your doctor immediately.
• This oral medicine is not meant to treat acute asthma attacks. If an attack occurs, follow the instructions your doctor has given you. Always have your inhaled rescue medicine for asthma attacks with you.
• It is important that you or your child take all asthma medications prescribed by your doctor.
• This medicine should not be substituted for other asthma medications your doctor has prescribed for you.
• Any patient on anti-asthma medicines should be aware that if you develop a combination of symptoms such as a flu-like illness, pins and needles or numbness of arms or legs, worsening of pulmonary symptoms, and/or rash, you should consult your doctor.
• If you suffer from epilepsy or are at risk of convulsions, please ask your doctor for advice as use of may make seizures worse. If you are likely to be unable to be unable to empty your bladder (due to conditions such as a spinal cord injury or enlarged prostate), please ask your doctor for advice. If you are scheduled for allergy testing, ask your doctor if you should stop taking Nukast for several days before testing. This medicine may affect your allergy test results.

Patients should be aware that various neuropsychiatric events (for example behaviour and mood related changes) have been reported in adults, adolescents and children with Nukast. If you develop such symptoms while taking Nukast you should consult your doctor.

Tell your doctor if you are taking the following medicines before starting Nukast :

• Phenobarbital (used for treatment of epilepsy)
• Phenytoin (used for treatment of epilepsy)
• Rifampicin (used to treat tuberculosis and some other infections)
• Gemfibrozil (used for treatment of high lipid levels in plasma)

If you suffer from mild to moderate kidney failure, your doctor may prescribe a lower dose according to the severity of your kidney disease. Patients who only have impaired liver function should take the usual prescribed dose. Patients who have both impaired liver and kidney function may be given a lower dose depending on the severity of the kidney disease.