Inderal Tablets 10mg

1. Name Of The Medicinal Product

Inderal Tablets 10 mg.

2. Qualitative And Quantitative Composition

Propranolol Hydrochloride Ph. Eur. 10 mg.

3. Pharmaceutical Form

Round pink film coated tablets.

4. Clinical Particulars

4.1 Therapeutic Indications

a) the control of hypertension;

b) the management of angina pectoris;

c) long term management against re-infarction after recovery from acute myocardial infarction;

d) the control of most forms of cardiac dysrhythmias;

e) the prophylaxis of migraine;

f) the management of essential tremor;

g) relief of situational anxiety and generalised anxiety symptoms, particularly those of somatic type;

h) prophylaxis of upper gastrointestinal bleeding in patients with portal hypertension and oesophageal varices;

i) the adjunctive management of thyrotoxicosis and thyrotoxic crisis;

j) management of hypertrophic obstructive cardiomyopathy;

k) management of phaeochromocytoma peri-operatively (with an alpha-blocker).

4.2 Posology And Method Of Administration

For oral administration

Adults

Hypertension

A starting dose of 80 mg twice a day may be increased at weekly intervals according to response. The usual dose range is 160 to 320 mg per day. With concurrent diuretic or other antihypertensive drugs a further reduction of blood pressure is obtained.

Angina, migraine and essential tremor

A starting dose of 40 mg two or three times daily may be increased by the same amount at weekly intervals according to patient response. An adequate response in migraine and essential tremor is usually seen in the range 80 to 160 mg/day and in angina in the range 120 to 240 mg/day.

Situational and generalised anxiety

A dose of 40 mg daily may provide short term relief of acute situational anxiety. Generalised anxiety, requiring longer term therapy, usually responds adequately to 40 mg twice daily which, in individual cases, may be increased to 40 mg three times daily. Treatment should be continued according to response. Patients should be reviewed after 6 to 12 months treatment.

Dysrhythmias, anxiety tachycardia, hypertrophic obstructive cardiomyopathy and thyrotoxicosis

A dosage range of 10 to 40 mg three or four times a day usually achieves the required response.

Post myocardial infarction

Treatment should start between days 5 and 21 after myocardial infarction, with an initial dose of 40 mg four times a day for 2 or 3 days. In order to improve compliance the total daily dosage may thereafter be given as 80 mg twice a day.

Portal hypertension

Dosage should be titrated to achieve approximately 25% reduction in resting heart rate. Dosage should begin with 40 mg twice daily, increasing to 80 mg twice daily depending on heart rate response. If necessary, the dose may be increased incrementally to a maximum of 160 mg twice daily.

Phaeochromocytoma

(Used only with an alpha-receptor blocking drug).

Pre-operative: 60 mg daily for 3 days is recommended. Non-operable malignant cases: 30 mg daily.

Elderly

Evidence concerning the relation between blood level and age is conflicting. With regard to the elderly, the optimum dose should be individually determined according to clinical response.

Children

Dysrhythmias, phaeochromocytoma, thyrotoxicosis

Dosage should be individually determined and the following is only a guide:

Oral: 0.25 to 0.5 mg/kg three or four times daily as required.

Migraine

Oral: Under the age of 12: 20 mg two or three times daily.

Over the age of 12: The adult dose.

Fallot's tetralogy

The value of Inderal in this condition is confined mainly to the relief of right-ventricular outflow tract shut-down. It is also useful for treatment of associated dysrhythmias and angina. Dosage should be individually determined and the following is only a guide:

Oral: Up to 1 mg/kg repeated three or four times daily as required.

4.3 Contraindications

Inderal must not be used if there is a history of bronchial asthma or bronchospasm. The product label states the following warning: “Do not take Inderal if you have a history of asthma or wheezing”. A similar warning appears in the patient information leaflet.

Bronchospasm can usually be reversed by beta₂- agonist bronchodilators such as salbutamol. Large doses of the beta₂- agonist bronchodilator may be required to overcome the beta-blockade produced by propranolol and the dose should be titrated according to the clinical response; both intravenous and inhalational administration should be considered. The use of intravenous aminophylline and/or the use of ipratropium (given by nebuliser) may also be considered. Glucagon (1 to 2 mg given intravenously) has also been reported to produce a bronchodilator effect in asthmatic patients. Oxygen or artificial ventilation may be required in severe cases.

Inderal as with other beta-adrenoceptor blocking drugs must not be used in patients with any of the following: known hypersensitivity to the substance; bradycardia; cardiogenic shock; hypotension; metabolic acidosis; after prolonged fasting; severe peripheral arterial circulatory disturbances; second or third degree heart block; sick sinus syndrome; untreated phaeochromocytoma; uncontrolled heart failure; Prinzmetal's angina.

4.4 Special Warnings And Precautions For Use

Inderal as with other beta-adrenoceptor blocking drugs:

- although contraindicated in uncontrolled heart failure (see Section 4.3), may be used in patients whose signs of heart failure have been controlled. Caution must be exercised in patients whose cardiac reserve is poor.

- although contraindicated in severe peripheral arterial circulatory disturbances (see Section 4.3), may also aggravate less severe peripheral arterial circulatory disturbances.

- due to its negative effect on conduction time, caution must be exercised if it is given to patients with first degree heart block.

- may modify the tachycardia of hypoglycaemia (see Section 4.5).

- may mask the signs of thyrotoxicosis.

- will reduce heart rate as a result of its pharmacological action. In the rare instances when a treated patient develops symptoms which may be attributable to a slow heart rate, the dose may be reduced.

- should not be discontinued abruptly in patients suffering from ischaemic heart disease. Either the equivalent dosage of another beta-adrenoceptor blocking drug may be substituted or the withdrawal of Inderal should be gradual.

- may cause a more severe reaction to a variety of allergens when given to patients with a history of anaphylactic reaction to such allergens. Such patients may be unresponsive to the usual doses of adrenaline used to treat the allergic reactions.

Since the half-life may be increased in patients with significant hepatic or renal impairment, caution must be exercised when starting treatment and selecting the initial dose.

Inderal must be used with caution in patients with decompensated cirrhosis.

In patients with portal hypertension, liver function may deteriorate and hepatic encephalopathy may develop. There have been reports suggesting that treatment with propranolol may increase the risk of developing hepatic encephalopathy.

Interference with laboratory tests. Inderal has been reported to interfere with the estimation of serum bilirubin by the diazo method and with the determination of catecholamines by methods using fluorescence.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Inderal modifies the tachycardia of hypoglycaemia. Caution must be exercised in the concurrent use of Inderal and hypoglycaemic therapy in diabetic patients. Inderal may prolong the hypoglycaemic response to insulin.

Caution must be exercised in prescribing a beta-adrenoceptor blocking drug with Class I antiarrhythmic agents such as disopyramide.

Digitalis glycosides in association with beta-adrenoceptor blocking drugs may increase atrioventricular conduction time.

Combined use of beta-adrenoceptor blocking drugs and calcium channel blockers with negative inotropic effects (eg, verapamil, diltiazem) can lead to an exaggeration of these effects particularly in patients with impaired ventricular function and/or SA or AV conduction abnormalities. This may result in severe hypotension, bradycardia and cardiac failure. Neither the beta-adrenoceptor blocking drug nor the calcium channel blocker should be administered intravenously within 48 hours of discontinuing the other.

Concomitant therapy with dihydropyridine calcium channel blockers, eg, nifedipine, may increase the risk of hypotension, and cardiac failure may occur in patients with latent cardiac insufficiency.

Concomitant use of sympathomimetic agents eg, adrenaline, may counteract the effect of beta-adrenoceptor blocking drugs. Caution must be exercised in the parenteral administration of preparations containing adrenaline to patients taking beta-adrenoceptor blocking drugs as, in rare cases, vasoconstriction, hypertension and bradycardia may result.

Administration of Inderal during infusion of lignocaine may increase the plasma concentration of lignocaine by approximately 30%. Patients already receiving Inderal tend to have higher lignocaine levels than controls. The combination should be avoided.

Concomitant use of cimetidine or hydralazine will increase, whereas concomitant use of alcohol will decrease, the plasma levels of propranolol.

Beta-adrenoceptor blocking drugs may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. If the two drugs are co-administered, the beta-adrenoceptor blocking drug should be withdrawn several days before discontinuing clonidine. If replacing clonidine by beta-adrenoceptor blocking drug therapy, the introduction of beta-adrenoceptor blocking drugs should be delayed for several days after clonidine administration has stopped.

Caution must be exercised if ergotamine, dihydroergotamine or related compounds are given in combination with Inderal since vasospastic reactions have been reported in a few patients.

Concomitant use of prostaglandin synthetase inhibiting drugs eg, ibuprofen and indomethacin, may decrease the hypotensive effects of Inderal.

Concomitant administration of Inderal and chlorpromazine may result in an increase in plasma levels of both drugs. This may lead to an enhanced antipsychotic effect for chlorpromazine and an increased antihypertensive effect for Inderal.

Caution must be exercised when using anaesthetic agents with Inderal. The anaesthetist should be informed and the choice of anaesthetic should be an agent with as little negative inotropic activity as possible. Use of beta-adrenoceptor blocking drugs with anaesthetic drugs may result in attenuation of the reflex tachycardia and increase the risk of hypotension. Anaesthetic agents causing myocardial depression are best avoided.

Pharmacokinetic studies have shown that the following agents may interact with propranolol due to effects on enzyme systems in the liver which metabolise propranolol and these agents: quinidine, propafenone, rifampicin, theophylline, warfarin, thioridazine and dihydropyridine calcium channel blockers such as nifedipine, nisoldipine, nicardipine, isradipine and lacidipine. Owing to the fact that blood concentrations of either agent may be affected, dosage adjustments may be needed according to clinical judgement. (See also the interaction above concerning the concomitant therapy with dihydropyridine calcium channel blockers).

4.6 Pregnancy And Lactation

Pregnancy

As with all drugs Inderal should not be given during pregnancy unless its use is essential. There is no evidence of teratogenicity with Inderal. However beta-adrenoceptor blocking drugs reduce placental perfusion, which may result in intra-uterine foetal death, immature and premature deliveries. In addition, adverse effects (especially hypoglycaemia and bradycardia in the neonate and bradycardia in the foetus) may occur. There is an increased risk of cardiac and pulmonary complications in the neonate in the post-natal period.

Lactation

Most beta-adrenoceptor blocking drugs, particularly lipophilic compounds, will pass into breast milk although to a variable extent. Breast feeding is therefore not recommended following administration of these compounds.

4.7 Effects On Ability To Drive And Use Machines

Use is unlikely to result in any impairment of the ability of patients to drive or operate machinery. However it should be taken into account that occasionally dizziness or fatigue may occur.

4.8 Undesirable Effects

Inderal is usually well tolerated. In clinical studies the undesired events reported are usually attributable to the pharmacological actions of propranolol.

The following undesired events, listed by body system, have been reported.

Cardiovascular: bradycardia; heart failure deterioration; postural hypotension which may be associated with syncope; cold extremities. In susceptible patients: precipitation of heart block; exacerbation of intermittent claudication; Raynaud's phenomenon.

CNS: confusion; dizziness; mood changes; nightmares; psychoses and hallucinations; sleep disturbances.

Endocrine: hypoglycaemia in children.

Gastrointestinal: gastrointestinal disturbance.

Haematological: purpura; thrombocytopenia.

Integumentary: alopecia; dry eyes; psoriasiform skin reactions; exacerbation of psoriasis; skin rashes.

Neurological: paraesthesia.

Respiratory: bronchospasm may occur in patients with bronchial asthma or a history of asthmatic complaints, sometimes with fatal outcome (see Section 4.3).

Special senses: visual disturbances.

Others: fatigue and/or lassitude (often transient); an increase in ANA (Antinuclear Antibodies) has been observed, however the clinical relevance of this is not clear; isolated reports of myasthenia gravis like syndrome or exacerbation of myasthenia gravis have been reported.

Discontinuance of the drug should be considered if, according to clinical judgement, the well-being of the patient is adversely affected by any of the above reactions. Cessation of therapy with a beta-adrenoceptor blocking drug should be gradual. In the rare event of intolerance, manifested as bradycardia and hypotension, the drug should be withdrawn and, if necessary, treatment for overdosage instituted.

4.9 Overdose

The symptoms of overdosage may include bradycardia, hypotension, acute cardiac insufficiency and bronchospasm.

General treatment should include: close supervision, treatment in an intensive care ward, the use of gastric lavage, activated charcoal and a laxative to prevent absorption of any drug still present in the gastrointestinal tract, the use of plasma or plasma substitutes to treat hypotension and shock.

Excessive bradycardia can be countered with atropine 1 to 2 mg intravenously and/or a cardiac pacemaker. If necessary, this may be followed by a bolus dose of glucagon 10 mg intravenously. If required, this may be repeated or followed by an intravenous infusion of glucagon 1 to 10 mg/hour depending on response. If no response to glucagon occurs or if glucagon is unavailable, a beta-adrenoceptor stimulant such as dobutamine 2.5 to 10 microgram/kg/minute by intravenous infusion may be given. Dobutamine, because of its positive inotropic effect, could also be used to treat hypotension and acute cardiac insufficiency. It is likely that these doses would be inadequate to reverse the cardiac effects of beta-adrenoceptor blockade if a large overdose has been taken. The dose of dobutamine should therefore be increased if necessary to achieve the required response according to the clinical condition of the patient.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Inderal is a competitive antagonist at both the beta₁- and beta₂ adrenoceptors. It has no agonist activity at the beta-adrenoceptor, but has membrane stabilising activity at concentrations exceeding 1 to 3 mg/litre, though such concentrations are rarely achieved during oral therapy. Competitive beta-adrenoceptor blockade has been demonstrated in man by a parallel shift to the right in the dose-heart rate response curve to beta agonists such as isoprenaline.

Propranolol as with other beta-adrenoceptor blocking drugs, has negative inotropic effects, and is therefore contraindicated in uncontrolled heart failure.

Inderal is a racemic mixture and the active form is the S (-) isomer of propranolol. With the exception of inhibition of the conversion of thyroxine to triiodothyronine, it is unlikely that any additional ancillary properties possessed by R (+) propranolol, in comparison with the racemic mixture, will give rise to different therapeutic effects.

Inderal is effective and well tolerated in most ethnic populations, although the response may be less in black patients.

5.2 Pharmacokinetic Properties

Following intravenous administration the plasma half-life of propranolol is about 2 hours and the ratio of metabolites to parent drug in the blood is lower than after oral administration. In particular 4-hydroxypropranolol is not present after intravenous administration. Propranolol is completely absorbed after oral administration and peak plasma concentrations occur 1 to 2 hours after dosing in fasting patients. The liver removes up to 90% of an oral dose with an elimination half-life of 3 to 6 hours. Propranolol is widely and rapidly distributed throughout the body with highest levels occurring in the lungs, liver, kidney, brain and heart. Propranolol is highly protein bound (80 to 95%).

5.3 Preclinical Safety Data

Propranolol is a drug on which extensive clinical experience has been obtained. Relevant information for the prescriber is provided elsewhere in this Summary of Product Characteristics.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Calcium Carboxymethyl Cellulose USNF Carmine BPC (E120) Gelatin Ph. Eur. Glycerol Ph. Eur. Lactose Ph. Eur. Light Magnesium Carbonate Ph. Eur. Magnesium Stearate Ph. Eur. Methylhydroxypropylcellulose Ph. Eur. Titanium Dioxide Ph. Eur. (E171)

6.2 Incompatibilities

None known.

6.3 Shelf Life

5 years.

6.4 Special Precautions For Storage

Store below 30°C, protected from light and moisture.

6.5 Nature And Contents Of Container

HDPE bottles of 100 tablets.

6.6 Special Precautions For Disposal And Other Handling

None stated.

7. Marketing Authorisation Holder

AstraZeneca UK Limited Home Park Kings Langley Hertfordshire WD4 8DH United Kingdom

8. Marketing Authorisation Number(S)

PL 17901/0021

9. Date Of First Authorisation/Renewal Of The Authorisation

11.06.00

10. Date Of Revision Of The Text

11^th June 2000

Malarone

Dosage Form: tablet, film coated
Malarone®

(atovaquone and proguanil hydrochloride)

Tablets

Malarone®

(atovaquone and proguanil hydrochloride)

Pediatric Tablets

Malarone Description

Malarone (atovaquone and proguanil hydrochloride) is a fixed-dose combination of the antimalarial agents atovaquone and proguanil hydrochloride. The chemical name of atovaquone is trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione. Atovaquone is a yellow crystalline solid that is practically insoluble in water. It has a molecular weight of 366.84 and the molecular formula C22H19ClO3. The compound has the following structural formula:

The chemical name of proguanil hydrochloride is 1-(4-chlorophenyl)-5-isopropyl-biguanide hydrochloride. Proguanil hydrochloride is a white crystalline solid that is sparingly soluble in water. It has a molecular weight of 290.22 and the molecular formula C11H16ClN5•HCl. The compound has the following structural formula:

Malarone Tablets and Malarone Pediatric Tablets are for oral administration. Each Malarone Tablet contains 250 mg of atovaquone and 100 mg of proguanil hydrochloride and each Malarone Pediatric Tablet contains 62.5 mg of atovaquone and 25 mg of proguanil hydrochloride. The inactive ingredients in both tablets are low-substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, poloxamer 188, povidone K30, and sodium starch glycolate. The tablet coating contains hypromellose, polyethylene glycol 400, polyethylene glycol 8000, red iron oxide, and titanium dioxide.

Malarone - Clinical Pharmacology

Microbiology

Mechanism of Action

The constituents of Malarone, atovaquone and proguanil hydrochloride, interfere with 2 different pathways involved in the biosynthesis of pyrimidines required for nucleic acid replication. Atovaquone is a selective inhibitor of parasite mitochondrial electron transport. Proguanil hydrochloride primarily exerts its effect by means of the metabolite cycloguanil, a dihydrofolate reductase inhibitor. Inhibition of dihydrofolate reductase in the malaria parasite disrupts deoxythymidylate synthesis.

Activity In Vitro and In Vivo

Atovaquone and cycloguanil (an active metabolite of proguanil) are active against the erythrocytic and exoerythrocytic stages of Plasmodium spp. Enhanced efficacy of the combination compared to either atovaquone or proguanil hydrochloride alone was demonstrated in clinical studies in both immune and non-immune patients (see CLINICAL STUDIES).

Drug Resistance

Strains of P. falciparum with decreased susceptibility to atovaquone or proguanil/cycloguanil alone can be selected in vitro or in vivo. The combination of atovaquone and proguanil hydrochloride may not be effective for treatment of recrudescent malaria that develops after prior therapy with the combination.

Pharmacokinetics

Absorption

Atovaquone is a highly lipophilic compound with low aqueous solubility. The bioavailability of atovaquone shows considerable inter-individual variability.

Dietary fat taken with atovaquone increases the rate and extent of absorption, increasing AUC 2 to 3 times and Cmax 5 times over fasting. The absolute bioavailability of the tablet formulation of atovaquone when taken with food is 23%. Malarone Tablets should be taken with food or a milky drink.

Proguanil hydrochloride is extensively absorbed regardless of food intake.

Distribution

Atovaquone is highly protein bound (>99%) over the concentration range of 1 to 90 mcg/mL. A population pharmacokinetic analysis demonstrated that the apparent volume of distribution of atovaquone (V/F) in adult and pediatric patients after oral administration is approximately 8.8 L/kg.

Proguanil is 75% protein bound. A population pharmacokinetic analysis demonstrated that the apparent V/F of proguanil in adult and pediatric patients >15 years of age with body weights from 31 to 110 kg ranged from 1,617 to 2,502 L. In pediatric patients ≤15 years of age with body weights from 11 to 56 kg, the V/F of proguanil ranged from 462 to 966 L.

In human plasma, the binding of atovaquone and proguanil was unaffected by the presence of the other.

Metabolism

In a study where 14C-labeled atovaquone was administered to healthy volunteers, greater than 94% of the dose was recovered as unchanged atovaquone in the feces over 21 days. There was little or no excretion of atovaquone in the urine (less than 0.6%). There is indirect evidence that atovaquone may undergo limited metabolism; however, a specific metabolite has not been identified. Between 40% to 60% of proguanil is excreted by the kidneys. Proguanil is metabolized to cycloguanil (primarily via CYP2C19) and 4-chlorophenylbiguanide. The main routes of elimination are hepatic biotransformation and renal excretion.

Elimination

The elimination half-life of atovaquone is about 2 to 3 days in adult patients.

The elimination half-life of proguanil is 12 to 21 hours in both adult patients and pediatric patients, but may be longer in individuals who are slow metabolizers.

A population pharmacokinetic analysis in adult and pediatric patients showed that the apparent clearance (CL/F) of both atovaquone and proguanil are related to the body weight. The values CL/F for both atovaquone and proguanil in subjects with body weight ≥11 kg are shown in Table 1.

Table 1. Apparent Clearance for Atovaquone and Proguanil in Patients as a Function of Body Weight

Body Weight	Atovaquone		Proguanil
	N	CL/F (L/hr) Mean ± SD* (range)	N	CL/F (L/hr) Mean ± SD* (range)
11-20 kg	159	1.34 ± 0.63 (0.52-4.26)	146	29.5 ± 6.5 (10.3-48.3)
21-30 kg	117	1.87 ± 0.81 (0.52-5.38)	113	40.0 ± 7.5 (15.9-62.7)
31-40 kg	95	2.76 ± 2.07 (0.97-12.5)	91	49.5 ± 8.30 (25.8-71.5)
>40 kg	368	6.61 ± 3.92 (1.32-20.3)	282	67.9 ± 19.9 (14.0-145)

* SD = standard deviation.

The pharmacokinetics of atovaquone and proguanil in patients with body weight below 11 kg have not been adequately characterized.

Special Populations

Pediatrics

The pharmacokinetics of proguanil and cycloguanil are similar in adult patients and pediatric patients. However, the elimination half-life of atovaquone is shorter in pediatric patients (1 to 2 days) than in adult patients (2 to 3 days). In clinical trials, plasma trough levels of atovaquone and proguanil in pediatric patients weighing 5 to 40 kg were within the range observed in adults after dosing by body weight.

Geriatrics

In a single-dose study, the pharmacokinetics of atovaquone, proguanil, and cycloguanil were compared in 13 elderly subjects (age 65 to 79 years) to 13 younger subjects (age 30 to 45 years). In the elderly subjects, the extent of systemic exposure (AUC) of cycloguanil was increased (point estimate = 2.36, CI = 1.70, 3.28). Tmax was longer in elderly subjects (median 8 hours) compared with younger subjects (median 4 hours) and average elimination half-life was longer in elderly subjects (mean 14.9 hours) compared with younger subjects (mean 8.3 hours).

Hepatic Impairment

In a single-dose study, the pharmacokinetics of atovaquone, proguanil, and cycloguanil were compared in 13 subjects with hepatic impairment (9 mild, 4 moderate, as indicated by the Child-Pugh method) to 13 subjects with normal hepatic function. In subjects with mild or moderate hepatic impairment as compared to healthy subjects, there were no marked differences (<50%) in the rate or extent of systemic exposure of atovaquone. However, in subjects with moderate hepatic impairment, the elimination half-life of atovaquone was increased (point estimate = 1.28, 90% CI = 1.00 to 1.63). Proguanil AUC, Cmax, and its t1/2 increased in subjects with mild hepatic impairment when compared to healthy subjects (Table 2). Also, the proguanil AUC and its t1/2 increased in subjects with moderate hepatic impairment when compared to healthy subjects. Consistent with the increase in proguanil AUC, there were marked decreases in the systemic exposure of cycloguanil (Cmax and AUC) and an increase in its elimination half-life in subjects with mild hepatic impairment when compared to healthy volunteers (Table 2). There were few measurable cycloguanil concentrations in subjects with moderate hepatic impairment (see DOSAGE AND ADMINISTRATION). The pharmacokinetics of atovaquone, proguanil, and cycloguanil after administration of Malarone have not been studied in patients with severe hepatic impairment.

Table 2. Point Estimates (90% CI) for Proguanil and Cycloguanil Parameters in Subjects With Mild and Moderate Hepatic Impairment Compared to Healthy Volunteers

Parameter	Comparison	Proguanil	Cycloguanil
AUC(0-inf)*	mild:healthy	1.96 (1.51, 2.54)	0.32 (0.22, 0.45)
Cmax*	mild:healthy	1.41 (1.16, 1.71)	0.35 (0.24, 0.50)
t1/2†	mild:healthy	1.21 (0.92, 1.60)	0.86 (0.49, 1.48)
AUC(0-inf)*	moderate:healthy	1.64 (1.14, 2.34)	ND
Cmax*	moderate:healthy	0.97 (0.69, 1.36)	ND
t1/2†	moderate:healthy	1.46 (1.05, 2.05)	ND

ND = not determined due to lack of quantifiable data.

* Ratio of geometric means.

† Mean difference.

Renal Impairment

In patients with mild renal impairment (creatinine clearance 50 to 80 mL/min), oral clearance and/or AUC data for atovaquone, proguanil, and cycloguanil are within the range of values observed in patients with normal renal function (creatinine clearance >80 mL/min). In patients with moderate renal impairment (creatinine clearance 30 to 50 mL/min), mean oral clearance for proguanil was reduced by approximately 35% compared with patients with normal renal function (creatinine clearance >80 mL/min) and the oral clearance of atovaquone was comparable between patients with normal renal function and mild renal impairment. No data exist on the use of Malarone for long-term prophylaxis (over 2 months) in individuals with moderate renal failure. In patients with severe renal impairment (creatinine clearance <30 mL/min), atovaquone Cmax and AUC are reduced but the elimination half-lives for proguanil and cycloguanil are prolonged, with corresponding increases in AUC, resulting in the potential of drug accumulation and toxicity with repeated dosing (see CONTRAINDICATIONS).

Drug Interactions

There are no pharmacokinetic interactions between atovaquone and proguanil at the recommended dose.

Concomitant treatment with tetracycline has been associated with approximately a 40% reduction in plasma concentrations of atovaquone.

Concomitant treatment with metoclopramide has also been associated with decreased bioavailability of atovaquone.

Concomitant administration of rifampin or rifabutin is known to reduce atovaquone levels by approximately 50% and 34%, respectively (see PRECAUTIONS: Drug Interactions). The mechanisms of these interactions are unknown.

Concomitant administration of atovaquone (750 mg BID with food for 14 days) and indinavir (800 mg TID without food for 14 days) did not result in any change in the steady-state AUC and Cmax of indinavir but resulted in a decrease in the Ctrough of indinavir (23% decrease [90% CI 8%, 35%]). Caution should be exercised when prescribing atovaquone with indinavir due to the decrease in trough levels of indinavir.

Atovaquone is highly protein bound (>99%) but does not displace other highly protein-bound drugs in vitro, indicating significant drug interactions arising from displacement are unlikely (see PRECAUTIONS: Drug Interactions). Proguanil is metabolized primarily by CYP2C19. Potential pharmacokinetic interactions with other substrates or inhibitors of this pathway are unknown.

Indications and Usage for Malarone

Prevention of Malaria

Malarone is indicated for the prophylaxis of P. falciparum malaria, including in areas where chloroquine resistance has been reported (see CLINICAL STUDIES).

Treatment of Malaria

Malarone is indicated for the treatment of acute, uncomplicated P. falciparum malaria. Malarone has been shown to be effective in regions where the drugs chloroquine, halofantrine, mefloquine, and amodiaquine may have unacceptable failure rates, presumably due to drug resistance.

Contraindications

Malarone is contraindicated in individuals with known hypersensitivity to atovaquone or proguanil hydrochloride or any component of the formulation. Rare cases of anaphylaxis following treatment with atovaquone/proguanil have been reported.

Malarone is contraindicated for prophylaxis of P. falciparum malaria in patients with severe renal impairment (creatinine clearance <30 mL/min) (see CLINICAL PHARMACOLOGY: Special Populations: Renal Impairment).

Precautions

General

Malarone has not been evaluated for the treatment of cerebral malaria or other severe manifestations of complicated malaria, including hyperparasitemia, pulmonary edema, or renal failure. Patients with severe malaria are not candidates for oral therapy.

Elevated liver function tests and rare cases of hepatitis have been reported with prophylactic use of Malarone. A single case of hepatic failure requiring liver transplantation has also been reported with prophylactic use.

Absorption of atovaquone may be reduced in patients with diarrhea or vomiting. If Malarone is used in patients who are vomiting (see DOSAGE AND ADMINISTRATION), parasitemia should be closely monitored and the use of an antiemetic considered. Vomiting occurred in up to 19% of pediatric patients given treatment doses of Malarone. In the controlled clinical trials of Malarone, 15.3% of adults who were treated with atovaquone/proguanil received an antiemetic drug during that part of the trial when they received atovaquone/proguanil. Of these patients, 98.3% were successfully treated. In patients with severe or persistent diarrhea or vomiting, alternative antimalarial therapy may be required.

Parasite relapse occurred commonly when P. vivax malaria was treated with Malarone alone.

In the event of recrudescent P. falciparum infections after treatment with Malarone or failure of chemoprophylaxis with Malarone, patients should be treated with a different blood schizonticide.

Information for Patients

Patients should be instructed:

• to take Malarone tablets at the same time each day with food or a milky drink.


• to take a repeat dose of Malarone if vomiting occurs within 1 hour after dosing.


• to take a dose as soon as possible if a dose is missed, then return to their normal dosing schedule. However, if a dose is skipped, the patient should not double the next dose.


• that rare serious adverse events such as hepatitis, severe skin reactions, neurological, and hematological events have been reported when Malarone was used for the prophylaxis or treatment of malaria.


• to consult a healthcare professional regarding alternative forms of prophylaxis if prophylaxis with Malarone is prematurely discontinued for any reason.


• that protective clothing, insect repellents, and bednets are important components of malaria prophylaxis.


• that no chemoprophylactic regimen is 100% effective; therefore, patients should seek medical attention for any febrile illness that occurs during or after return from a malaria-endemic area and inform their healthcare professional that they may have been exposed to malaria.


• that falciparum malaria carries a higher risk of death and serious complications in pregnant women than in the general population. Pregnant women anticipating travel to malarious areas should discuss the risks and benefits of such travel with their physicians (see Pregnancy section).

Drug Interactions

Concomitant treatment with tetracycline has been associated with approximately a 40% reduction in plasma concentrations of atovaquone. Parasitemia should be closely monitored in patients receiving tetracycline. While antiemetics may be indicated for patients receiving Malarone, metoclopramide may reduce the bioavailability of atovaquone and should be used only if other antiemetics are not available.

Concomitant administration of rifampin or rifabutin is known to reduce atovaquone levels by approximately 50% and 34%, respectively. The concomitant administration of Malarone and rifampin or rifabutin is not recommended.

Proguanil may potentiate the anticoagulant effect of warfarin and other coumarin-based anticoagulants. The mechanism of this potential drug interaction has not been established. Caution is advised when initiating or withdrawing malaria prophylaxis or treatment with Malarone in patients on continuous treatment with coumarin-based anticoagulants. When these products are administered concomitantly, suitable coagulation tests should be closely monitored.

Atovaquone is highly protein bound (>99%) but does not displace other highly protein-bound drugs in vitro, indicating significant drug interactions arising from displacement are unlikely.

Potential interactions between proguanil or cycloguanil and other drugs that are CYP2C19 substrates or inhibitors are unknown.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Atovaquone

Carcinogenicity studies in rats were negative; 24-month studies in mice showed treatment-related increases in incidence of hepatocellular adenoma and hepatocellular carcinoma at all doses tested which ranged from approximately 5 to 8 times the average steady-state plasma concentrations in humans during prophylaxis of malaria. Atovaquone was negative with or without metabolic activation in the Ames Salmonella mutagenicity assay, the Mouse Lymphoma mutagenesis assay, and the Cultured Human Lymphocyte cytogenetic assay. No evidence of genotoxicity was observed in the in vivo Mouse Micronucleus assay.

Proguanil

No evidence of a carcinogenic effect was observed in 24-month studies conducted in CD-1 mice (doses up to 1.5 times the average systemic human exposure based on AUC) and in Wistar Hannover rats (doses up to 1.1 times the average systemic human exposure).

Proguanil was negative with or without metabolic activation in the Ames Salmonella mutagenicity assay and the Mouse Lymphoma mutagenesis assay. No evidence of genotoxicity was observed in the in vivo Mouse Micronucleus assay.

Cycloguanil, the active metabolite of proguanil, was also negative in the Ames test, but was positive in the Mouse Lymphoma assay and the Mouse Micronucleus assay. These positive effects with cycloguanil, a dihydrofolate reductase inhibitor, were significantly reduced or abolished with folinic acid supplementation.

A fertility study in Sprague-Dawley rats revealed no adverse effects at doses up to 16 mg/kg/day of proguanil hydrochloride (up to 0.2-times the average human exposure based on AUC comparisons.) Fertility studies of proguanil in animals at exposures similar to or greater than those observed in humans have not been conducted.

Genotoxicity studies have not been performed with atovaquone in combination with proguanil. Effects of Malarone on male and female reproductive performance are unknown.

Pregnancy

Pregnancy Category C. Falciparum malaria carries a higher risk of morbidity and mortality in pregnant women than in the general population. Maternal death and fetal loss are both known complications of falciparum malaria in pregnancy. In pregnant women who must travel to malaria-endemic areas, personal protection against mosquito bites should always be employed (see Information for Patients) in addition to antimalarials.

Atovaquone was not teratogenic and did not cause reproductive toxicity in rats at maternal plasma concentrations up to 5 to 6.5 times the estimated human exposure during treatment of malaria. Following single-dose administration of 14C-labeled atovaquone to pregnant rats, concentrations of radiolabel in rat fetuses were 18% (mid-gestation) and 60% (late gestation) of concurrent maternal plasma concentrations. In rabbits, atovaquone caused maternal toxicity at plasma concentrations that were approximately 0.6 to 1.3 times the estimated human exposure during treatment of malaria. Adverse fetal effects in rabbits, including decreased fetal body lengths and increased early resorptions and post-implantation losses, were observed only in the presence of maternal toxicity. Concentrations of atovaquone in rabbit fetuses averaged 30% of the concurrent maternal plasma concentrations.

A pre- and post-natal study in Sprague-Dawley rats revealed no adverse effects at doses up to 16 mg/kg/day of proguanil hydrochloride (up to 0.2-times the average human exposure based on AUC comparisons). Pre- and post-natal studies of proguanil in animals at exposures similar to or greater than those observed in humans have not been conducted.

The combination of atovaquone and proguanil hydrochloride was not teratogenic in rats at plasma concentrations up to 1.7 and 0.10 times, respectively, the estimated human exposure during treatment of malaria. In rabbits, the combination of atovaquone and proguanil hydrochloride was not teratogenic or embryotoxic to rabbit fetuses at plasma concentrations up to 0.34 and 0.82 times, respectively, the estimated human exposure during treatment of malaria.

While there are no adequate and well-controlled studies of atovaquone and/or proguanil hydrochloride in pregnant women, Malarone may be used if the potential benefit justifies the potential risk to the fetus. The proguanil component of Malarone acts by inhibiting the parasitic dihydrofolate reductase (see CLINICAL PHARMACOLOGY: Microbiology: Mechanism of Action). However, there are no clinical data indicating that folate supplementation diminishes drug efficacy, and for women of childbearing age receiving folate supplements to prevent neural tube birth defects, such supplements may be continued while taking Malarone.

Nursing Mothers

It is not known whether atovaquone is excreted into human milk. In a rat study, atovaquone concentrations in the milk were 30% of the concurrent atovaquone concentrations in the maternal plasma.

Proguanil is excreted into human milk in small quantities.

Caution should be exercised when Malarone is administered to a nursing woman.

Pediatric Use

Treatment of Malaria

The efficacy and safety of Malarone for the treatment of malaria have been established in controlled studies involving pediatric patients weighing 5 kg or more (see CLINICAL STUDIES). Safety and effectiveness have not been established in pediatric patients who weigh less than 5 kg.

Prophylaxis of Malaria

The efficacy and safety of Malarone have been established for the prophylaxis of malaria in controlled studies involving pediatric patients weighing 11 kg or more (see CLINICAL STUDIES). Safety and effectiveness have not been established in pediatric patients who weigh less than 11 kg.

Geriatric Use

Clinical studies of Malarone did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, the higher systemic exposure to cycloguanil (see CLINICAL PHARMACOLOGY: Special Populations: Geriatrics), and the greater frequency of concomitant disease or other drug therapy.

Adverse Reactions

Because Malarone contains atovaquone and proguanil hydrochloride, the type and severity of adverse reactions associated with each of the compounds may be expected. The higher treatment doses of Malarone were less well tolerated than the lower prophylactic doses.

Among adults who received Malarone for treatment of malaria, attributable adverse experiences that occurred in ≥5% of patients were abdominal pain (17%), nausea (12%), vomiting (12%), headache (10%), diarrhea (8%), asthenia (8%), anorexia (5%), and dizziness (5%). Treatment was discontinued prematurely due to an adverse experience in 4 of 436 adults treated with Malarone.

Among pediatric patients (weighing 11 to 40 kg) who received Malarone for the treatment of malaria, attributable adverse experiences that occurred in ≥5% of patients were vomiting (10%) and pruritus (6%). Vomiting occurred in 43 of 319 (13%) pediatric patients who did not have symptomatic malaria but were given treatment doses of Malarone for 3 days in a clinical trial. The design of this clinical trial required that any patient who vomited be withdrawn from the trial. Among pediatric patients with symptomatic malaria treated with Malarone, treatment was discontinued prematurely due to an adverse experience in 1 of 116 (0.9%).

In a study of 100 pediatric patients (5 to <11 kg body weight) who received Malarone for the treatment of uncomplicated P. falciparum malaria, only diarrhea (6%) occurred in ≥5% of patients as an adverse experience attributable to Malarone. In 3 patients (3%), treatment was discontinued prematurely due to an adverse experience.

Abnormalities in laboratory tests reported in clinical trials were limited to elevations of transaminases in malaria patients being treated with Malarone. The frequency of these abnormalities varied substantially across studies of treatment and were not observed in the randomized portions of the prophylaxis trials.

In one phase III trial of malaria treatment in Thai adults, early elevations of ALT and AST were observed to occur more frequently in patients treated with Malarone compared to patients treated with an active control drug. Rates for patients who had normal baseline levels of these clinical laboratory parameters were: Day 7: ALT 26.7% vs. 15.6%; AST 16.9% vs. 8.6%. By day 14 of this 28-day study, the frequency of transaminase elevations equalized across the 2 groups.

In this and other studies in which transaminase elevations occurred, they were noted to persist for up to 4 weeks following treatment with Malarone for malaria. None were associated with untoward clinical events.

Among subjects who received Malarone for prophylaxis of malaria in placebo-controlled trials, adverse experiences occurred in similar proportions of subjects receiving Malarone or placebo (Table 3). The most commonly reported adverse experiences possibly attributable to Malarone or placebo were headache and abdominal pain. Prophylaxis with Malarone was discontinued prematurely due to a treatment-related adverse experience in 3 of 381 adults and 0 of 125 pediatric patients.

Table 3. Adverse Experiences in Placebo-Controlled Clinical Trials of Malarone for Prophylaxis of Malaria

Adverse Experience	Percent of Subjects With Adverse Experiences (Percent of Subjects With Adverse Experiences Attributable to Therapy)
	Adults						Children and Adolescents
	Placebo n = 206		Malarone* n = 206		Malarone† n = 381		Placebo n = 140		Malarone n = 125
Headache	27	(7)	22	(3)	17	(5)	21	(14)	19	(14)
Fever	13	(1)	5	(0)	3	(0)	11	(<1)	6	(0)
Myalgia	11	(0)	12	(0)	7	(0)	0	(0)	0	(0)
Abdominal pain	10	(5)	9	(4)	6	(3)	29	(29)	33	(31)
Cough	8	(<1)	6	(<1)	4	(1)	9	(0)	9	(0)
Diarrhea	8	(3)	6	(2)	4	(1)	3	(1)	2	(0)
Upper respiratory infection	7	(0)	8	(0)	5	(0)	0	(0)	<1	(0)
Dyspepsia	5	(4)	3	(2)	2	(1)	0	(0)	0	(0)
Back pain	4	(0)	8	(0)	4	(0)	0	(0)	0	(0)
Gastritis	3	(2)	3	(3)	2	(2)	0	(0)	0	(0)
Vomiting	2	(<1)	1	(<1)	<1	(<1)	6	(6)	7	(7)
Flu syndrome	1	(0)	2	(0)	4	(0)	6	(0)	9	(0)
Any adverse experience	65	(32)	54	(17)	49	(17)	62	(41)	60	(42)

* Subjects receiving the recommended dose of atovaquone and proguanil hydrochloride in placebo-controlled trials.

† Subjects receiving the recommended dose of atovaquone and proguanil hydrochloride in any trial.

In an additional placebo-controlled study of malaria prophylaxis with Malarone involving 330 pediatric patients in a malaria-endemic area (see CLINICAL STUDIES), the safety profile of Malarone was consistent with that described above. The most common treatment-emergent adverse events with Malarone were abdominal pain (13%), headache (13%), and cough (10%). Abdominal pain (13% vs. 8%) and vomiting (5% vs. 3%) were reported more often with Malar

Pontocaine

Generic Name: tetracaine (Topical application route)

TE-tra-kane

Commonly used brand name(s)

In the U.S.

• Cepacol Viractin


• Pontocaine

In Canada

• Supracaine

Available Dosage Forms:

• Cream


• Ointment


• Gel/Jelly


• Solution

Therapeutic Class: Anesthetic, Local

Chemical Class: Amino Ester

Uses For Pontocaine

Tetracaine is used in different parts of the body to cause numbness or loss of feeling in some patients before having a medical test or procedure.

Tetracaine belongs to a group of medicines known as topical local anesthetics. It deadens the nerve endings in the skin. This medicine does not cause unconsciousness as general anesthetics do when used for surgery.

This medicine is available only with your doctor's prescription.

Before Using Pontocaine

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

No information is available on the relationship of age to the effects of tetracaine in the pediatric population. Safety and efficacy have not been established.

Geriatric

No information is available on the relationship of age to the effects of tetracaine in geriatric patients.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Brain or spinal problems or


• Eye problems or


• Heart and blood vessel problems—Use with caution. May make these conditions worse.

• Infection at or near the place of application or


• Large sores, broken skin, or severe injury at the area of application—The chance of side effects may be increased.

Proper Use of tetracaine

This section provides information on the proper use of a number of products that contain tetracaine. It may not be specific to Pontocaine. Please read with care.

A nurse or other trained health professional will give you this medicine. This medicine is for use on the skin only.

Be careful not to get any of this medicine in your nose, mouth, and especially in your eyes, because it can cause severe eye irritation. If any of the medicine does get into these areas especially the eyes, wash it with water and check with your doctor right away.

Precautions While Using Pontocaine

It is very important that your doctor check you closely for any problems or unwanted effects that may be caused by this medicine.

Stop using this medicine and check with your doctor right away if you have a skin rash, burning, stinging, swelling, or irritation of your skin.

Do not use cosmetics or other skin care products on the treated skin areas.

Pontocaine Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

Incidence not known

• Blurred vision


• chest pain or discomfort


• confusion


• dizziness


• dizziness, faintness, or lightheadedness when getting up from a lying or sitting position suddenly


• fainting


• fast or irregular heartbeat


• lightheadedness or fainting


• no blood pressure or pulse


• no breathing


• numbness


• seizures


• shakiness in the legs, arms, hands, or feet


• shortness of breath


• slow or irregular heartbeat


• stopping of heart


• sweating


• trembling or shaking of the hands or feet


• unconsciousness


• unusual tiredness or weakness

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Incidence not known

• Continuing ringing or buzzing or other unexplained noise in the ears


• fear or nervousness


• hearing loss


• restlessness


• sleepiness

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Pontocaine resources

• Pontocaine Support Group
• 0 Reviews for Pontocaine - Add your own review/rating

• Pontocaine Concise Consumer Information (Cerner Multum)

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• Allergic Urticaria
• Cold Sores
• Local Anesthesia
• Skin Rash
• Urticaria

Antiparkinson agents

Antiparkinson agents aim to replace dopamine either by drugs that release dopamine or those that mimic the action of dopamine. Parkinson

See also

• anticholinergic antiparkinson agents
• dopaminergic antiparkinsonism agents
• miscellaneous antiparkinson agents

Drug List:

Kaopectate Suspension

Pronunciation: BIZ-muth SUB-sa-LIS-i-late
Generic Name: Bismuth Subsalicylate
Brand Name: Examples include Kaopectate and Pepto-Bismol

Kaopectate Suspension is used for:

Treating heartburn, upset stomach, indigestion, nausea, gas, diarrhea, or symptoms associated with eating or drinking too much. It may also be used to decrease the number of bowel movements and make the stool firmer. It may also be used to treat other conditions as determined by your doctor.

Kaopectate Suspension is a salicylate. Exactly how it works is not known. It is thought to limit secretions in the digestive tract, reduce inflammation in the stomach and intestines, and inhibit the growth of certain bacteria and viruses that can cause intestinal tract diseases.

Do NOT use Kaopectate Suspension if:

• you are allergic to any ingredient in Kaopectate Suspension


• you have had a severe allergic reaction (eg, severe rash, hives, difficulty breathing, dizziness) to a salicylate (eg, aspirin) or a nonsteroidal anti-inflammatory drug (NSAID) (eg, ibuprofen, naproxen, celecoxib)


• you have bleeding problems (eg, hemophilia), an active bleeding ulcer, black or bloody stools, or von Willebrand disease


• you are taking another salicylate medicine (eg, aspirin)


• the patient is a child with a viral infection (eg, chickenpox, flu symptoms)

Contact your doctor or health care provider right away if any of these apply to you.

Before using Kaopectate Suspension:

Some medical conditions may interact with Kaopectate Suspension. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have diabetes, gout, arthritis, fever, mucus in the stool, inflammation of the stomach, Kawasaki syndrome, kidney problems, chickenpox, the flu, or joint problems (in children), or if you are dehydrated


• if you have a history of stroke, stomach ulcers, or a certain type of bulging blood vessel (aneurysm) in the brain

Some MEDICINES MAY INTERACT with Kaopectate Suspension. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Diabetes medicine (eg, insulin, glipizide), methotrexate, or valproic acid because their actions and the risk of their side effects may be increased by Kaopectate Suspension


• Anticoagulants (eg, warfarin) or clopidogrel because the risk of bleeding may be increased by Kaopectate Suspension


• Salicylates (eg, aspirin) or NSAIDs (eg, ibuprofen, naproxen) because the risk of their side effects may be increased by Kaopectate Suspension


• Angiotensin-converting enzyme (ACE) inhibitors (eg, lisinopril) or sulfinpyrazone because their effectiveness may be decreased by Kaopectate Suspension

This may not be a complete list of all interactions that may occur. Ask your health care provider if Kaopectate Suspension may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Kaopectate Suspension:

Use Kaopectate Suspension as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Kaopectate Suspension may be taken with or without food.


• Do not take tetracyclines (eg, doxycycline) within 2 hours before or after taking Kaopectate Suspension.


• Use Kaopectate Suspension exactly as directed on the package, unless instructed differently by your doctor.


• Shake well before each use.


• Use a measuring device marked for medicine dosing. Ask your pharmacist for help if you are unsure of how to measure your dose.


• Drinking extra fluids while you are taking Kaopectate Suspension is recommended. Check with your doctor for instructions.


• If you miss a dose of Kaopectate Suspension and you are taking it regularly, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Kaopectate Suspension.

Important safety information:

• Do NOT take more than the recommended dose or use for longer than 48 hours without checking with your doctor. If your symptoms do not improve within 48 hours or if they become worse or you develop a fever, check with your doctor.


• Kaopectate Suspension may color the tongue or stool gray or black. This is normal and not a cause for concern.


• Use of Kaopectate Suspension has been linked to a serious illness called Reye syndrome. Do not give Kaopectate Suspension to a child or teenager who has the flu, chickenpox, or a viral infection. Contact your doctor with any questions or concerns.


• Use Kaopectate Suspension with extreme caution in CHILDREN; they may be more sensitive to its effects.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Kaopectate Suspension while you are pregnant. Kaopectate Suspension is found in breast milk. Do not breast-feed while taking Kaopectate Suspension.

Possible side effects of Kaopectate Suspension:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Temporary and harmless darkening of the tongue or stool.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); black, tarry stools; bloody or dark urine; fever; hearing loss; nausea; ringing in the ears; severe constipation; unusual bruising or bleeding; vomiting that may or may not look like coffee grounds.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Kaopectate side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include coma; confusion; dehydration; dizziness; new or worsening nausea; ringing in the ears; seizures; unusual bruising or bleeding; vomiting.

Proper storage of Kaopectate Suspension:

Store Kaopectate Suspension at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Avoid temperatures above 104 degrees F (40 degrees C). Keep Kaopectate Suspension out of the reach of children and away from pets.

General information:

• If you have any questions about Kaopectate Suspension, please talk with your doctor, pharmacist, or other health care provider.


• Kaopectate Suspension is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Kaopectate Suspension. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

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• Kaopectate Side Effects (in more detail)
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• Kaopectate Drug Interactions
• Kaopectate Support Group
• 0 Reviews for Kaopectate - Add your own review/rating

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Monomax XL 60mg Prolonged Release Tablets

1. Name Of The Medicinal Product

SLOMON XL 60

MONOMAX XL 60 mg Tablets

2. Qualitative And Quantitative Composition

Each prolonged release tablet contains 60mg of isosorbide mononitrate.

For excipients, see 6.1

3. Pharmaceutical Form

Prolonged release tablets

White, oval convex tablets with a score line between "SL" and "60", which are embossed on one side

4. Clinical Particulars

4.1 Therapeutic Indications

For the prophylactic treatment of angina pectoris

4.2 Posology And Method Of Administration

Route of Administration

Oral use

Tablets may be taken with or without food, and should be swallowed whole and not chewed.

Dosage

Adults: Usual adult dose is one isosorbide mononitrate XL 60mg tablet per day (taken in the morning). If necessary, the dosage may be increased to 120mg once daily (i.e. 2 x 60mg tablets taken in the morning).The dosage can be titrated to minimise the possibility of headache by initiating treatment with 30mg (half a tablet), for the first two to four days.

Children: Safety and efficacy in children have not been established.

Elderly: There is no evidence of a need for routine dosage adjustment in the elderly, but special care may be needed in those with increased susceptibility to hypotension or marked hepatic or renal insufficiency.

4.3 Contraindications

This product should not be given to patients with a known sensitivity to nitrates and a known hypersensitivity to the constituents of the tablets.

Relative contraindications to the use of isosorbide mononitrate are severe cerebral vascular insufficiency and hypotension.

Sildenafil has been shown to potentiate the hypotensive effects of nitrates, and its co-administration with nitrates or nitric oxide donors is therefore contraindicated.

Isosorbide mononitrate is contraindicated in patients with constrictive cardiomyopathy and pericarditis, aortic stenosis, cardiac tamponade, mitral stenosis and severe anaemia.

4.4 Special Warnings And Precautions For Use

Isosorbide mononitrate XL 60 mg tablets are not indicated for relief of acute angina attacks; in the event of an acute attack, sublingual or buccal glyceryl trinitrate tablets / sprays should be used.

Isosorbide mononitrate should be used with caution in patients who are predisposed to closed angle glaucoma.

Isosorbide mononitrate should be used with caution in patients suffering from head trauma, cerebral haemorrhage, recent history of myocardial infarction, hypothyroidism, hypothermia, malnutrition, severe liver or renal disease.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Only limited information is available on the possible interaction between isosorbide mononitrate and other drugs.

Some of the effects of alcohol may be potentiated by this agent.

Vasodilators, antihypertensives and diuretics may potentiate the hypotension caused by nitrates particularly in the elderly.

The hypotensive effects of nitrates are potentiated by concurrent administration of sildenafil.

There is no evidence of interaction with food.

4.6 Pregnancy And Lactation

Since its safety and efficacy have not been established, this product should not be used during pregnancy or lactation unless considered essential by the physician.

4.7 Effects On Ability To Drive And Use Machines

Since postural hypotension with symptoms such as dizziness has been reported, patients should be advised to be careful when driving or operating machinery if they suffer from these symptoms.

4.8 Undesirable Effects

Most of the adverse reactions are pharmacodynamically mediated and dose dependent. Side effects including flushing, postural hypotension and dry skin rashes may occur occasionally. Headache may occur at the onset of treatment but may be minimised by commencing with low doses of 30mg and gradually increasing the dose. Hypotension, with symptoms such as dizziness and nausea, has occasionally been reported. These symptoms generally disappear during continued treatment. Pruritis has been reported rarely and myalgia, reported very rarely.

4.9 Overdose

Symptoms

A pulsating headache is the commonest.

More serious symptoms are excitation, flushing, cold perspiration, nausea, vomiting, vertigo, syncope, tachycardia and a fall in blood pressure.

Management

Induce emesis. Use activated charcoal.

If pronounced hypotension, place the patient in the supine position with legs raised. If necessary, intravenous fluids should be administered.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Anatomical Therapeutic Chemical (ATC) code: C01D A14;

Vasodilators used in cardiac diseases, organic nitrates

The principal pharmacological action of isosorbide mononitrate, an active metabolite of isosorbide dinitrate, is relaxation of vascular smooth muscle, producing vasodilation of both arteries and veins with the venous effect predominating. The effect of the treatment is dependent on the dose. Low plasma concentrations lead to venous dilation, resulting in peripheral pooling of blood, decreased venous return and reduction in left ventricular end

The net effect, when administering isosorbide mononitrate, is therefore a reduced workload on the heart and an improved oxygen supply / demand balance in the myocardium.

5.2 Pharmacokinetic Properties

In man, isosorbide mononitrate is absorbed completely and rapidly following oral administration.

Isosorbide mononitrate is not subject to the hepatic first-pass effect, and provides a low degree of inter-individual variation of blood levels, leading to predictable and reproducible clinical effects.

Isosorbide mononitrate XL 60mg tablets have all the pharmacokinetic characteristics of a true modified-release dosage form. Compared with an immediate-release dosage form, the peak plasma concentration obtained is lower and occurs later, while the apparent elimination half-life is unchanged. Thus compared to ordinary tablets, the absorption phase is prolonged and the duration of effect is extended.

Isosorbide mononitrate is effective in monotherapy as well as in combination with long term beta

The clinical effects of nitrates may be reduced following repeated administration due to too high and/or constant plasma levels. This can be avoided by allowing low plasma levels for a certain period between doses. Isosorbide mononitrate XL 60mg tablets, when administered once daily in the morning, produces a plasma profile of high levels during the day and low levels during the night. Thus, no development of tolerance should be seen with Isosorbide mononitrate XL, when 60mg or 120mg is taken once daily in the morning.

5.3 Preclinical Safety Data

Isosorbide mononitrate produces very few toxic effects and is less toxic than isosorbide dinitrate. After chronic administration at high doses (60mg/kg), signs of toxicity have been detected in canine liver and kidneys. Tests conducted have shown no evidence of a teratogenic or mutagenic potential.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose monohydrate

Hypromellose

Glyceryl palmitostearate

Maize starch

Magnesium stearate

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

36 months

6.4 Special Precautions For Storage

Store in the original container. Do not store above 25°C.

6.5 Nature And Contents Of Container

The tablets are enclosed in blisters composed of 250μm PVC film/25μm aluminium foil.

The blisters are packed into folded printed cardboard cartons with a patient information leaflet. Packs contain 28 or 30 prolonged release tablets.

6.6 Special Precautions For Disposal And Other Handling

None

ADMINISTRATIVE DATA

7. Marketing Authorisation Holder

Chiesi Limited

Cheadle Royal Business Park

Highfield

Cheadle

SK8 3GY

United Kingdom

8. Marketing Authorisation Number(S)

PL 08829/0102

9. Date Of First Authorisation/Renewal Of The Authorisation

24^th February 2000

10. Date Of Revision Of The Text

09/06/2009

11. LEGAL CATEGORY

P