Quinimax

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Quinimax uses

Quinimax consists of Cinchonidine Hydrochloride, Quinidine Hydrochloride, Quinine Hydrochloride.

Quinidine Hydrochloride:


DESCRIPTION

Quinimax (Quinidine Hydrochloride) is an antimalarial schizonticide and an antiarrhythmic agent with class 1A activity; it is the d-isomer of quinine, and its molecular weight is 324.43.

Quinimax (Quinidine Hydrochloride) sulfate is the sulfate salt of Quinimax (Quinidine Hydrochloride); its chemical name is cinchonan-9-ol, 6’-methoxy-, (9S)-, sulfate(2:1) dihydrate; its structural formula is:

Its molecular formula is: C40H48N4O4-H2SO4-2H2O; and its molecular weight is 782.96, of which 82.9% is Quinimax (Quinidine Hydrochloride) base.

Quinimax (Quinidine Hydrochloride) sulfate occurs as fine needle-like, white crystals, frequently cohering in masses, or fine, white powder. It is odorless, has a very bitter taste, and darkens on exposure to light. It is slightly soluble in water, soluble in alcohol and in chloroform, and insoluble in ether.

Each tablet, for oral administration, contains 200 mg and 300 mg of Quinimax (Quinidine Hydrochloride) sulfate (equivalent to 166 mg or 249 mg of Quinimax (Quinidine Hydrochloride) base). In addition, each tablet contains the following inactive ingredients: calcium stearate, microcrystalline cellulose, sodium starch glycolate and starch (corn).

Quinimax (Quinidine Hydrochloride) Sulfate Structural Formula

CLINICAL PHARMACOLOGY

Pharmacokinetics and Metabolism

The absolute bioavailability of Quinimax from Quinimax (Quinidine Hydrochloride) sulfate tablets is about 70%, but this varies widely (45 to 100%) between patients. The less-than-complete bioavailability is the result of first-pass metabolism in the liver. Peak serum levels generally appear about 2 hours after dosing; the rate of absorption is somewhat slowed when the drug is taken with food, but the extent of absorption is not changed.

The volume of distribution of Quinimax (Quinidine Hydrochloride) is 2 to 3 L/kg in healthy young adults, but this may be reduced to as little as 0.5 L/kg in patients with congestive heart failure, or increased to 3 to 5 L/kg in patients with cirrhosis of the liver. At concentrations of 2 to 5 mg/L (6.5 to 16.2 μmol/L), the fraction of Quinimax (Quinidine Hydrochloride) bound to plasma proteins (mainly to α1-acid glycoprotein and to albumin) is 80 to 88% in adults and older children, but it is lower in pregnant women, and in infants and neonates it may be as low as 50 to 70%. Because α1-acid glycoprotein levels are increased in response to stress, serum levels of total Quinimax (Quinidine Hydrochloride) may be greatly increased in settings such as acute myocardial infarction, even though the serum content of unbound (active) drug may remain normal. Protein binding is also increased in chronic renal failure, but binding abruptly descends toward or below normal when heparin is administered for hemodialysis.

Quinimax (Quinidine Hydrochloride) clearance typically proceeds at 3 to 5 mL/min/kg in adults, but clearance in children may be twice or three times as rapid. The elimination half-life is 6 to 8 hours in adults and 3 to 4 hours in children. Quinimax (Quinidine Hydrochloride) clearance is unaffected by hepatic cirrhosis, so the increased volume of distribution seen in cirrhosis leads to a proportionate increase in the elimination half-life.

Most Quinimax (Quinidine Hydrochloride) is eliminated hepatically via the action of cytochrome P450IIIA4; there are several different hydroxylated metabolites, and some of these have antiarrhythmic activity.

The most important of quinidine’s metabolites is 3-hydroxyquinidine (3HQ), serum levels of which can exceed those of Quinimax (Quinidine Hydrochloride) in patients receiving conventional doses of Quinimax (Quinidine Hydrochloride) sulfate. The volume of distribution of 3HQ appears to be larger than that of Quinimax (Quinidine Hydrochloride), and the elimination half-life of 3HQ is about 12 hours.

As measured by antiarrhythmic effects in animals, by QTC prolongation in human volunteers, or by various in vitro techniques, 3HQ has at least half the antiarrhythmic activity of the parent compound, so it may be responsible for a substantial fraction of the effect of Quinimax (Quinidine Hydrochloride) sulfate in chronic use.

When the urine pH is less than 7, about 20% of administered Quinimax (Quinidine Hydrochloride) appears unchanged in the urine, but this fraction drops to as little as 5% when the urine is more alkaline. Renal clearance involves both glomerular filtration and active tubular secretion, moderated by (pH-dependent) tubular reabsorption. The net renal clearance is about 1 mL/min/kg in healthy adults. When renal function is taken into account, Quinimax (Quinidine Hydrochloride) clearance is apparently independent of patient age.

Assays of serum Quinimax (Quinidine Hydrochloride) levels are widely available, but the results of modern assays may not be consistent with results cited in the older medical literature. The serum levels of Quinimax (Quinidine Hydrochloride) cited in this package insert are those derived from specific assays, using either benzene extraction or (preferably) reverse-phase high-pressure liquid chromatography. In matched samples, older assays might unpredictably have given results that were as much as two or three times higher. A typical “therapeutic” concentration range is 2 to 6 mg/L (6.2 to 18.5 μmol/L).

Mechanisms of Action

In patients with malaria, Quinimax (Quinidine Hydrochloride) acts primarily as an intra-erythrocytic schizonticide, with little effect upon sporozites or upon pre-erythrocytic parasites. Quinimax (Quinidine Hydrochloride) is gametocidal to Plasmodium vivax and P. malariae, but not to P. falciparum.

In cardiac muscle and in Purkinje fibers, Quinimax (Quinidine Hydrochloride) depresses the rapid inward depolarizing sodium current, thereby slowing phase-0 depolarization and reducing the amplitude of the action potential without affecting the resting potential. In normal Purkinje fibers, it reduces the slope of phase-4 depolarization, shifting the threshold voltage upward toward zero. The result is slowed conduction and reduced automaticity in all parts of the heart, with increase of the effective refractory period relative to the duration of the action potential in the atria, ventricles, and Purkinje tissues. Quinimax (Quinidine Hydrochloride) also raises the fibrillation thresholds of the atria and ventricles, and it raises the ventricular defibrillation threshold as well. Quinidine’s actions fall into class 1A in the Vaughan-Williams classification.

By slowing conduction and prolonging the effective refractory period, Quinimax (Quinidine Hydrochloride) can interrupt or prevent reentrant arrhythmias and arrhythmias due to increased automaticity, including atrial flutter, atrial fibrillation, and paroxysmal supraventricular tachycardia.

In patients with the sick sinus syndrome, Quinimax (Quinidine Hydrochloride) can cause marked sinus node depression and bradycardia. In most patients, however, use of Quinimax (Quinidine Hydrochloride) is associated with an increase in the sinus rate.

Quinimax (Quinidine Hydrochloride) prolongs the QT interval in a dose-related fashion. This may lead to increased ventricular automaticity and polymorphic ventricular tachycardias, including torsades de pointes (see WARNINGS ).

In addition, Quinimax (Quinidine Hydrochloride) has anticholinergic activity, it has negative inotropic activity, and it acts peripherally as an α-adrenergic antagonist (that is, as a vasodilator).

Clinical Effects

Maintenance of sinus rhythm after conversion from atrial fibrillation: In six clinical trials (published between 1970 and 1984) with a total of 808 patients, Quinimax (Quinidine Hydrochloride) (418 patients) was compared to nontreatment (258 patients) or placebo (132 patients) for the maintenance of sinus rhythm after cardioversion from chronic atrial fibrillation. Quinimax (Quinidine Hydrochloride) was consistently more efficacious in maintaining sinus rhythm, but a meta-analysis found that mortality in the quinidine-exposed patients (2.9%) was significantly greater than mortality in the patients who had not been treated with active drug (0.8%). Suppression of atrial fibrillation with Quinimax (Quinidine Hydrochloride) has theoretical patient benefits (e.g., improved exercise tolerance; reduction in hospitalization for cardioversion; lack of arrhythmia-related palpitations, dyspnea, and chest pain; reduced incidence of systemic embolism and/or stroke), but these benefits have never been demonstrated in clinical trials. Some of these benefits (e.g., reduction in stroke incidence) may be achievable by other means (anticoagulation).

By slowing the rate of atrial flutter/fibrillation, Quinimax (Quinidine Hydrochloride) can decrease the degree of atrioventricular block and cause an increase, sometimes marked, in the rate at which supraventricular impulses are successfully conducted by the atrioventricular node, with a resultant paradoxical increase in ventricular rate (see WARNINGS ). Non-life-threatening ventricular arrhythmias: In studies of patients with a variety of ventricular arrhythmias (mainly frequent ventricular premature beats and non-sustained ventricular tachycardia), Quinimax (Quinidine Hydrochloride) (total N=502) has been compared to flecainide (N=141), mexiletine (N=246), propafenone (N=53), and tocainide (N=67). In each of these studies, the mortality in the Quinimax (Quinidine Hydrochloride) group was numerically greater than the mortality in the comparator group. When the studies were combined in a meta-analysis, Quinimax (Quinidine Hydrochloride) was associated with a statistically significant threefold relative risk of death.

At therapeutic doses, quinidine’s only consistent effect upon the surface electrocardiogram is an increase in the QT interval. This prolongation can be monitored as a guide to safety, and it may provide better guidance than serum drug levels (see WARNINGS ).

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INDICATIONS AND USAGE

Conversion of atrial fibrillation/flutter

In patients with symptomatic atrial fibrillation/flutter whose symptoms are not adequately controlled by measures that reduce the rate of ventricular response, Quinimax sulfate is indicated as a means of restoring normal sinus rhythm. If this use of Quinimax (Quinidine Hydrochloride) sulfate does not restore sinus rhythm within a reasonable time (see DOSAGE AND ADMINISTRATION ), then Quinimax (Quinidine Hydrochloride) sulfate should be discontinued.

Reduction of frequency of relapse into atrial fibrillation/flutter

Chronic therapy with Quinimax (Quinidine Hydrochloride) sulfate is indicated for some patients at high risk of symptomatic atrial fibrillation/flutter, generally patients who have had previous episodes of atrial fibrillation/flutter that were so frequent and poorly tolerated as to outweigh, in the judgment of the physician and the patient, the risks of prophylactic therapy with Quinimax (Quinidine Hydrochloride) sulfate. The increased risk of death should specifically be considered. Quinimax (Quinidine Hydrochloride) sulfate should be used only after alternative measures (e.g., use of other drugs to control the ventricular rate) have been found to be inadequate.

In patients with histories of frequent symptomatic episodes of atrial fibrillation/flutter, the goal of therapy should be an increase in the average time between episodes. In most patients, the tachyarrhythmia will recur during therapy, and a single recurrence should not be interpreted as therapeutic failure.

Suppression of ventricular arrhythmias

Quinimax sulfate is also indicated for the suppression of recurrent documented ventricular arrhythmias, such as sustained ventricular tachycardia, that in the judgment of the physician are life-threatening. Because of the proarrhythmic effects of Quinimax (Quinidine Hydrochloride), its use with ventricular arrhythmias of lesser severity is generally not recommended, and treatment of patients with asymptomatic ventricular premature contractions should be avoided. Where possible, therapy should be guided by the results of programmed electrical stimulation and/or Holter monitoring with exercise.

Antiarrhythmic drugs (including Quinimax (Quinidine Hydrochloride) sulfate) have not been shown to enhance survival in patients with ventricular arrhythmias.

Treatment of malaria

Quinimax (Quinidine Hydrochloride) sulfate is also indicated in the treatment of life-threatening Plasmodium falciparum malaria.

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CONTRAINDICATIONS

Quinimax (Quinidine Hydrochloride) is contraindicated in patients who are known to be allergic to it, or who have developed thrombocytopenic purpura during prior therapy with Quinimax (Quinidine Hydrochloride) or quinine.

In the absence of a functioning artificial pacemaker, Quinimax (Quinidine Hydrochloride) is also contraindicated in any patient whose cardiac rhythm is dependent upon a junctional or idioventricular pacemaker, including patients in complete atrioventricular block.

Quinimax (Quinidine Hydrochloride) is also contraindicated in patients who, like those with myasthenia gravis, might be adversely affected by an anticholinergic agent.

WARNINGS

Mortality

In many trials of antiarrhythmic therapy for non-life-threatening arrhythmias, active antiarrhythmic therapy has resulted in increased mortality; the risk of active therapy is probably greatest in patients with structural heart disease.
In the case of Quinimax used to prevent or defer recurrence of atrial flutter/fibrillation, the best available data come from a meta-analysis described under CLINICAL PHARMACOLOGY/Clinical Effects above. In the patients studied in the trials there analyzed, the mortality associated with the use of Quinimax (Quinidine Hydrochloride) was more than three times as great as the mortality associated with the use of placebo.
Another meta-analysis, also described under CLINICAL PHARMACOLOGY/Clinical Effects , showed that in patients with various non-life-threatening ventricular arrhythmias, the mortality associated with the use of Quinimax (Quinidine Hydrochloride) was consistently greater than that associated with the use of any of a variety of alternative antiarrhythmics.

Proarrhythmic effects

Like many other drugs (including all other class IA antiarrhythmics), Quinimax (Quinidine Hydrochloride) prolongs the QTC interval, and this can lead to torsades de pointes, a life-threatening ventricular arrhythmia (see OVERDOSAGE ). The risk of torsades is increased by bradycardia, hypokalemia, hypomagnesemia, hypocalcemia, or high serum levels of Quinimax (Quinidine Hydrochloride), but it may appear in the absence of any of these risk factors. The best predictor of this arrhythmia appears to be the length of the QTC interval, and Quinimax (Quinidine Hydrochloride) should be used with extreme care in patients who have preexisting long-QT syndromes, who have histories of torsades de pointes of any cause, or who have previously responded to Quinimax (Quinidine Hydrochloride) (or other drugs that prolong ventricular repolarization) with marked lengthening of the QTC interval. Estimation of the incidence of torsades in patients with therapeutic levels of Quinimax (Quinidine Hydrochloride) is not possible from the available data.

Other ventricular arrhythmias that have been reported with Quinimax (Quinidine Hydrochloride) include frequent extrasystoles, ventricular tachycardia, ventricular flutter, and ventricular fibrillation.

Paradoxical increase in ventricular rate in atrial flutter/fibrillation

When Quinimax is administered to patients with atrial flutter/fibrillation, the desired pharmacologic reversion to sinus rhythm may (rarely) be preceded by a slowing of the atrial rate with a consequent increase in the rate of beats conducted to the ventricles. The resulting ventricular rate may be very high (greater than 200 beats per minute) and poorly tolerated. This hazard may be decreased if partial atrioventricular block is achieved prior to initiation of Quinimax (Quinidine Hydrochloride) therapy, using conduction-reducing drugs such as digitalis, verapamil, diltiazem, or a ß-receptor blocking agent.

Exacerbated bradycardia in sick sinus syndrome

In patients with the sick sinus syndrome, Quinimax (Quinidine Hydrochloride) has been associated with marked sinus node depression and bradycardia.

Pharmacokinetic considerations

Renal or hepatic dysfunction causes the elimination of Quinimax to be slowed, while congestive heart failure causes a reduction in quinidine’s apparent volume of distribution. Any of these conditions can lead to Quinimax (Quinidine Hydrochloride) toxicity if dosage is not appropriately reduced. In addition, interactions with coadministered drugs can alter the serum concentration and activity of Quinimax (Quinidine Hydrochloride), leading either to toxicity or to lack of efficacy if the dose of Quinimax (Quinidine Hydrochloride) is not appropriately modified. (See PRECAUTIONS/Drug Interactions .)

Vagolysis

Because Quinimax (Quinidine Hydrochloride) opposes the atrial and A-V nodal effects of vagal stimulation, physical or pharmacological vagal maneuvers undertaken to terminate paroxysmal supraventricular tachycardia may be ineffective in patients receiving Quinimax (Quinidine Hydrochloride).

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PRECAUTIONS

Heart Block

In patients without implanted pacemakers who are at high risk of complete atrioventricular block, Quinimax (Quinidine Hydrochloride) should be used only with caution.

Drug Interactions

Altered pharmacokinetics of Quinimax (Quinidine Hydrochloride): Drugs that alkalinize the urine (carbonic-anhydrase inhibitors, sodium bicarbonate, thiazide diuretics) reduce renal elimination of Quinimax (Quinidine Hydrochloride).

By pharmacokinetic mechanisms that are not well understood, Quinimax (Quinidine Hydrochloride) levels are increased by coadministration of amiodarone or cimetidine. Very rarely, and again by mechanisms not understood, Quinimax (Quinidine Hydrochloride) levels are decreased by coadministration of nifedipine.

Hepatic elimination of Quinimax (Quinidine Hydrochloride) may be accelerated by coadministration of drugs (phenobarbital, phenytoin, rifampin) that induce production of cytochrome P450IIIA4.

Perhaps because of competition for the P450IIIA4 metabolic pathway, Quinimax (Quinidine Hydrochloride) levels rise when ketaconazole is coadministered.

Coadministration of propranolol usually does not affect Quinimax (Quinidine Hydrochloride) pharmacokinetics, but in some studies the ß-blocker appeared to cause increases in the peak serum levels of Quinimax (Quinidine Hydrochloride), decreases in quinidine’s volume of distribution, and decreases in total Quinimax (Quinidine Hydrochloride) clearance. The effects (if any) of coadministration of other ß-blockers on Quinimax (Quinidine Hydrochloride) pharmacokinetics have not been adequately studied.

Hepatic clearance of Quinimax (Quinidine Hydrochloride) is significantly reduced during coadministration of verapamil, with corresponding increases in serum levels and half-life.

Altered pharmacokinetics of other drugs: Quinimax (Quinidine Hydrochloride) slows the elimination of digoxin and simultaneously reduces digoxin’s apparent volume of distribution. As a result, serum digoxin levels may be as much as doubled. When Quinimax (Quinidine Hydrochloride) and digoxin are coadministered, digoxin doses usually need to be reduced. Serum levels of digitoxin are also raised when Quinimax (Quinidine Hydrochloride) is coadministered, although the effect appears to be smaller.

By a mechanism that is not understood, Quinimax (Quinidine Hydrochloride) potentiates the anticoagulatory action of warfarin, and the anticoagulant dosage may need to be reduced.

Cytochrome P450IID6 is an enzyme critical to the metabolism of many drugs, notably including mexiletine, some phenothiazines, and most polycyclic antidepressants. Constitutional deficiency of cytochrome P450IID6 is found in less than 1% of Orientals, in about 2% of American blacks, and in about 8% of American whites. Testing with debrisoquine is sometimes used to distinguish the P450IID6-deficient “poor metabolizers” from the majority-phenotype “extensive metabolizers”.

When drugs whose metabolism is P450IID6-dependent are given to poor metabolizers, the serum levels achieved are higher, sometimes much higher, than the serum levels achieved when identical doses are given to extensive metabolizers. To obtain similar clinical benefit without toxicity, doses given to poor metabolizers may need to be greatly reduced. In the cases of prodrugs whose actions are actually mediated by P450IID6-produced metabolites (for example, codeine and hydrocodone, whose analgesic and antitussive effects appear to be mediated by morphine and hydromorphone, respectively), it may not be possible to achieve the desired clinical benefits in poor metabolizers.

Quinimax (Quinidine Hydrochloride) is not metabolized by cytochrome P450IID6, but therapeutic serum levels of Quinimax (Quinidine Hydrochloride) inhibit the action of cytochrome P450IID6, effectively converting extensive metabolizers into poor metabolizers. Caution must be exercised whenever Quinimax (Quinidine Hydrochloride) is prescribed together with drugs metabolized by cytochrome P450IID6.

Perhaps by competing for pathways of renal clearance, coadministration of Quinimax (Quinidine Hydrochloride) causes an increase in serum levels of procainamide.

Serum levels of haloperidol are increased when Quinimax (Quinidine Hydrochloride) is coadministered.

Presumably because both drugs are metabolized by cytochrome P450IIIA4, coadministration of Quinimax (Quinidine Hydrochloride) causes variable slowing of the metabolism of nifedipine. Interactions with other dihydropyridine calcium-channel blockers have not been reported, but these agents (including felodipine, nicardipine, and nimodipine) are all dependent upon P450IIIA4 for metabolism, so similar interactions with Quinimax (Quinidine Hydrochloride) should be anticipated.

Altered pharmacodynamics of other drugs: Quinidine’s anticholinergic, vasodilating, and negative inotropic actions may be additive to those of other drugs with these effects, and antagonistic to those of drugs with cholinergic, vasoconstricting, and positive inotropic effects. For example, when Quinimax (Quinidine Hydrochloride) and verapamil are coadministered in doses that are each well tolerated as monotherapy, hypotension attributable to additive peripheral α-blockade is sometimes reported.

Quinimax (Quinidine Hydrochloride) potentiates the actions of depolarizing (succinylcholine, decamethonium) and nondepolarizing (d-tubocurarine, pancuronium) neuromuscular blocking agents. These phenomena are not well understood, but they are observed in animal models as well as in humans. In addition, in vitro addition of Quinimax (Quinidine Hydrochloride) to the serum of pregnant women reduces the activity of pseudocholinesterase, an enzyme that is essential to the metabolism of succinylcholine.

Non-interactions of Quinimax (Quinidine Hydrochloride) with other drugs: Quinimax (Quinidine Hydrochloride) has no clinically significant effect on the pharmacokinetics of diltiazem, flecainide, mephenytoin, metoprolol, propafenone, propranolol, quinine, timolol, or tocainide.

Conversely, the pharmacokinetics of Quinimax (Quinidine Hydrochloride) are not significantly affected by caffeine, ciprofloxacin, digoxin, diltiazem, felodipine, omeprazole, or quinine. Quinidine’s pharmacokinetics are also unaffected by cigarette smoking.

Information for patients

Before prescribing Quinimax sulfate as prophylaxis against recurrence of atrial fibrillation, the physician should inform the patient of the risks and benefits to be expected (see CLINICAL PHARMACOLOGY ). Discussion should include the facts:


  • that the goal of therapy will be a reduction (probably not to zero) in the frequency of episodes of atrial fibrillation; and


  • that reduced frequency of fibrillatory episodes may be expected, if achieved, to bring symptomatic benefit; but


  • that no data are available to show that reduced frequency of fibrillatory episodes will reduce the risks of irreversible harm through stroke or death; and in fact


  • that such data as are available suggest that treatment with Quinimax (Quinidine Hydrochloride) sulfate is likely to increase the patient’s risk of death.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Animal studies to evaluate quinidine’s carcinogenic or mutagenic potential have not been performed. Similarly, there are no animal data as to quinidine’s potential to impair fertility.

Pregnancy

Pregnancy Category C

Animal reproductive studies have not been conducted with Quinimax. There are no adequate and well-controlled studies in pregnant women. Quinimax (Quinidine Hydrochloride) should be given to a pregnant woman only if clearly needed.

Human placental transport of Quinimax (Quinidine Hydrochloride) has not been systematically studied. In one neonate whose mother had received Quinimax (Quinidine Hydrochloride) throughout her pregnancy, the serum level of Quinimax (Quinidine Hydrochloride) was equal to that of the mother, with no apparent ill effect. The level of Quinimax (Quinidine Hydrochloride) in amniotic fluid was about three times higher than that found in serum. In another case, the levels of Quinimax (Quinidine Hydrochloride) and 3-hydroxyquinidine in cord blood were about 30% of simultaneous maternal levels.

Labor and Delivery

Quinine is said to be oxytocic in humans, but there are no adequate data as to quinidine’s effects (if any) on human labor and delivery.

Nursing Mothers

Quinimax is present in human milk at levels slightly lower than those in maternal serum; a human infant ingesting such milk should (scaling directly by weight) be expected to develop serum Quinimax (Quinidine Hydrochloride) levels at least an order of magnitude lower than those of the mother. On the other hand, the pharmacokinetics and pharmacodynamics of Quinimax (Quinidine Hydrochloride) in human infants have not been adequately studied, and neonates’ reduced protein binding of Quinimax (Quinidine Hydrochloride) may increase their risk of toxicity at low total serum levels. Administration of Quinimax (Quinidine Hydrochloride) should (if possible) be avoided in lactating women who continue to nurse.

Geriatric Use

Safety and efficacy of Quinimax (Quinidine Hydrochloride) in elderly patients has not been systematically studied.

Pediatric Use

In antimalarial trials, Quinimax (Quinidine Hydrochloride) was as safe and effective in pediatric patients as in adults. Notwithstanding the known pharmacokinetic differences between children and adults (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism ), children in these trials received the same doses (on a mg/kg basis) as adults.

Safety and effectiveness of antiarrhythmic use in pediatric patients have not been established.

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ADVERSE REACTIONS

Quinimax (Quinidine Hydrochloride) preparations have been used for many years, but there are only sparse data from which to estimate the incidence of various adverse reactions. The adverse reactions most frequently reported have consistently been gastrointestinal, including diarrhea, nausea, vomiting, and heartburn/esophagitis. In one study of 245 adult outpatients who received Quinimax (Quinidine Hydrochloride) to suppress premature ventricular contractions, the incidences of reported adverse experiences were as shown in the table below. The most serious quinidine-associated adverse reactions are described above under WARNINGS .

Adverse Experiences in a 245-Patient PVC Trial
Incidence (%)
diarrhea 85 (35)
“upper gastrointestinal distress” 55 (22)
lightheadedness 37 (15)
headache 18 (7)
fatigue 17 (7)
palpitations 16 (7)
angina-like pain 14 (6)
weakness 13 (5)
rash 11 (5)
visual problems 8 (3)
change in sleep habits 7 (3)
tremor 6 (2)
nervousness 5 (2)
discoordination 3 (1)

Vomiting and diarrhea can occur as isolated reactions to therapeutic levels of Quinimax (Quinidine Hydrochloride), but they may also be the first signs of cinchonism, a syndrome that may also include tinnitus, reversible high-frequency hearing loss, deafness, vertigo, blurred vision, diplopia, photophobia, headache, confusion, and delirium. Cinchonism is most often a sign of chronic Quinimax (Quinidine Hydrochloride) toxicity, but it may appear in sensitive patients after a single moderate dose.

A few cases of hepatotoxicity, including granulomatous hepatitis, have been reported in patients receiving Quinimax (Quinidine Hydrochloride). All of these have appeared during the first few weeks of therapy, and most (not all) have remitted once Quinimax (Quinidine Hydrochloride) was withdrawn.

Autoimmune and inflammatory syndromes associated with Quinimax (Quinidine Hydrochloride) therapy have included fever, urticaria, flushing, exfoliative rash, bronchospasm, psoriaform rash, pruritus and lymphadenopathy, hemolytic anemia, vasculitis, pneumonitis, thrombocytopenic purpura, uveitis, angioedema, agranulocytosis, the sicca syndrome, arthralgia, myalgia, elevation in serum levels of skeletal-muscle enzymes, and a disorder resembling systemic lupus erythematosus.

Convulsions, apprehension, and ataxia have been reported, but it is not clear that these were not simply the results of hypotension and consequent cerebral hypoperfusion. There are many reports of syncope. Acute psychotic reactions have been reported to follow the first dose of Quinimax (Quinidine Hydrochloride), but these reactions appear to be extremely rare.

Other adverse reactions occasionally reported include depression, mydriasis, disturbed color perception, night blindness, scotomata, optic neuritis, visual field loss, photosensitivity, and abnormalities of pigmentation.

OVERDOSAGE

Overdoses with various oral formulations of Quinimax have been well described. Death has been described after a 5-gram ingestion by a toddler, while an adolescent was reported to survive after ingesting 8 grams of Quinimax (Quinidine Hydrochloride).

The most important ill effects of acute Quinimax (Quinidine Hydrochloride) overdoses are ventricular arrhythmias and hypotension. Other signs and symptoms of overdose may include vomiting, diarrhea, tinnitus, high-frequency hearing loss, vertigo, blurred vision, diplopia, photophobia, headache, confusion, and delirium.

Arrhythmias

Serum Quinimax (Quinidine Hydrochloride) levels can be conveniently assayed and monitored, but the electrocardiographic QTC interval is a better predictor of quinidine-induced ventricular arrhythmias.

The necessary treatment of hemodynamically unstable polymorphic ventricular tachycardia (including torsades de pointes) is withdrawal of treatment with Quinimax (Quinidine Hydrochloride) and either immediate cardioversion or, if a cardiac pacemaker is in place or immediately available, immediate overdrive pacing. After pacing or cardioversion, further management must be guided by the length of the QTC interval.

Quinidine-associated ventricular tachyarrhythmias with normal underlying QTC intervals have not been adequately studied. Because of the theoretical possibility of QT-prolonging effects that might be additive to those of Quinimax (Quinidine Hydrochloride), other antiarrhythmics with Class I (disopyramide, procainamide) or Class III activities should (if possible) be avoided. Similarly, although the use of bretylium in Quinimax (Quinidine Hydrochloride) overdose has not been reported, it is reasonable to expect that the α-blocking properties of bretylium might be additive to those of Quinimax (Quinidine Hydrochloride), resulting in problematic hypotension.

If the post-cardioversion QTC interval is prolonged, then the pre-cardioversion polymorphic ventricular tachyarrhythmia was (by definition) torsades de pointes. In this case, lidocaine and bretylium are unlikely to be of value, and other Class I antiarrhythmics (disopyramide, procainamide) are likely to exacerbate the situation. Factors contributing to QTC prolongation (especially hypokalemia, hypomagnesemia, and hypocalcemia) should be sought out and (if possible) aggressively corrected. Prevention of recurrent torsades may require sustained overdrive pacing or the cautious administration of isoproterenol (30 to 150 ng/kg/min).

Hypotension

Quinidine-induced hypotension that is not due to an arrhythmia is likely to be a consequence of quinidine-related α-blockade and vasorelaxation. Simple repletion of central volume may be sufficient therapy; other interventions reported to have been beneficial in this setting are those that increase peripheral vascular resistance, including α-agonist catecholamines (norepinephrine, metaraminol) and the Military Anti-Shock Trousers.

Treatment

To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison-Control Center. Telephone numbers of certified poison-control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdose, consider the possibilities of multiple-drug overdoses, drug-drug interactions, and unusual drug kinetics in your patient.

Accelerated removal

Adequate studies of orally-administered activated charcoal in human overdoses of Quinimax (Quinidine Hydrochloride) have not been reported, but there are animal data showing significant enhancement of systemic elimination following this intervention, and there is at least one human case report in which the elimination half-life of Quinimax (Quinidine Hydrochloride) in the serum was apparently shortened by repeated gastric lavage. Activated charcoal should be avoided if an ileus is present; the conventional dose is 1 gram/kg, administered every 2 to 6 hours as a slurry with 8 mL/kg of tap water. Although renal elimination of Quinimax (Quinidine Hydrochloride) might theoretically be accelerated by maneuvers to acidify the urine, such maneuvers are potentially hazardous and of no demonstrated benefit.

Quinimax (Quinidine Hydrochloride) is not usefully removed from the circulation by dialysis.

Following Quinimax (Quinidine Hydrochloride) overdose, drugs that delay elimination of Quinimax (Quinidine Hydrochloride) (cimetidine, carbonic-anhydrase inhibitors, thiazide diuretics) should be withdrawn unless absolutely required.

DOSAGE AND ADMINISTRATION

Treatment of P. falciparum malaria

Quinimax sulfate tablets are used in one of the approved regimens for the treatment of life-threatening P. falciparum malaria. The central component of the regimen is Quinimax (Quinidine Hydrochloride) Gluconate Injection, and the regimen is described in the package insert of Quinimax (Quinidine Hydrochloride) Gluconate Injection.

Conversion of atrial fibrillation/flutter to sinus rhythm

Especially in patients with known structural heart disease or other risk factors for toxicity, initiation or dose-adjustment of treatment with Quinimax (Quinidine Hydrochloride) sulfate should generally be performed in a setting where facilities and personnel for monitoring and resuscitation are continuously available. Patients with symptomatic atrial fibrillation/flutter should be treated with Quinimax (Quinidine Hydrochloride) sulfate only after ventricular rate control (e.g., with digitalis or ß-blockers) has failed to provide satisfactory control of symptoms.

Adequate trials have not identified an optimal regimen of Quinimax (Quinidine Hydrochloride) sulfate for conversion of atrial fibrillation/flutter to sinus rhythm. In one reported regimen, the patient first receives two tablets (400 mg; 332 mg of Quinimax (Quinidine Hydrochloride) base) of Quinimax (Quinidine Hydrochloride) sulfate every six hours. If this regimen has not resulted in conversion after 4 or 5 doses, then the dose is cautiously increased. If, at any point during administration, the QRS complex widens to 130% of its pre-treatment duration; the QTC interval widens to 130% of its pre-treatment duration and is then longer than 500 ms; P waves disappear; or the patient develops significant tachycardia, symptomatic bradycardia, or hypotension, then Quinimax (Quinidine Hydrochloride) sulfate is discontinued, and other means of conversion (e.g., direct-current cardioversion) are considered.

Reduction of frequency of release into atrial fibrillation/flutter

In a patient with a history of frequent symptomatic episodes of atrial fibrillation/flutter, the goal of therapy with Quinimax sulfate should be an increase in the average time between episodes. In most patients, the tachyarrhythmia will recur during therapy with Quinimax (Quinidine Hydrochloride) sulfate, and a single recurrence should not be interpreted as therapeutic failure.

Especially in patients with known structural heart disease or other risk factors for toxicity, initiation or dose-adjustment of treatment with Quinimax (Quinidine Hydrochloride) sulfate should generally be performed in a setting where facilities and personnel for monitoring and resuscitation are continuously available. Monitoring should be continued for two or three days after initiation of the regimen on which the patient will be discharged.

Therapy with Quinimax (Quinidine Hydrochloride) sulfate should be begun with 200 mg (equivalent to 166 mg of Quinimax (Quinidine Hydrochloride) base) every six hours. If this regimen is well tolerated, if the serum Quinimax (Quinidine Hydrochloride) level is still well within the laboratory’s therapeutic range, and if the average time between arrhythmic episodes has not been satisfactorily increased, then the dose may be cautiously raised. The total daily dosage should be reduced if the QRS complex widens to 130% of its pre-treatment duration; the QTC interval widens to 130% of its pre-treatment duration and is then longer than 500 ms; P waves disappear; or the patient develops significant tachycardia, symptomatic bradycardia, or hypotension.

Suppression of ventricular arrhythmias

Dosing regimens for the use of Quinimax (Quinidine Hydrochloride) sulfate in suppressing life-threatening ventricular arrhythmias have not been adequately studied. Described regimens have generally been similar to the regimen described just above for the prophylaxis of symptomatic atrial fibrillation/flutter. Where possible, therapy should be guided by the results of programmed electrical stimulation and/or Holter monitoring with exercise.

HOW SUPPLIED

Quinimax (Quinidine Hydrochloride) Sulfate Tablets USP 200 mg are 12/32”, scored, round, white tablets imprinted DAN DAN and 5438 supplied in bottles of 100 and 1000.

Quinimax (Quinidine Hydrochloride) Sulfate Tablets USP 300 mg are 14/32”, scored, round, white tablets imprinted DAN DAN and 5454 supplied in bottles of 100.

Dispense in well-closed, light-resistant container with child-resistant closure.

Store at 20° - 25°C (68° - 77°F).

Protect from light and moisture.

Manufactured By:

Watson Pharma Private Limited

Verna, Salcette Goa 403 722 INDIA

Distributed By:

Watson Pharma, Inc.

Corona, CA 92880 USA

Revised: June 2009 190782

0609B

Quinine Hydrochloride:


WARNING:

Quinimax (Quinine Hydrochloride)® use for the treatment or prevention of nocturnal leg cramps may result in serious and life-threatening hematologic reactions, including thrombocytopenia and hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP). Chronic renal impairment associated with the development of TTP has been reported. The risk associated with Quinimax (Quinine Hydrochloride) use in the absence of evidence of its effectiveness in the treatment or prevention of nocturnal leg cramps outweighs any potential benefit.

WARNING:

Quinimax (Quinine Hydrochloride)® use for the treatment or prevention of nocturnal leg cramps may result in serious and life-threatening hematologic reactions, including thrombocytopenia and hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP). Chronic renal impairment associated with the development of TTP has been reported. The risk associated with Quinimax (Quinine Hydrochloride) use in the absence of evidence of its effectiveness in the treatment or prevention of nocturnal leg cramps outweighs any potential benefit.

Dose and Administration
Hepatic Impairment (2.3) 4/2013
Warnings and Precautions
QT Prolongation and Ventricular Arrhythmias (5.3) 9/2012

1 INDICATIONS AND USAGE

Quinimax (Quinine Hydrochloride) (quinine sulfate) is an antimalarial drug indicated only for treatment of uncomplicated Plasmodium falciparum malaria. Quinimax (Quinine Hydrochloride) sulfate has been shown to be effective in geographical regions where resistance to chloroquine has been documented [see Clinical Studies (14) ].

Quinimax (Quinine Hydrochloride) oral capsules are not approved for:

  • Treatment of severe or complicated P. falciparum malaria.
  • Prevention of malaria.
  • Treatment or prevention of nocturnal leg cramps [see Warnings and Precautions (5.1) ].

Quinimax (Quinine Hydrochloride)® (quinine sulfate) is a cinchona alkaloid indicated for treatment of uncomplicated Plasmodium falciparum malaria (1).

2 DOSAGE AND ADMINISTRATION

  • Adults : 648 mg (two capsules) every 8 hours for 7 days (2.1).
  • Patients with severe chronic renal impairment: one loading dose of 648 mg (two capsules) followed 12 hours later by 324 mg (one capsule) every 12 hours for 7 days (2.2).

2.1 Treatment of Uncomplicated P. falciparum Malaria

For treatment of uncomplicated P. falciparum malaria in adults: Orally, 648 mg (two capsules) every 8 hours for 7 days [see Clinical Studies (14) ].

Quinimax (Quinine Hydrochloride) should be taken with food to minimize gastric upset [see Clinical Pharmacology (12.3) ].

2.2 Renal Impairment

In patients with acute uncomplicated malaria and severe chronic renal impairment, the following dosage regimen is recommended: one loading dose of 648 mg Quinimax followed 12 hours later by maintenance doses of 324 mg every 12 hours.

The effects of mild and moderate renal impairment on the safety and pharmacokinetics of Quinimax (Quinine Hydrochloride) sulfate are not known [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3) ].

2.3 Hepatic Impairment

Adjustment of the recommended dose is not required in mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, but patients should be monitored closely for adverse effects of Quinimax (Quinine Hydrochloride). Quinimax (Quinine Hydrochloride) should not be administered in patients with severe (Child-Pugh C) hepatic impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3) ].

3 DOSAGE FORMS AND STRENGTHS

324 mg capsules - hard gelatin, clear cap/clear body, imprinted with 'AR 102'

  • 324 mg hard gelatin, clear cap/clear body capsules, imprinted with 'AR 102' (3).

4 CONTRAINDICATIONS

Quinimax (Quinine Hydrochloride) is contraindicated in patients with the following:

  • Prolonged QT interval. One case of a fatal ventricular arrhythmia was reported in an elderly patient with a prolonged QT interval at baseline, who received Quinimax (Quinine Hydrochloride) sulfate intravenously for P. falciparum malaria [see Warnings and Precautions (5.3) ].
  • Glucose-6-phosphate dehydrogenase (G6PD) deficiency.
  • Hemolysis can occur in patients with G6PD deficiency receiving Quinimax (Quinine Hydrochloride).
  • Known hypersensitivity reactions to Quinimax (Quinine Hydrochloride).
    • These include, but are not limited to, the following [see Warnings and Precautions (5.6) ]:
      • Thrombocytopenia
      • Idiopathic thrombocytopenia purpura (ITP) and Thrombotic thrombocytopenic purpura (TTP)
      • Hemolytic uremic syndrome (HUS)
      • Blackwater fever (acute intravascular hemolysis, hemoglobinuria, and hemoglobinemia)
  • Known hypersensitivity to mefloquine or quinidine: cross-sensitivity to Quinimax (Quinine Hydrochloride) has been documented [see Warnings and Precautions (5.6) ].
    • Myasthenia gravis. Quinimax (Quinine Hydrochloride) has neuromuscular blocking activity, and may exacerbate muscle weakness.
    • Optic neuritis. Quinimax (Quinine Hydrochloride) may exacerbate active optic neuritis [see Adverse Reactions (6) ].

Quinimax (Quinine Hydrochloride) is contraindicated in patients with the following:

  • Prolongation of QT interval (4)
  • Glucose-6-phosphate dehydrogenase (G6PD) deficiency (4)
  • Myasthenia gravis (4)
  • Known hypersensitivity to Quinimax (Quinine Hydrochloride), mefloquine, or quinidine (4)
  • Optic neuritis (4)

5 WARNINGS AND PRECAUTIONS

  • Not indicated for the prevention or treatment of nocturnal leg cramps. Risk of serious and life-threatening adverse reactions.
  • Thrombocytopenia, including ITP and HUS/TTP, has been reported. Discontinue drug (5.2).
  • QT prolongation and ventricular arrhythmias. Avoid concomitant use with drugs known to prolong QT interval (5.3).
  • Avoid concomitant use with rifampin. Quinimax (Quinine Hydrochloride) treatment failures have been reported (5.4).
  • Avoid concomitant use with neuromuscular blocking agents. Quinimax (Quinine Hydrochloride) may potentiate neuromuscular blockade and cause respiratory depression (5.5).
  • Serious and life threatening hypersensitivity reactions. Discontinue drug (4, 5.6).
  • Atrial fibrillation and flutter. Paradoxical increase in ventricular rate may occur. Closely monitor digoxin levels if used concomitantly (5.7).
  • Hypoglycemia. Monitor for signs and symptoms (5.8).

5.1 Use of Quinimax (Quinine Hydrochloride) for Treatment or Prevention of Nocturnal Leg Cramps

Quinimax (Quinine Hydrochloride) may cause unpredictable serious and life-threatening hematologic reactions including thrombocytopenia and hemolytic-uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP) in addition to hypersensitivity reactions, QT prolongation, serious cardiac arrhythmias including torsades de pointes, and other serious adverse events requiring medical intervention and hospitalization. Chronic renal impairment associated with the development of TTP, and fatalities have also been reported. The risk associated with the use of Quinimax (Quinine Hydrochloride) in the absence of evidence of its effectiveness for treatment or prevention of nocturnal leg cramps, outweighs any potential benefit in treating and/or preventing this benign, self-limiting condition [see Boxed Warning and Contraindications (4) ].

5.2 Thrombocytopenia

Quinine-induced thrombocytopenia is an immune-mediated disorder. Severe cases of thrombocytopenia that are fatal or life threatening have been reported, including cases of HUS/TTP. Chronic renal impairment associated with the development of TTP has also been reported. Thrombocytopenia usually resolves within a week upon discontinuation of Quinimax. If Quinimax (Quinine Hydrochloride) is not stopped, a patient is at risk for fatal hemorrhage. Upon re-exposure to Quinimax (Quinine Hydrochloride) from any source, a patient with quinine-dependent antibodies could develop thrombocytopenia that is more rapid in onset and more severe than the original episode.

5.3 QT Prolongation and Ventricular Arrhythmias

QT interval prolongation has been a consistent finding in studies which evaluated electrocardiographic changes with oral or parenteral Quinimax (Quinine Hydrochloride) administration, regardless of age, clinical status, or severity of disease. The maximum increase in QT interval has been shown to correspond with peak Quinimax (Quinine Hydrochloride) plasma concentration [see Clinical Pharmacology (12.2) ]. Quinimax (Quinine Hydrochloride) sulfate has been rarely associated with potentially fatal cardiac arrhythmias, including torsades de pointes, and ventricular fibrillation.

Quinimax (Quinine Hydrochloride) has been shown to cause concentration-dependent prolongation of the PR and QRS interval. At particular risk are patients with underlying structural heart disease and preexisting conduction system abnormalities, elderly patients with sick sinus syndrome, patients with atrial fibrillation with slow ventricular response, patients with myocardial ischemia or patients receiving drugs known to prolong the PR interval (e.g. verapamil) or QRS interval (e.g. flecainide or quinidine) [see Clinical Pharmacology (12.2) ].

Quinimax (Quinine Hydrochloride) is not recommended for use with other drugs known to cause QT prolongation, including Class IA antiarrhythmic agents (e.g., quinidine, procainamide, disopyramide), and Class III antiarrhythmic agents (e.g., amiodarone, sotalol, dofetilide).

The use of macrolide antibiotics such as erythromycin should be avoided in patients receiving Quinimax (Quinine Hydrochloride). Fatal torsades de pointes was reported in an elderly patient who received concomitant Quinimax (Quinine Hydrochloride), erythromycin, and dopamine. Although a causal relationship between a specific drug and the arrhythmia was not established in this case, erythromycin is a CYP3A4 inhibitor and has been shown to increase Quinimax (Quinine Hydrochloride) plasma levels when used concomitantly. A related macrolide antibiotic, troleandomycin, has also been shown to increase Quinimax (Quinine Hydrochloride) exposure in a pharmacokinetic study [see Drug Interactions (7.1) ].

Quinimax (Quinine Hydrochloride) may inhibit the metabolism of certain drugs that are CYP3A4 substrates and are known to cause QT prolongation, e.g., astemizole, cisapride, terfenadine, pimozide, halofantrine and quinidine. Torsades de pointes has been reported in patients who received concomitant Quinimax (Quinine Hydrochloride) and astemizole. Therefore, concurrent use of Quinimax (Quinine Hydrochloride) with these medications, or drugs with similar properties, should be avoided [see Drug Interactions (7.2) ].

Concomitant administration of Quinimax (Quinine Hydrochloride) with the antimalarial drugs, mefloquine or halofantrine, may result in electrocardiographic abnormalities, including QT prolongation, and increase the risk for torsades de pointes or other serious ventricular arrhythmias. Concurrent use of Quinimax (Quinine Hydrochloride) and mefloquine may also increase the risk of seizures [see Drug Interactions (7.2) ].

Quinimax (Quinine Hydrochloride) should also be avoided in patients with known prolongation of QT interval and in patients with clinical conditions known to prolong the QT interval, such as uncorrected hypokalemia, bradycardia, and certain cardiac conditions [see Contraindications (4) ].

5.4 Concomitant Use of Rifampin

Treatment failures may result from the concurrent use of rifampin with Quinimax, due to decreased plasma concentrations of Quinimax (Quinine Hydrochloride), and concomitant use of these medications should be avoided [see Drug Interactions (7.1) ].

5.5 Concomitant Use of Neuromuscular Blocking Agents

The use of neuromuscular blocking agents should be avoided in patients receiving Quinimax (Quinine Hydrochloride). In one patient who received pancuronium during an operative procedure, subsequent administration of Quinimax (Quinine Hydrochloride) resulted in respiratory depression and apnea. Although there are no clinical reports with succinylcholine or tubocurarine, Quinimax (Quinine Hydrochloride) may also potentiate neuromuscular blockade when used with these drugs [see Drug Interactions (7.2) ].

5.6 Hypersensitivity

Serious hypersensitivity reactions reported with Quinimax sulfate include anaphylactic shock, anaphylactoid reactions, urticaria, serious skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis, angioedema, facial edema, bronchospasm, and pruritus.

A number of other serious adverse reactions reported with Quinimax (Quinine Hydrochloride), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), thrombocytopenia, immune thrombocytopenic purpura (ITP), blackwater fever, disseminated intravascular coagulation, leukopenia, neutropenia, granulomatous hepatitis, and acute interstitial nephritis may also be due to hypersensitivity reactions.

Quinimax (Quinine Hydrochloride) should be discontinued in case of any signs or symptoms of hypersensitivity [see Contraindications (4) ].

5.7 Atrial Fibrillation and Flutter

Quinimax (Quinine Hydrochloride) should be used with caution in patients with atrial fibrillation or atrial flutter. A paradoxical increase in ventricular response rate may occur with Quinimax (Quinine Hydrochloride), similar to that observed with quinidine. If digoxin is used to prevent a rapid ventricular response, serum digoxin levels should be closely monitored, because digoxin levels may be increased with use of Quinimax (Quinine Hydrochloride) [see Drug Interactions (7.2) ].

5.8 Hypoglycemia

Quinimax (Quinine Hydrochloride) stimulates release of insulin from the pancreas, and patients, especially pregnant women, may experience clinically significant hypoglycemia.

6 ADVERSE REACTIONS

Most common adverse reactions are a cluster of symptoms called "cinchonism", which occurs to some degree in almost all patients taking Quinimax : headache, vasodilation and sweating, nausea, tinnitus, hearing impairment, vertigo or dizziness, blurred vision, disturbance in color perception, vomiting, diarrhea, abdominal pain, deafness, blindness, and disturbances in cardiac rhythm or conduction (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Mutual Pharmaceutical Company, Inc. at 1-888-351-3786 or drugsafetyQuinimax (Quinine Hydrochloride)urlpharma.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Overall

Quinimax (Quinine Hydrochloride) can adversely affect almost every body system. The most common adverse events associated with Quinimax (Quinine Hydrochloride) use are a cluster of symptoms called "cinchonism", which occurs to some degree in almost all patients taking Quinimax (Quinine Hydrochloride). Symptoms of mild cinchonism include headache, vasodilation and sweating, nausea, tinnitus, hearing impairment, vertigo or dizziness, blurred vision, and disturbance in color perception. More severe symptoms of cinchonism are vomiting, diarrhea, abdominal pain, deafness, blindness, and disturbances in cardiac rhythm or conduction. Most symptoms of cinchonism are reversible and resolve with discontinuation of Quinimax (Quinine Hydrochloride).

The following ADVERSE REACTIONS have been reported with Quinimax (Quinine Hydrochloride) sulfate. Most of these reactions are thought to be uncommon, but the actual incidence is unknown:

General: fever, chills, sweating, flushing, asthenia, lupus-like syndrome, and hypersensitivity reactions.

Hematologic: agranulocytosis, hypoprothrombinemia, thrombocytopenia, disseminated intravascular coagulation, hemolytic anemia; hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, petechiae, ecchymosis, hemorrhage, coagulopathy, blackwater fever, leukopenia, neutropenia, pancytopenia, aplastic anemia, and lupus anticoagulant.

Neuropsychiatric: headache, diplopia, confusion, altered mental status, seizures, coma, disorientation, tremors, restlessness, ataxia, acute dystonic reaction, aphasia, and suicide.

Dermatologic: cutaneous rashes, including urticarial, papular, or scarlatinal rashes, pruritus, bullous dermatitis, exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, fixed drug eruption, photosensitivity reactions, allergic contact dermatitis, acral necrosis, and cutaneous vasculitis.

Respiratory: asthma, dyspnea, pulmonary edema.

Cardiovascular: chest pain, vasodilatation, hypotension, postural hypotension, tachycardia, bradycardia, palpitations, syncope, atrioventricular block, atrial fibrillation, irregular rhythm, unifocal premature ventricular contractions, nodal escape beats, U waves, QT prolongation, ventricular fibrillation, ventricular tachycardia, torsades de pointes, and cardiac arrest.

Gastrointestinal: nausea, vomiting, diarrhea, abdominal pain, gastric irritation, and esophagitis.

Hepatobiliary: granulomatous hepatitis, hepatitis, jaundice, and abnormal liver function tests.

Metabolic: hypoglycemia and anorexia.

Musculoskeletal: myalgias and muscle weakness.

Renal: hemoglobinuria, renal failure, renal impairment, and acute interstitial nephritis.

Special Senses: visual disturbances, including blurred vision with scotomata, sudden loss of vision, photophobia, diplopia, night blindness, diminished visual fields, fixed pupillary dilatation, disturbed color vision, optic neuritis, blindness, vertigo, tinnitus, hearing impairment, and deafness.

7 DRUG INTERACTIONS

Interacting Drug Interaction
Drugs known to prolong QT interval. Quinimax (Quinine Hydrochloride) prolongs QT interval, ECG abnormalities including QT prolongation and Torsades de Pointes. Avoid concomitant use (5.3).
Other antimalarials (e.g., halofantrine, mefloquine). ECG abnormalities including QT prolongation. Avoid concomitant use (5.3, 7.2).
CYP3A4 inducers or inhibitors Alteration in plasma Quinimax (Quinine Hydrochloride) concentration. Monitor for lack of efficacy or increased adverse events of Quinimax (Quinine Hydrochloride) (7.1).
CYP3A4 and CYP2D6 substrates Quinimax (Quinine Hydrochloride) is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug (7.2).
Digoxin Increased digoxin plasma concentration (5.8, 7.1).

7.1 Effects of Drugs and Other Substances on Quinimax (Quinine Hydrochloride) Pharmacokinetics

Quinimax (Quinine Hydrochloride) is a P-gp substrate and is primarily metabolized by CYP3A4. Other enzymes, including CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1 may contribute to the metabolism of Quinimax (Quinine Hydrochloride) [see Clinical Pharmacology (12.3) ].

Antacids: Antacids containing aluminum and/or magnesium may delay or decrease absorption of Quinimax (Quinine Hydrochloride). Concomitant administration of these antacids with Quinimax (Quinine Hydrochloride) should be avoided.

Antiepileptics (AEDs) (carbamazepine, phenobarbital, and phenytoin): Carbamazepine, phenobarbital, and phenytoin are CYP3A4 inducers and may decrease Quinimax (Quinine Hydrochloride) plasma concentrations if used concurrently with Quinimax (Quinine Hydrochloride).

Cholestyramine: In 8 healthy subjects who received Quinimax (Quinine Hydrochloride) sulfate 600 mg with or without 8 grams of cholestyramine resin, no significant difference in Quinimax (Quinine Hydrochloride) pharmacokinetic parameters was seen.

Cigarette Smoking (CYP1A2 inducer): In healthy male heavy smokers, the mean Quinimax (Quinine Hydrochloride) AUC following a single 600 mg dose was 44% lower, the mean Cmax was 18% lower, and the elimination half-life was shorter (7.5 hours versus 12 hours) than in their non-smoking counterparts. However, in malaria patients who received the full 7-day course of Quinimax (Quinine Hydrochloride) therapy, cigarette smoking produced only a 25% decrease in median Quinimax (Quinine Hydrochloride) AUC and a 16.5% decrease in median Cmax, suggesting that the already reduced clearance of Quinimax (Quinine Hydrochloride) in acute malaria could have diminished the metabolic induction effect of smoking. Because smoking did not appear to influence the therapeutic outcome in malaria patients, it is not necessary to increase the dose of Quinimax (Quinine Hydrochloride) in the treatment of acute malaria in heavy cigarette smokers.

Grapefruit juice (P-gp/CYP3A4 inhibitor): In a pharmacokinetic study involving 10 healthy subjects, the administration of a single 600 mg dose of Quinimax (Quinine Hydrochloride) sulfate with grapefruit juice (full-strength or half-strength) did not significantly alter the pharmacokinetic parameters of Quinimax (Quinine Hydrochloride). Quinimax (Quinine Hydrochloride) may be taken with grapefruit juice.

Histamine H2-receptor blockers [cimetidine, ranitidine (nonspecific CYP450 inhibitors)]: In healthy subjects who were given a single oral 600 mg dose of Quinimax (Quinine Hydrochloride) sulfate after pretreatment with cimetidine (200 mg three times daily and 400 mg at bedtime for 7 days) or ranitidine (150 mg twice daily for 7 days), the apparent oral clearance of Quinimax (Quinine Hydrochloride) decreased and the mean elimination half-life increased significantly when given with cimetidine but not with ranitidine. Compared to untreated controls, the mean AUC of Quinimax (Quinine Hydrochloride) increased by 20% with ranitidine and by 42% with cimetidine (p<0.05) without a significant change in mean Quinimax (Quinine Hydrochloride) Cmax. When Quinimax (Quinine Hydrochloride) is to be given concomitantly with a histamine H2-receptor blocker, the use of ranitidine is preferred over cimetidine. Although cimetidine and ranitidine may be used concomitantly with Quinimax (Quinine Hydrochloride), patients should be monitored closely for adverse events associated with Quinimax (Quinine Hydrochloride).

Isoniazid: Isoniazid 300 mg/day pretreatment for 1 week did not significantly alter the pharmacokinetic parameter values of Quinimax (Quinine Hydrochloride). Adjustment of Quinimax (Quinine Hydrochloride) dosage is not necessary when isoniazid is given concomitantly.

Ketoconazole (CYP3A4 inhibitor): In a crossover study, healthy subjects (N=9) who received a single oral dose of Quinimax (Quinine Hydrochloride) hydrochloride (500 mg) concomitantly with ketoconazole (100 mg twice daily for 3 days) had a mean Quinimax (Quinine Hydrochloride) AUC that was higher by 45% and a mean oral clearance of Quinimax (Quinine Hydrochloride) that was 31% lower than after receiving Quinimax (Quinine Hydrochloride) alone. Although no change in the Quinimax (Quinine Hydrochloride) dosage regimen is necessary with concomitant ketoconazole, patients should be monitored closely for adverse reactions associated with Quinimax (Quinine Hydrochloride).

Macrolide antibiotics (erythromycin, troleandomycin) (CYP3A4 inhibitors): In a crossover study (N=10), healthy subjects who received a single oral 600 mg dose of Quinimax (Quinine Hydrochloride) sulfate with the macrolide antibiotic, troleandomycin (500 mg every 8 hours) exhibited a 87% higher mean Quinimax (Quinine Hydrochloride) AUC, a 45% lower mean oral clearance of Quinimax (Quinine Hydrochloride), and a 81% lower formation clearance of the main metabolite, 3-hydroxyquinine, than when Quinimax (Quinine Hydrochloride) was given alone.

Erythromycin was shown to inhibit the in vitro metabolism of Quinimax (Quinine Hydrochloride) in human liver microsomes, an observation confirmed by an in vivo interaction study. In a crossover study (N=10), healthy subjects who received a single oral 500 mg dose of Quinimax (Quinine Hydrochloride) sulfate with erythromycin (600 mg every 8 hours for four days) showed a decrease in Quinimax (Quinine Hydrochloride) oral clearance (CL/F), an increase in half-life, and a decreased metabolite (3-hydroxyquinine) to Quinimax (Quinine Hydrochloride) AUC ratio, as compared to when Quinimax (Quinine Hydrochloride) was given with placebo.

Therefore, concomitant administration of macrolide antibiotics such as erythromycin or troleandomycin with Quinimax (Quinine Hydrochloride) should be avoided [see Warnings and Precautions (5.3) ].

Oral contraceptives (estrogen, progestin): In 7 healthy females who were using single-ingredient progestin or combination estrogen-containing oral contraceptives, the pharmacokinetic parameters of a single 600 mg dose of Quinimax (Quinine Hydrochloride) sulfate were not altered in comparison to those observed in 7 age-matched female control subjects not using oral contraceptives.

Rifampin (CYP3A4 inducer): In patients with uncomplicated P. falciparum malaria who received Quinimax (Quinine Hydrochloride) sulfate 10 mg/kg concomitantly with rifampin 15 mg/kg/day for 7 days (N=29), the median AUC of Quinimax (Quinine Hydrochloride) between days 3 and 7 of therapy was 75% lower as compared to those who received Quinimax (Quinine Hydrochloride) monotherapy. In healthy subjects (N=9) who received a single oral 600 mg dose of Quinimax (Quinine Hydrochloride) sulfate after 2 weeks of pretreatment with rifampin 600 mg/day, the mean Quinimax (Quinine Hydrochloride) AUC and Cmax decreased by 85% and 55%, respectively. Therefore, the concomitant administration of rifampin with Quinimax (Quinine Hydrochloride) should be avoided [see Warnings and Precautions (5.4) ].

Ritonavir: In healthy subjects who received a single oral 600 mg dose of Quinimax (Quinine Hydrochloride) sulfate with the 15th dose of ritonavir (200 mg every 12 hours for 9 days), there were 4-fold increases in the mean Quinimax (Quinine Hydrochloride) AUC and Cmax, and an increase in the mean elimination half-life (13.4 hours versus 11.2 hours), compared to when Quinimax (Quinine Hydrochloride) was given alone. Therefore, the concomitant administration of ritonavir with Quinimax (Quinine Hydrochloride) capsules should be avoided [see also Drug Interactions (7.2) ].

Tetracycline: In 8 patients with acute uncomplicated P. falciparum malaria who were treated with oral Quinimax (Quinine Hydrochloride) sulfate (600 mg every 8 hours for 7 days) in combination with oral tetracycline (250 mg every 6 hours for 7 days), the mean plasma Quinimax (Quinine Hydrochloride) concentrations were about two-fold higher than in 8 patients who received Quinimax (Quinine Hydrochloride) monotherapy. Although tetracycline may be concomitantly administered with Quinimax (Quinine Hydrochloride), patients should be monitored closely for adverse reactions associated with Quinimax (Quinine Hydrochloride) sulfate.

Theophylline or aminophylline: In 20 healthy subjects who received multiple doses of Quinimax (Quinine Hydrochloride) (648 mg every 8 hours × 7 days) with a single 300 mg oral dose of theophylline, the Quinimax (Quinine Hydrochloride) mean Cmax and AUC were increased by 13% and 14% respectively. Although no change in the Quinimax (Quinine Hydrochloride) dosage regimen is necessary with concomitant theophylline or aminophylline, patients should be monitored closely for adverse reactions associated with Quinimax (Quinine Hydrochloride).

Urinary alkalizers (acetazolamide, sodium bicarbonate): Urinary alkalinizing agents may increase plasma Quinimax (Quinine Hydrochloride) concentrations.

7.2 Effects of Quinimax on the Pharmacokinetics of Other Drugs

Results of in vivo drug interaction studies suggest that Quinimax (Quinine Hydrochloride) has the potential to inhibit the metabolism of drugs that are substrates of CYP3A4 and CYP2D6. Quinimax (Quinine Hydrochloride) inhibits P-gp and has the potential to affect the transport of drugs that are P-gp substrates.

Anticonvulsants (carbamazepine, phenobarbital, and phenytoin): A single 600 mg oral dose of Quinimax (Quinine Hydrochloride) sulfate increased the mean plasma Cmax, and AUC0–24 of single oral doses of carbamazepine (200 mg) and phenobarbital (120 mg) but not phenytoin (200 mg) in 8 healthy subjects. The mean AUC increases of carbamazepine, phenobarbital and phenytoin were 104%, 81% and 4%, respectively; the mean increases in Cmax were 56%, 53%, and 4%, respectively. Mean urinary recoveries of the three antiepileptics over 24 hours were also profoundly increased by Quinimax (Quinine Hydrochloride). If concomitant administration with carbamazepine or phenobarbital cannot be avoided, frequent monitoring of anticonvulsant drug concentrations is recommended. Additionally, patients should be monitored closely for adverse reactions associated with these anticonvulsants.

Astemizole (CYP3A4 substrate): Elevated plasma astemizole concentrations were reported in a subject who experienced torsades de pointes after receiving three doses of Quinimax (Quinine Hydrochloride) sulfate for nocturnal leg cramps concomitantly with chronic astemizole 10 mg/day. The concurrent use of Quinimax (Quinine Hydrochloride) with astemizole and other CYP3A4 substrates with QT prolongation potential (e.g., cisapride, terfenadine, halofantrine, pimozide and quinidine) should also be avoided [see Warnings and Precautions (5.3) ].

Atorvastatin (CYP3A4 substrate): Rhabdomyolysis with acute renal failure secondary to myoglobinuria was reported in a patient taking atorvastatin administered with a single dose of Quinimax (Quinine Hydrochloride). Quinimax (Quinine Hydrochloride) may increase plasma concentrations of atorvastatin, thereby increasing the risk of myopathy or rhabdomyolysis. Thus, clinicians considering combined therapy of Quinimax (Quinine Hydrochloride) with atorvastatin or other HMG-CoA reductase inhibitors ("statins") that are CYP3A4 substrates (e.g., simvastatin, lovastatin) should carefully weigh the potential benefits and risks of each medication. If Quinimax (Quinine Hydrochloride) is used concomitantly with any of these statins, lower starting and maintenance doses of the statin should be considered. Patients should also be monitored closely for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy. If marked creatine phosphokinase (CPK) elevation occurs or myopathy (defined as muscle aches or muscle weakness in conjunction with CPK values >10 times the upper limit of normal) is diagnosed or suspected, atorvastatin or other statin should be discontinued.

Desipramine (CYP2D6 substrate): Quinimax (Quinine Hydrochloride) (750 mg/day for 2 days) decreased the metabolism of desipramine in patients who were extensive CYP2D6 metabolizers, but had no effect in patients who were poor CYP2D6 metabolizers. Lower doses (80 mg to 400 mg) of Quinimax (Quinine Hydrochloride) did not significantly affect the pharmacokinetics of other CYP2D6 substrates, namely, debrisoquine, dextromethorphan, and methoxyphenamine. Although clinical drug interaction studies have not been performed, antimalarial doses (greater than or equal to 600 mg) of Quinimax (Quinine Hydrochloride) may inhibit the metabolism of other drugs that are CYP2D6 substrates (e.g., flecainide, debrisoquine, dextromethorphan, metoprolol, paroxetine). Patients taking medications that are CYP2D6 substrates with Quinimax (Quinine Hydrochloride) should be monitored closely for adverse reactions associated with these medications.

Digoxin (P-gp substrate): In 4 healthy subjects who received digoxin (0.5 to 0.75 mg/day) during treatment with Quinimax (Quinine Hydrochloride) (750 mg/day), a 33% increase in mean steady state AUC of digoxin and a 35% reduction in the steady state biliary clearance of digoxin were observed compared to digoxin alone. Thus, if Quinimax (Quinine Hydrochloride) is administered to patients receiving digoxin, plasma digoxin concentrations should be closely monitored, and the digoxin dose adjusted, as necessary [see Warnings and Precautions (5.7) ].

Halofantrine: Although not studied clinically, Quinimax (Quinine Hydrochloride) was shown to inhibit the metabolism of halofantrine in vitro using human liver microsomes. Therefore, concomitant administration of Quinimax (Quinine Hydrochloride) is likely to increase plasma halofantrine concentrations [see Warnings and Precautions (5.3) ].

Mefloquine: In 7 healthy subjects who received mefloquine (750 mg) at 24 hours before an oral 600 mg dose of Quinimax (Quinine Hydrochloride) sulfate, the AUC of mefloquine was increased by 22% compared to mefloquine alone. In this study, the QTc interval was significantly prolonged in the subjects who received mefloquine and Quinimax (Quinine Hydrochloride) sulfate 24 hours apart. The concomitant administration of mefloquine and Quinimax (Quinine Hydrochloride) may produce electrocardiographic abnormalities (including QTc prolongation) and may increase the risk of seizures [see Warnings and Precautions (5.3) ].

Midazolam (CYP3A4 substrate): In 23 healthy subjects who received multiple doses of Quinimax (Quinine Hydrochloride) 324 mg three times daily × 7 days with a single oral 2 mg dose of midazolam, the mean AUC and Cmax of midazolam and 1-hydroxymidazolam were not significantly affected. This finding indicates that 7-day dosing with Quinimax (Quinine Hydrochloride) 324 mg every 8 hours did not induce the metabolism of midazolam.

Neuromuscular blocking agents (pancuronium, succinylcholine, tubocurarine): In one report, Quinimax (Quinine Hydrochloride) potentiated neuromuscular blockade in a patient who received pancuronium during an operative procedure, and subsequently (3 hours after receiving pancuronium) received Quinimax (Quinine Hydrochloride) 1800 mg daily. Quinimax (Quinine Hydrochloride) may also enhance the neuromuscular blocking effects of succinylcholine and tubocurarine [see Warnings and Precautions (5.5) ].

Ritonavir: In healthy subjects who received a single oral 600 mg dose of Quinimax (Quinine Hydrochloride) sulfate with the 15th dose of ritonavir (200 mg every 12 hours for 9 days), the mean ritonavir AUC, Cmax, and elimination half-life were slightly but not significantly increased compared to when ritonavir was given alone. However, due to the significant effect of ritonavir on Quinimax (Quinine Hydrochloride) pharmacokinetics, the concomitant administration of Quinimax (Quinine Hydrochloride) capsules with ritonavir should be avoided [see also Drug Interactions (7.1) ].

Theophylline or aminophylline (CYP1A2 substrate): In 19 healthy subjects who received multiple doses of Quinimax (Quinine Hydrochloride) 648 mg every 8 hours x 7 days with a single 300 mg oral dose of theophylline, the mean theophylline AUC was 10% lower than when theophylline was given alone. There was no significant effect on mean theophylline Cmax. Therefore, if Quinimax (Quinine Hydrochloride) is co-administered to patients receiving theophylline or aminophylline, plasma theophylline concentrations should be monitored frequently to ensure therapeutic concentrations.

Warfarin and oral anticoagulants: Cinchona alkaloids, including Quinimax (Quinine Hydrochloride), may have the potential to depress hepatic enzyme synthesis of vitamin K-dependent coagulation pathway proteins and may enhance the action of warfarin and other oral anticoagulants. Quinimax (Quinine Hydrochloride) may also interfere with the anticoagulant effect of heparin. Thus, in patients receiving these anticoagulants, the prothrombin time (PT), partial thromboplastin time (PTT), or international normalization ratio (INR) should be closely monitored as appropriate, during concurrent therapy with Quinimax (Quinine Hydrochloride).

7.3 Drug/Laboratory Interactions

Quinimax (Quinine Hydrochloride) may produce an elevated value for urinary 17-ketogenic steroids when the Zimmerman method is used.

Quinimax (Quinine Hydrochloride) may interfere with urine qualitative dipstick protein assays as well as quantitative methods (e.g., pyrogallol red-molybdate).

8 USE IN SPECIFIC POPULATIONS

  • Renal impairment: Reduce dose and dosing frequency for patients with severe chronic renal impairment.
  • Hepatic impairment: Closely monitor for adverse events. Quinimax (Quinine Hydrochloride) should not be administered in patients with severe (Child-Pugh C) hepatic impairment (2.3, 8.7, 12.3).
  • Pregnancy: Based on animal data may cause fetal harm. Use only if the potential benefit justifies the risk (8.1).
  • Nursing Mothers: Exercise caution when administering to a nursing woman (8.3).

8.1 Pregnancy

Pregnancy Category C

There are extensive published data but few well-controlled studies of Quinimax (Quinine Hydrochloride) in pregnant women. Published data on over 1,000 pregnancy exposures to Quinimax (Quinine Hydrochloride) did not show an increase in teratogenic effects over the background rate in the general population; however, the majority of these exposures were not in the first trimester. In developmental and reproductive toxicity studies, central nervous system (CNS) and ear abnormalities and increased fetal deaths occurred in some species when pregnant animals received Quinimax (Quinine Hydrochloride) at doses about 1 to 4 times the human clinical dose. Quinimax (Quinine Hydrochloride) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

P. falciparum malaria carries a higher risk of morbidity and mortality in pregnant women than in the general population. Pregnant women with P. falciparum malaria have an increased incidence of fetal loss (including spontaneous abortion and stillbirth), preterm labor and delivery, intrauterine growth retardation, low birth weight, and maternal death. Therefore, treatment of malaria in pregnancy is important.

Hypoglycemia, due to increased pancreatic secretion of insulin, has been associated with Quinimax (Quinine Hydrochloride) use, particularly in pregnant women.

Quinimax (Quinine Hydrochloride) crosses the placenta with measurable blood concentrations in the fetus. In 8 women who delivered live infants 1 to 6 days after starting Quinimax (Quinine Hydrochloride) therapy, umbilical cord plasma Quinimax (Quinine Hydrochloride) concentrations were between 1.0 and 4.6 mg/L (mean 2.4 mg/L) and the mean (±SD) ratio of cord plasma to maternal plasma Quinimax (Quinine Hydrochloride) concentrations was 0.32 ± 0.14. Quinimax (Quinine Hydrochloride) levels in the fetus may not be therapeutic. If congenital malaria is suspected after delivery, the infant should be evaluated and treated appropriately.

A study from Thailand (1999) of women with P. falciparum malaria who were treated with oral Quinimax (Quinine Hydrochloride) sulfate 10 mg/kg 3 times daily for 7 days at anytime in pregnancy reported no significant difference in the rate of stillbirths at >28 weeks of gestation in women treated with Quinimax (Quinine Hydrochloride) (10 of 633 women [1.6%]) as compared with a control group without malaria or exposure to antimalarial drugs during pregnancy (40 of 2201 women [1.8%]). The overall rate of congenital malformations (9 of 633 offspring [1.4%]) was not different for women who were treated with Quinimax (Quinine Hydrochloride) sulfate compared with the control group (38 of 2201 offspring [1.7%]). The spontaneous abortion rate was higher in the control group (10.9%) than in women treated with Quinimax (Quinine Hydrochloride) sulfate (3.5%) [OR = 3.1; 95% CI 2.1-4.7]. An epidemiologic survey that included 104 mother-child pairs exposed to Quinimax (Quinine Hydrochloride) during the first 4 months of pregnancy, found no increased risk of structural birth defects was seen (2 fetal malformations [1.9%]). Rare and isolated case reports describe deafness and optic nerve hypoplasia in children exposed in utero due to maternal ingestion of high doses of Quinimax (Quinine Hydrochloride).

In animal developmental studies conducted in multiple animal species, pregnant animals received Quinimax (Quinine Hydrochloride) by the subcutaneous or intramuscular route at dose levels similar to the maximum recommended human dose (MRHD; 32 mg/kg/day) based on body surface area (BSA) comparisons. There were increases in fetal death in utero in rabbits at maternal doses ≥ 100 mg/kg/day and in dogs at ≥ 15 mg/kg/day corresponding to dose levels approximately 0.5 and 0.25 times the MRHD respectively based on BSA comparisons. Rabbit offspring had increased rates of degenerated auditory nerve and spiral ganglion and increased rates of CNS anomalies such as anencephaly and microcephaly at a dose of 130 mg/kg/day corresponding to a maternal dose approximately 1.3 times the MRHD based on BSA comparison. Guinea pig offspring had increased rates of hemorrhage and mitochondrial change in the cochlea at maternal doses of 200 mg/kg corresponding to a dose level of approximately 1.4 times the MRHD based on BSA comparison. There were no teratogenic findings in rats at maternal doses up to 300 mg/kg/day and in monkeys at doses up to 200 mg/kg/day corresponding to doses approximately 1 and 2 times the MRHD respectively based on BSA comparisons.

In a pre- postnatal study in rats, an estimated oral dose of Quinimax (Quinine Hydrochloride) sulfate of 20 mg/kg/day corresponding to approximately 0.1 times the MRHD based on BSA comparison resulted in offspring with impaired growth, lower body weights at birth and during the lactation period, and delayed physical development of teeth eruption and eye opening during the lactation period.

8.2 Labor and Delivery

There is no evidence that Quinimax causes uterine contractions at the doses recommended for the treatment of malaria. In doses several-times higher than those used to treat malaria, Quinimax (Quinine Hydrochloride) may stimulate the pregnant uterus.

8.3 Nursing Mothers

There is limited information on the safety of Quinimax (Quinine Hydrochloride) in breastfed infants. No toxicity was reported in infants in a single study where oral Quinimax (Quinine Hydrochloride) sulfate (10 mg/kg every 8 hours for 1 to 10 days) was administered to 25 lactating women. It is estimated from this study that breastfed infants would receive less than 2 to 3 mg per day of Quinimax (Quinine Hydrochloride) base (< 0.4% of the maternal dose) via breast milk [see Clinical Pharmacology (12.3) ].

Although Quinimax (Quinine Hydrochloride) is generally considered compatible with breastfeeding, the risks and benefits to infant and mother should be assessed. Caution should be exercised when administered to a nursing woman.

If malaria is suspected in the infant, appropriate evaluation and treatment should be provided. Plasma Quinimax (Quinine Hydrochloride) levels may not be therapeutic in infants of nursing mothers receiving Quinimax (Quinine Hydrochloride).

8.4 Pediatric Use

The safety and efficacy of Quinimax in pediatric patients under the age of 16 has not been established.

8.5 Geriatric Use

Clinical studies of Quinimax (Quinine Hydrochloride) sulfate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond to treatment differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

8.6 Renal Impairment

Clearance of Quinimax is decreased in patients with severe chronic renal failure. The dosage and dosing frequency should be reduced [see Dosage and Administration (2.2), Clinical Pharmacology (12.3) ].

8.7 Hepatic Impairment

In patients with severe hepatic impairment (Child-Pugh C), Quinimax (Quinine Hydrochloride) oral clearance (CL/F) is decreased, volume of distribution (Vd/F) is increased, and half-life is prolonged, relative to subjects with normal liver function. Therefore, Quinimax (Quinine Hydrochloride) is not indicated in patients with severe hepatic impairment and alternate therapy should be administered [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ].

Close monitoring is recommended for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, as exposure to Quinimax (Quinine Hydrochloride) may be increased relative to subjects with normal liver function [see Clinical Pharmacology (12.3) ].

10 OVERDOSAGE

Quinimax (Quinine Hydrochloride) overdose can be associated with serious complications, including visual impairment, hypoglycemia, cardiac arrhythmias, and death. Visual impairment can range from blurred vision and defective color perception, to visual field constriction and permanent blindness. Cinchonism occurs in virtually all patients with Quinimax (Quinine Hydrochloride) overdose. Symptoms range from headache, nausea, vomiting, abdominal pain, diarrhea, tinnitus, vertigo, hearing impairment, sweating, flushing, and blurred vision, to deafness, blindness, serious cardiac arrhythmias, hypotension, and circulatory collapse. Central nervous system toxicity (drowsiness, disturbances of consciousness, ataxia, convulsions, respiratory depression and coma) has also been reported with Quinimax (Quinine Hydrochloride) overdose, as well as pulmonary edema and adult respiratory distress syndrome.

Most toxic reactions are dose-related; however, some reactions may be idiosyncratic because of the variable sensitivity of patients to the toxic effects of Quinimax (Quinine Hydrochloride). A lethal dose of Quinimax (Quinine Hydrochloride) has not been clearly defined, but fatalities have been reported after the ingestion of 2 to 8 grams in adults.

Quinimax (Quinine Hydrochloride), like quinidine, has Class I antiarrhythmic properties. The cardiotoxicity of Quinimax (Quinine Hydrochloride) is due to its negative inotropic action, and to its effect on cardiac conduction, resulting in decreased rates of depolarization and conduction, and increased action potential and effective refractory period. ECG changes observed with Quinimax (Quinine Hydrochloride) overdose include sinus tachycardia, PR prolongation, T wave inversion, bundle branch block, an increased QT interval, and a widening of the QRS complex. Quinine's alpha-blocking properties may result in hypotension and further exacerbate myocardial depression by decreasing coronary perfusion. Quinimax (Quinine Hydrochloride) overdose has been also associated with hypotension, cardiogenic shock, and circulatory collapse, ventricular arrhythmias, including ventricular tachycardia, ventricular fibrillation, idioventricular rhythm, and torsades de pointes, as well as bradycardia, and atrioventricular block [see Warnings and Precautions (5), Clinical Pharmacology (12.3) ].

Quinimax (Quinine Hydrochloride) is rapidly absorbed, and attempts to remove residual Quinimax (Quinine Hydrochloride) sulfate from the stomach by gastric lavage may not be effective. Multiple-dose activated charcoal has been shown to decrease plasma Quinimax (Quinine Hydrochloride) concentrations [see Clinical Pharmacology (12.3) ].

Forced acid diuresis, hemodialysis, charcoal column hemoperfusion, and plasma exchange were not found to be effective in significantly increasing Quinimax (Quinine Hydrochloride) elimination in a series of 16 patients.

11 DESCRIPTION

Quinimax (Quinine Hydrochloride) (quinine sulfate) is a cinchona alkaloid chemically described as cinchonan-9-ol, 6'-methoxy-, (8α, 9R)-, sulfate (2:1) (salt), dihydrate with a molecular formula of (C20H24N2O2)2-H2SO4-2H2O and a molecular weight of 782.96.

The structural formula of Quinimax (Quinine Hydrochloride) sulfate is:

Quinimax (Quinine Hydrochloride) sulfate occurs as a white, crystalline powder that darkens on exposure to light. It is odorless and has a persistent very bitter taste. It is only slightly soluble in water, alcohol, chloroform, and ether.

Quinimax (Quinine Hydrochloride) is supplied for oral administration as capsules containing 324 mg of the active ingredient Quinimax (Quinine Hydrochloride) sulfate USP, equivalent to 269 mg free base. Inactive ingredients: corn starch, magnesium stearate, and talc.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Quinimax is an antimalarial agent [see Clinical Pharmacology (12.4) ].

12.2 Pharmacodynamics

QTc interval prolongation was studied in a double-blind, multiple dose, placebo- and positive-controlled crossover study in young (N=13, 20 to 39 years) and elderly (N=13, 65 to 78 years) subjects. After 7 days of dosing with Quinimax (Quinine Hydrochloride) 648 mg three times daily, the maximum mean (95% upper confidence bound) differences in QTcI from placebo after baseline correction was 27.7 (32.2) ms.

Prolongation of the PR and QRS interval was also noted in subjects receiving Quinimax (Quinine Hydrochloride). The maximum mean (95% upper confidence bound) difference in PR from placebo after baseline-correction was 14.5 (18.0) ms. The maximum mean (95% upper confidence bound) difference in QRS from placebo after baseline-correction was 11.5 (13.3) ms. [see Warnings and Precautions (5.3) ].

12.3 Pharmacokinetics

Absorption

The oral bioavailability of Quinimax is 76 to 88% in healthy adults. Quinimax (Quinine Hydrochloride) exposure is higher in patients with malaria than in healthy subjects. After a single oral dose of Quinimax (Quinine Hydrochloride) sulfate, the mean Quinimax (Quinine Hydrochloride) Tmax was longer, and mean AUC and Cmax were higher in patients with uncomplicated P. falciparum malaria than in healthy subjects, as shown in Table 1 below.

Healthy Subjects

(N = 23)

Mean ± SD

Uncomplicated P. falciparum Malaria Patients

(N = 15)

Mean ± SD

Dose (mg/kg)Quinimax (Quinine Hydrochloride) Sulfate dose was 648 mg (approximately 8.7 mg/kg) in healthy subjects; and 10 mg/kg in patients with malaria 8.7 10
Tmax (h) 2.8 ± 0.8 5.9 ± 4.7
Cmax (mcg/mL) 3.2 ± 0.7 8.4
AUC0–12 (mcg*h/mL) 28.0 73.0

Quinimax (Quinine Hydrochloride) capsules may be administered without regard to meals. When a single oral 324 mg capsule of Quinimax (Quinine Hydrochloride) was administered to healthy subjects (N=26) with a standardized high-fat breakfast, the mean Tmax of Quinimax (Quinine Hydrochloride) was prolonged to about 4.0 hours, but the mean Cmax and AUC0-24h were similar to those achieved when Quinimax (Quinine Hydrochloride) capsule was given under fasted conditions [see Dosage and Administration (2.1) ].

Distribution

In patients with malaria, the volume of distribution (Vd/F) decreases in proportion to the severity of the infection. In published studies with healthy subjects who received a single oral 600 mg dose of Quinimax (Quinine Hydrochloride) sulfate, the mean Vd/F ranged from 2.5 to 7.1 L/kg.

Quinimax (Quinine Hydrochloride) is moderately protein-bound in blood in healthy subjects, ranging from 69 to 92%. During active malarial infection, protein binding of Quinimax (Quinine Hydrochloride) is increased to 78 to 95%, corresponding to the increase in α1-acid glycoprotein that occurs with malaria infection.

Intra-erythrocytic levels of Quinimax (Quinine Hydrochloride) are approximately 30 to 50% of the plasma concentration.

Quinimax (Quinine Hydrochloride) penetrates relatively poorly into the cerebrospinal fluid (CSF) in patients with cerebral malaria, with CSF concentration approximately 2 to 7% of plasma concentration.

In one study, Quinimax (Quinine Hydrochloride) concentrations in placental cord blood and breast milk were approximately 32% and 31%, respectively, of Quinimax (Quinine Hydrochloride) concentrations in maternal plasma. The estimated total dose of Quinimax (Quinine Hydrochloride) secreted into breast milk was less than 2 to 3 mg per day [see Use in Specific Populations (8.1, 8.3) ].

Metabolism

Quinimax (Quinine Hydrochloride) is metabolized almost exclusively via hepatic oxidative cytochrome P450 (CYP) pathways, resulting in four primary metabolites, 3-hydroxyquinine, 2´-quinone, O-desmethylquinine, and 10,11-dihydroxydihydroquinine. Six secondary metabolites result from further biotransformation of the primary metabolites. The major metabolite, 3-hydroxyquinine, is less active than the parent drug.

In vitro studies using human liver microsomes and recombinant P450 enzymes have shown that Quinimax (Quinine Hydrochloride) is metabolized mainly by CYP3A4. Depending on the in vitro experimental conditions, other enzymes, including CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1 were shown to have some role in the metabolism of Quinimax (Quinine Hydrochloride).

Elimination/Excretion

Quinimax (Quinine Hydrochloride) is eliminated primarily via hepatic biotransformation. Approximately 20% of Quinimax (Quinine Hydrochloride) is excreted unchanged in urine. Because Quinimax (Quinine Hydrochloride) is reabsorbed when the urine is alkaline, renal excretion of the drug is twice as rapid when the urine is acidic than when it is alkaline.

In various published studies, healthy subjects who received a single oral 600 mg dose of Quinimax (Quinine Hydrochloride) sulfate exhibited a mean plasma clearance ranging from 0.08 to 0.47 L/h/kg (median value: 0.17 L/h/kg) with a mean plasma elimination half-life of 9.7 to 12.5 hours.

In 15 patients with uncomplicated malaria who received a 10 mg/kg oral dose of Quinimax (Quinine Hydrochloride) sulfate, the mean total clearance of Quinimax (Quinine Hydrochloride) was slower (approximately 0.09 L/h/kg) during the acute phase of the infection, and faster (approximately 0.16 L/h/kg) during the recovery or convalescent phase.

Extracorporeal Elimination: Administration of multiple-dose activated charcoal (50 grams administered 4 hours after Quinimax (Quinine Hydrochloride) dosing followed by 3 further doses over the next 12 hours) decreased the mean Quinimax (Quinine Hydrochloride) elimination half-life from 8.2 to 4.6 hours, and increased the mean Quinimax (Quinine Hydrochloride) clearance by 56% (from 11.8 L/h to 18.4 L/h) in 7 healthy adult subjects who received a single oral 600 mg dose of Quinimax (Quinine Hydrochloride) sulfate. Likewise, in 5 symptomatic patients with acute Quinimax (Quinine Hydrochloride) poisoning who received multiple-dose activated charcoal (50 grams every 4 hours), the mean Quinimax (Quinine Hydrochloride) elimination half-life was shortened to 8.1 hours in comparison to a half-life of approximately 26 hours in patients who did not receive activated charcoal [see Overdosage (10) ].

In 6 patients with Quinimax (Quinine Hydrochloride) poisoning, forced acid diuresis did not change the half-life of Quinimax (Quinine Hydrochloride) elimination (25.1 ± 4.6 hours vs. 26.5 ± 5.8 hours), or the amount of unchanged Quinimax (Quinine Hydrochloride) recovered in the urine, in comparison to 8 patients not treated in this manner [see Overdosage (10) ].

Specific Populations

Pediatric Patients: The pharmacokinetics of Quinimax (Quinine Hydrochloride) in children (1.5 to 12 years old) with uncomplicated P. falciparum malaria appear to be similar to that seen in adults with uncomplicated malaria. Furthermore, as seen in adults, the mean total clearance and the volume of distribution of Quinimax (Quinine Hydrochloride) were reduced in pediatric patients with malaria as compared to the healthy pediatric controls. Table 2 below provides a comparison of the mean ± SD pharmacokinetic parameters of Quinimax (Quinine Hydrochloride) in pediatric patients vs. healthy pediatric controls.

Healthy Pediatric Controlsage 1.5 to 12 years

(N = 5)

Mean ± SD

P. falciparum Malaria Pediatric Patients

(N = 15)

Mean ± SD

Tmax (h) 2.0 4.0
Cmax (mcg/mL) 3.4 ± 1.18 7.5 ± 1.1
Half-life (h) 3.2 ± 0.3 12.1 ± 1.4
Total CL (L/h/kg) 0.30 ± 0.04 0.06 ± 0.01
Vd (L/kg) 1.43 ± 0.18 0.87 ± 0.12

Geriatric Patients: Following a single oral dose of 600 mg Quinimax (Quinine Hydrochloride) sulfate, the mean AUC was about 38% higher in 8 healthy elderly subjects (65 to 78 years old) than in 12 younger subjects (20 to 35 years old). The mean Tmax and Cmax were similar in elderly and younger subjects after a single oral dose of Quinimax (Quinine Hydrochloride) sulfate 600 mg. The mean oral clearance of Quinimax (Quinine Hydrochloride) was significantly decreased, and the mean elimination half-life was significantly increased in elderly subjects compared with younger subjects (0.06 vs. 0.08 L/h/kg, and 18.4 hours vs. 10.5 hours, respectively). Although there was no significant difference in the renal clearance of Quinimax (Quinine Hydrochloride) between the two age groups, elderly subjects excreted a larger proportion of the dose in urine as unchanged drug than younger subjects (16.6% vs. 11.2%).

After a single 648 mg dose or at steady state, following Quinimax (Quinine Hydrochloride) sulfate 648 mg given three times daily for 7 days, no difference in the rate and extent of absorption or clearance of Quinimax (Quinine Hydrochloride) was seen between 13 elderly subjects (65 to 78 years old) and 14 young subjects (20 to 39 years old). The mean elimination half-life was 20% longer in the elderly subjects (24.0 hours) than in younger subjects (20.0 hours). The steady state Cmax (±SD) and AUC0-8 (±SD) for healthy volunteers are 6.8 ± 1.24 mcg/mL and 48.8 ± 9.15 mcg*h/mL, respectively, following 7 days of oral Quinimax (Quinine Hydrochloride) sulfate 648 mg three times daily. The steady state pharmacokinetic parameters in healthy elderly subjects were similar to the pharmacokinetic parameters in healthy young subjects.

Renal Impairment: Following a single oral 600 mg dose of Quinimax (Quinine Hydrochloride) sulfate in otherwise healthy subjects with severe chronic renal failure not receiving any form of dialysis (mean serum creatinine = 9.6 mg/dL), the median AUC was higher by 195% and the median Cmax was higher by 79% than in subjects with normal renal function (mean serum creatinine = 1 mg/dL). The mean plasma half-life in subjects with severe chronic renal impairment was prolonged to 26 hours compared to 9.7 hours in the healthy controls. Computer assisted modeling and simulation indicates that in patients with malaria and severe chronic renal failure, a dosage regimen consisting of one loading dose of 648 mg Quinimax (Quinine Hydrochloride) followed 12 hours later by a maintenance dosing regimen of 324 mg every 12 hours will provide adequate systemic exposure to Quinimax (Quinine Hydrochloride) [see Dosage and Administration (2.2) ]. The effects of mild and moderate renal impairment on the pharmacokinetics and safety of Quinimax (Quinine Hydrochloride) sulfate are not known.

Negligible to minimal amounts of circulating Quinimax (Quinine Hydrochloride) in the blood are removed by hemodialysis or hemofiltration. In subjects with chronic renal failure (CRF) on hemodialysis, only about 6.5% of Quinimax (Quinine Hydrochloride) is removed in 1 hour. Plasma Quinimax (Quinine Hydrochloride) concentrations do not change during or shortly after hemofiltration in subjects with CRF [see Overdosage (10) ].

Hepatic Impairment: In otherwise healthy subjects with mild hepatic impairment (Child-Pugh A; N=10), who received a single 500 mg dose of Quinimax (Quinine Hydrochloride) sulfate, there was no significant difference in Quinimax (Quinine Hydrochloride) pharmacokinetic parameters or exposure to the primary metabolite, 3-hydroxyquinine as compared to healthy controls (N=10). In otherwise healthy subjects with moderate hepatic impairment (Child-Pugh B; N=9) who received a single oral 600 mg dose of Quinimax (Quinine Hydrochloride) sulfate, the mean AUC increased by 55% without a significant change in mean Cmax, as compared to healthy volunteer controls (N=6). In subjects with hepatitis, the absorption of Quinimax (Quinine Hydrochloride) was prolonged, the elimination half-life was increased, the apparent volume of distribution was higher, but there was no significant difference in weight-adjusted clearance. Therefore, in patients with mild to moderate hepatic impairment, dosage adjustment is not needed, but patients should be monitored closely for adverse effects of Quinimax (Quinine Hydrochloride) [see Use in Specific Populations (8.7) ].

In subjects with severe hepatic impairment (Child-Pugh C; N=10), Quinimax (Quinine Hydrochloride) oral clearance (CL/F) was reduced as was formation of the primary 3-hydroxyquinine metabolite. Volume of distribution (Vd/F) was higher and the plasma elimination half-life was increased. Therefore, Quinimax (Quinine Hydrochloride) is not indicated in this population and alternate therapy should be administered [see Dosage and Administration (2.3) ].

12.4 Microbiology

Mechanism of Action

Quinimax (Quinine Hydrochloride) inhibits nucleic acid synthesis, protein synthesis, and glycolysis in Plasmodium falciparum and can bind with hemazoin in parasitized erythrocytes. However, the precise mechanism of the antimalarial activity of Quinimax (Quinine Hydrochloride) sulfate is not completely understood.

Activity In Vitro and In Vivo

Quinimax (Quinine Hydrochloride) sulfate acts primarily on the blood schizont form of P. falciparum. It is not gametocidal and has little effect on the sporozoite or pre-erythrocytic forms.

Drug Resistance

Strains of P. falciparum with decreased susceptibility to Quinimax (Quinine Hydrochloride) can be selected in vivo. P. falciparum malaria that is clinically resistant to Quinimax (Quinine Hydrochloride) has been reported in some areas of South America, Southeast Asia, and Bangladesh.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity studies of Quinimax (Quinine Hydrochloride) have not been conducted.

Mutagenesis

Genotoxicity studies of Quinimax (Quinine Hydrochloride) were positive in the Ames bacterial mutation assay with metabolic activation and in the sister chromatid exchange assay in mice. The sex-linked recessive lethal test performed in Drosophila, the in vivo mouse micronucleus assay, and the chromosomal aberration assay in mice and Chinese hamsters were negative.

Impairment of Fertility

Published studies indicate that Quinimax (Quinine Hydrochloride) produces testicular toxicity in mice at a single intraperitoneal dose of 300 mg/kg corresponding to a dose of approximately 0.75 times the maximum recommended human dose (MRHD; 32 mg/kg/day) and in rats at an intramuscular dose of 10 mg/kg/day, 5 days/week, for 8 weeks corresponding to a daily dose of approximately 0.05 times the MRHD based on body surface area (BSA) comparisons. The findings include atrophy or degeneration of the seminiferous tubules, decreased sperm count and motility, and decreased testosterone levels in the serum and testes. There was no effect on testes weight in studies of oral doses of up to 500 mg/kg/day in mice and 700 mg/kg/day in rats (approximately 1.2 and 3.5 times the MRHD respectively based on BSA comparisons). In a published study in 5 men receiving 600 mg of Quinimax (Quinine Hydrochloride) TID for one week, sperm motility was decreased and percent sperm with abnormal morphology was increased; sperm count and serum testosterone were unaffected.

14 CLINICAL STUDIES

Quinimax (Quinine Hydrochloride) has been used worldwide for hundreds of years in the treatment of malaria. Thorough searches of the published literature identified over 1300 references to the treatment of malaria with Quinimax (Quinine Hydrochloride), and from these, 21 randomized, active-controlled studies were identified which evaluated oral Quinimax (Quinine Hydrochloride) monotherapy or combination therapy for treatment of uncomplicated P. falciparum malaria. Over 2900 patients from malaria-endemic areas were enrolled in these studies, and more than 1400 patients received oral Quinimax (Quinine Hydrochloride). The following conclusions were drawn from review of these studies:

In areas where multi-drug resistance of P. falciparum is increasing, such as Southeast Asia, cure rates with 7 days of oral Quinimax (Quinine Hydrochloride) monotherapy were at least 80%; while cure rates for 7 days of oral Quinimax (Quinine Hydrochloride) combined with an antimicrobial agent (tetracycline or clindamycin) were greater than 90%. In areas where multi-drug resistance of the parasite was not as widespread, cure rates with 7 days of Quinimax (Quinine Hydrochloride) monotherapy ranged from 86 to 100%. Cure was defined as initial clearing of parasitemia within 7 days without recrudescence by day 28 after treatment initiation. P. falciparum malaria that is clinically resistant to Quinimax (Quinine Hydrochloride) has been reported in some areas of South America, Southeast Asia, and Bangladesh, and Quinimax (Quinine Hydrochloride) may not be as effective in those areas.

Completion of a 7-day oral Quinimax (Quinine Hydrochloride) treatment regimen may be limited by drug intolerance, and shorter courses (3 days) of Quinimax (Quinine Hydrochloride) combination therapy have been used. However, the published data from randomized, controlled clinical trials for shorter regimens of oral Quinimax (Quinine Hydrochloride) in conjunction with tetracycline, doxycycline, or clindamycin for treatment of uncomplicated P. falciparum malaria is limited, and these shorter course combination regimens may not be as effective as the longer regimens.

16 HOW SUPPLIED / STORAGE AND HANDLING

16.1 How Supplied

Quinimax capsules USP, 324 mg are available as clear/clear capsules imprinted AR 102:

Bottles of 30 NDC 13310-153-07
Bottles of 100 NDC 13310-153-01
Bottles of 500 NDC 13310-153-05
Bottles of 1000 NDC 13310-153-10

16.2 Storage

Store at 20° to 25°C (68° to 77°F).

Dispense in a tight container as defined in the USP.

17 PATIENT COUNSELING INFORMATION

See FDA-approved Medication Guide

17.1 Dosing Instructions

Patients should be instructed to:

  • Take all of the medication as directed.
  • Take no more of the medication than the amount prescribed.
  • Take with food to minimize possible gastrointestinal irritation.

If a dose is missed, patients should also be instructed not to double the next dose. If more than 4 hours has elapsed since the missed dose, the patient should wait and take the next dose as previously scheduled.

17.2 FDA-Approved Medication Guide

MEDICATION GUIDE

Quinimax (Quinine Hydrochloride)®

(kwol-a-kwin)

(Quinine sulfate) Capsules

Read the Medication Guide that comes with Quinimax (Quinine Hydrochloride) ® before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. You and your healthcare provider should talk about Quinimax (Quinine Hydrochloride) ® when you start taking it and at regular checkups. Quinimax (Quinine Hydrochloride) ® is not approved for the treatment of night-time leg cramps.

What is the most important information I should know about Quinimax (Quinine Hydrochloride)®?

Quinimax (Quinine Hydrochloride)® used to treat or prevent leg cramps may cause serious side effects or even death.

  • Quinimax (Quinine Hydrochloride) ® may cause your blood cell (platelet) count to drop causing serious bleeding problems. In some people, serious kidney problems can happen.
  • Quinimax (Quinine Hydrochloride)® may cause problems with your heart rhythm that can lead to death.
  • Quinimax (Quinine Hydrochloride)® may cause serious allergic reactions.

Call your healthcare provider right away if you have:

  • easy bruising
  • severe nose bleed
  • blood in urine or stool
  • bleeding gums
  • appearance of unusual purple, brown or red spots on your skin (bleeding under your skin)
  • rash
  • hives
  • severe itching
  • severe flushing
  • swelling of your face
  • trouble breathing
  • chest pain
  • rapid heartbeat
  • irregular heart rhythm
  • weakness
  • sweating
  • nervousness

Taking Quinimax (Quinine Hydrochloride)® with some other medicines can increase the chance of serious side effects. Tell your healthcare provider if you take any other medicines.

Certain medicines can cause the blood levels of Quinimax (Quinine Hydrochloride) ® to be too high or too low in your body. It is important for you to tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements.

Quinimax (Quinine Hydrochloride)® and other medicines may affect each other causing serious side effects or death. Even medicines that you may take for a short period of time, such as antibiotics, can mix in your blood with Quinimax (Quinine Hydrochloride)® and cause serious side effects or death. Do not start taking a new medicine without telling your healthcare provider or pharmacist.

What is Quinimax (Quinine Hydrochloride)®?

Quinimax (Quinine Hydrochloride) ® is a prescription medication used to treat malaria (uncomplicated) caused by the parasite Plasmodium falciparum.

Quinimax (Quinine Hydrochloride)® is Not approved to:

  • Prevent malaria
  • Treat severe or complicated malaria
  • Prevent or treat night-time leg cramps

It is not known if Quinimax (Quinine Hydrochloride)® is safe and works in children younger than 16 years old.

Who should not take Quinimax (Quinine Hydrochloride)®?

Do not take Quinimax (Quinine Hydrochloride)® if you have:

  • certain heart rhythm problems (atrial fibrillation) or abnormal electrocardiogram (ECG) (QT prolongation).
  • low levels of an enzyme called Glucose-6-phosphate dehydrogenase (G6PD).
  • an autoimmune disease (myasthenia gravis) that leads to muscle weakness.
  • had allergic reactions to Quinimax (Quinine Hydrochloride), quinidine, or mefloquine (Lariam®).
  • had serious side effects to Quinimax (Quinine Hydrochloride) (QUALAQUIN®), such as low platelets, which are necessary for your blood to clot.
  • an inflammation of the nerve important for vision (optic neuritis).

What should I tell my healthcare provider before starting Quinimax (Quinine Hydrochloride)®?

Before you take Quinimax (Quinine Hydrochloride)®, tell your healthcare provider if you:

  • Have heart problems.
  • Have kidney problems.
  • Have liver problems.
  • Have any other medical condition.
  • Are pregnant or could be pregnant. Treatment of malaria is important because it can be a serious disease for a pregnant woman and her unborn baby. Your healthcare provider can tell you more about the benefits and risks of taking this medication during pregnancy. Low blood sugar (hypoglycemia) can be seen in pregnant women while taking Quinimax (Quinine Hydrochloride)®. This can include sweating, weakness, nausea, vomiting, or confusion. You and your healthcare provider can decide if Quinimax (Quinine Hydrochloride) ® is right for you.
  • Are breast-feeding. Small amounts of Quinimax (Quinine Hydrochloride) ® can pass into your breast milk. You and your healthcare provider can decide if you should breastfeed while taking Quinimax (Quinine Hydrochloride) ® .

Tell your healthcare provider about all the medicines you take, including prescription medicines, vitamins and herbal supplements.

How should I take Quinimax (Quinine Hydrochloride)®?

  • Take Quinimax (Quinine Hydrochloride) ® exactly as your healthcare provider tells you to take it.
  • Your healthcare provider will tell you how many Quinimax (Quinine Hydrochloride)® capsules to take and when to take them.
  • To lower the chance of stomach upset, take Quinimax (Quinine Hydrochloride)® with food.
  • Finish all the Quinimax (Quinine Hydrochloride) ® that is prescribed even if you feel better. Do not stop taking the medication without talking to your healthcare provider.
  • Do not take more than the amount prescribed. Do not take more than 2 capsules at one time or more than 3 doses in one day. If you take more than the prescribed dose, call your healthcare provider right away.
  • If you forget to take Quinimax (Quinine Hydrochloride)®, do not double the next dose. If it has been more than 4 hours since the missed dose, just wait and take the regular dose at the next scheduled time. Call your healthcare provider if you are not sure what to do.
  • If you take too much Quinimax (Quinine Hydrochloride)®, call your healthcare provider or go to the nearest emergency room right away.

Call your healthcare provider right away if:

  • If you feel worse, or if you do not start feeling better within 1 or 2 days of starting to take Quinimax (Quinine Hydrochloride)®.
  • If your fever comes back after finishing treatment with Quinimax (Quinine Hydrochloride)®.

What are the possible side effects of Quinimax (Quinine Hydrochloride)®?

Quinimax (Quinine Hydrochloride)® may cause serious side effects.

  • See "What is the most important information I should know about Quinimax (Quinine Hydrochloride) ®" section.
  • Low blood sugar (hypoglycemia). This can include sweating, weakness, nausea, vomiting, or confusion.

Common side effects with Quinimax (Quinine Hydrochloride) ® include:

  • headache
  • sweating
  • flushing
  • nausea
  • ringing in your ears
  • diarrhea
  • deafness
  • hearing loss
  • dizziness (vertigo)
  • blurred vision
  • changes in how you see color
  • vomiting
  • stomach pain
  • blindness

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all of the possible side effects of Quinimax (Quinine Hydrochloride) ® . For more information, ask your healthcare provider or pharmacist.

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

How should I store Quinimax (Quinine Hydrochloride)®?

  • Keep the capsules in a tightly closed container.
  • Do not refrigerate or freeze.
  • Store at 20°C to 25°C (68ºF to 77°F).

Keep Quinimax (Quinine Hydrochloride)® and all medicines out of the reach of children.

General Information about Quinimax (Quinine Hydrochloride)®

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Quinimax (Quinine Hydrochloride) ® for a condition for which it was not prescribed. Do not give Quinimax (Quinine Hydrochloride) ® to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about Quinimax (Quinine Hydrochloride) ® . If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Quinimax (Quinine Hydrochloride) ® that is written for healthcare professionals.

For more information, go to www. QUALAQUIN.com or call 1-888-351-3786.

What are the ingredients in Quinimax (Quinine Hydrochloride)®?

Active Ingredients: Quinimax (Quinine Hydrochloride) Sulfate, USP

Inactive Ingredients: Corn starch, magnesium stearate, talc

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured for:

AR SCIENTIFIC, INC.

Philadelphia, PA 19124 USA

by:

MUTUAL PHARMACEUTICAL COMPANY, INC.

Philadelphia, PA 19124 USA

Rev 23, April 2013

PRINCIPAL DISPLAY PANEL - 324 mg Capsule Bottle Label

100 CAPSULES

NDC 13310-153-01

Quinimax (Quinine Hydrochloride) ®

Quinimax (Quinine Hydrochloride) sulfate

capsules USP

324 mg

DISPENSE THE ACCOMPANYING

MEDICATION GUIDE TO EACH PATIENT

AR

SCIENTIFIC

Rx only

Quinimax pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Quinimax available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Quinimax destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Quinimax Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Quinimax pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."QUININE SULFATE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."QUINIDINE SULFATE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "quinidine". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Quinimax?

Depending on the reaction of the Quinimax after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Quinimax not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Quinimax addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Quinimax, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Quinimax consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

Visitor reports

Visitor reported useful

No survey data has been collected yet

Visitor reported side effects

No survey data has been collected yet

Visitor reported price estimates

No survey data has been collected yet

Visitor reported frequency of use

No survey data has been collected yet

Two visitors reported doses

What is the dose of Quinimax drug you are taking?
According to the survey conducted among sdrugs.com website users, the maximum number of people are using the following dose 1-5mg. Few medications come in only one or two doses. Few are specific for adult dose and child dose. The dose of the medicine given to the patient depends on the severity of the symptom/disease. There can be dose adjustments made by the doctor, based on the progression of the disease. Follow-up is important.
Visitors%
1-5mg1
50.0%
201-500mg1
50.0%

One visitor reported time for results

What is the time duration Quinimax drug must be taken for it to be effective or for it to reduce the symptoms?
Most chronic conditions need at least some time so the dose and the drug action gets adjusted to the body to get the desired effect. The stastistics say sdrugs.com website users needed 2 days to notice the result from using Quinimax drug. The time needed to show improvement in health condition after using the medicine Quinimax need not be same for all the users. It varies based on other factors.
Visitors%
2 days1
100.0%

Visitor reported administration

No survey data has been collected yet

Six visitors reported age

Visitors%
30-452
33.3%
> 601
16.7%
46-601
16.7%
1-51
16.7%
16-291
16.7%

Visitor reviews


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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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