Holis 12 PR

Quinine:

• Warning:
• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied / storage and handling
• Patient counseling information
• Holis 12 PR (Quinine) reviews

WARNING:

Holis 12 PR (Quinine)^® 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 Holis 12 PR (Quinine) use in the absence of evidence of its effectiveness in the treatment or prevention of nocturnal leg cramps outweighs any potential benefit.

WARNING:

Holis 12 PR (Quinine)^® 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 Holis 12 PR (Quinine) use in the absence of evidence of its effectiveness in the treatment or prevention of nocturnal leg cramps outweighs any potential benefit.

1 INDICATIONS AND USAGE

Holis 12 PR (Quinine) (quinine sulfate) is an antimalarial drug indicated only for treatment of uncomplicated Plasmodium falciparum malaria. Holis 12 PR (Quinine) sulfate has been shown to be effective in geographical regions where resistance to chloroquine has been documented [see Clinical Studies (14) ].

Holis 12 PR (Quinine) 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) ].

Holis 12 PR (Quinine)^® (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) ].

Holis 12 PR (Quinine) 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 Holis 12 PR 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 Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine). Holis 12 PR (Quinine) 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

Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine).
• Known hypersensitivity reactions to Holis 12 PR (Quinine).
  • 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 Holis 12 PR (Quinine) has been documented [see Warnings and Precautions (5.6) ].
  • Myasthenia gravis. Holis 12 PR (Quinine) has neuromuscular blocking activity, and may exacerbate muscle weakness.
  • Optic neuritis. Holis 12 PR (Quinine) may exacerbate active optic neuritis [see Adverse Reactions (6) ].

Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine), 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. Holis 12 PR (Quinine) treatment failures have been reported (5.4).
• Avoid concomitant use with neuromuscular blocking agents. Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) for Treatment or Prevention of Nocturnal Leg Cramps

Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) 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 Holis 12 PR. If Holis 12 PR (Quinine) is not stopped, a patient is at risk for fatal hemorrhage. Upon re-exposure to Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) administration, regardless of age, clinical status, or severity of disease. The maximum increase in QT interval has been shown to correspond with peak Holis 12 PR (Quinine) plasma concentration [see Clinical Pharmacology (12.2) ]. Holis 12 PR (Quinine) sulfate has been rarely associated with potentially fatal cardiac arrhythmias, including torsades de pointes, and ventricular fibrillation.

Holis 12 PR (Quinine) 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) ].

Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine). Fatal torsades de pointes was reported in an elderly patient who received concomitant Holis 12 PR (Quinine), 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 Holis 12 PR (Quinine) plasma levels when used concomitantly. A related macrolide antibiotic, troleandomycin, has also been shown to increase Holis 12 PR (Quinine) exposure in a pharmacokinetic study [see Drug Interactions (7.1) ].

Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) and astemizole. Therefore, concurrent use of Holis 12 PR (Quinine) with these medications, or drugs with similar properties, should be avoided [see Drug Interactions (7.2) ].

Concomitant administration of Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) and mefloquine may also increase the risk of seizures [see Drug Interactions (7.2) ].

Holis 12 PR (Quinine) 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 Holis 12 PR, due to decreased plasma concentrations of Holis 12 PR (Quinine), 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 Holis 12 PR (Quinine). In one patient who received pancuronium during an operative procedure, subsequent administration of Holis 12 PR (Quinine) resulted in respiratory depression and apnea. Although there are no clinical reports with succinylcholine or tubocurarine, Holis 12 PR (Quinine) may also potentiate neuromuscular blockade when used with these drugs [see Drug Interactions (7.2) ].

5.6 Hypersensitivity

Serious hypersensitivity reactions reported with Holis 12 PR 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 Holis 12 PR (Quinine), 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.

Holis 12 PR (Quinine) should be discontinued in case of any signs or symptoms of hypersensitivity [see Contraindications (4) ].

5.7 Atrial Fibrillation and Flutter

Holis 12 PR (Quinine) should be used with caution in patients with atrial fibrillation or atrial flutter. A paradoxical increase in ventricular response rate may occur with Holis 12 PR (Quinine), 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 Holis 12 PR (Quinine) [see Drug Interactions (7.2) ].

5.8 Hypoglycemia

Holis 12 PR (Quinine) 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 Holis 12 PR : 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 drugsafetyHolis 12 PR (Quinine)urlpharma.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Overall

Holis 12 PR (Quinine) can adversely affect almost every body system. The most common adverse events associated with Holis 12 PR (Quinine) use are a cluster of symptoms called "cinchonism", which occurs to some degree in almost all patients taking Holis 12 PR (Quinine). 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 Holis 12 PR (Quinine).

The following ADVERSE REACTIONS have been reported with Holis 12 PR (Quinine) 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

7.1 Effects of Drugs and Other Substances on Holis 12 PR (Quinine) Pharmacokinetics

Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) [see Clinical Pharmacology (12.3) ].

Antacids: Antacids containing aluminum and/or magnesium may delay or decrease absorption of Holis 12 PR (Quinine). Concomitant administration of these antacids with Holis 12 PR (Quinine) should be avoided.

Antiepileptics (AEDs) (carbamazepine, phenobarbital, and phenytoin): Carbamazepine, phenobarbital, and phenytoin are CYP3A4 inducers and may decrease Holis 12 PR (Quinine) plasma concentrations if used concurrently with Holis 12 PR (Quinine).

Cholestyramine: In 8 healthy subjects who received Holis 12 PR (Quinine) sulfate 600 mg with or without 8 grams of cholestyramine resin, no significant difference in Holis 12 PR (Quinine) pharmacokinetic parameters was seen.

Cigarette Smoking (CYP1A2 inducer): In healthy male heavy smokers, the mean Holis 12 PR (Quinine) AUC following a single 600 mg dose was 44% lower, the mean C_max 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 Holis 12 PR (Quinine) therapy, cigarette smoking produced only a 25% decrease in median Holis 12 PR (Quinine) AUC and a 16.5% decrease in median C_max, suggesting that the already reduced clearance of Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) sulfate with grapefruit juice (full-strength or half-strength) did not significantly alter the pharmacokinetic parameters of Holis 12 PR (Quinine). Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) increased by 20% with ranitidine and by 42% with cimetidine (p<0.05) without a significant change in mean Holis 12 PR (Quinine) C_max. When Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine), patients should be monitored closely for adverse events associated with Holis 12 PR (Quinine).

Isoniazid: Isoniazid 300 mg/day pretreatment for 1 week did not significantly alter the pharmacokinetic parameter values of Holis 12 PR (Quinine). Adjustment of Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) hydrochloride (500 mg) concomitantly with ketoconazole (100 mg twice daily for 3 days) had a mean Holis 12 PR (Quinine) AUC that was higher by 45% and a mean oral clearance of Holis 12 PR (Quinine) that was 31% lower than after receiving Holis 12 PR (Quinine) alone. Although no change in the Holis 12 PR (Quinine) dosage regimen is necessary with concomitant ketoconazole, patients should be monitored closely for adverse reactions associated with Holis 12 PR (Quinine).

Macrolide antibiotics (erythromycin, troleandomycin) (CYP3A4 inhibitors): In a crossover study (N=10), healthy subjects who received a single oral 600 mg dose of Holis 12 PR (Quinine) sulfate with the macrolide antibiotic, troleandomycin (500 mg every 8 hours) exhibited a 87% higher mean Holis 12 PR (Quinine) AUC, a 45% lower mean oral clearance of Holis 12 PR (Quinine), and a 81% lower formation clearance of the main metabolite, 3-hydroxyquinine, than when Holis 12 PR (Quinine) was given alone.

Erythromycin was shown to inhibit the in vitro metabolism of Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) sulfate with erythromycin (600 mg every 8 hours for four days) showed a decrease in Holis 12 PR (Quinine) oral clearance (CL/F), an increase in half-life, and a decreased metabolite (3-hydroxyquinine) to Holis 12 PR (Quinine) AUC ratio, as compared to when Holis 12 PR (Quinine) was given with placebo.

Therefore, concomitant administration of macrolide antibiotics such as erythromycin or troleandomycin with Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) sulfate 10 mg/kg concomitantly with rifampin 15 mg/kg/day for 7 days (N=29), the median AUC of Holis 12 PR (Quinine) between days 3 and 7 of therapy was 75% lower as compared to those who received Holis 12 PR (Quinine) monotherapy. In healthy subjects (N=9) who received a single oral 600 mg dose of Holis 12 PR (Quinine) sulfate after 2 weeks of pretreatment with rifampin 600 mg/day, the mean Holis 12 PR (Quinine) AUC and C_max decreased by 85% and 55%, respectively. Therefore, the concomitant administration of rifampin with Holis 12 PR (Quinine) should be avoided [see Warnings and Precautions (5.4) ].

Ritonavir: In healthy subjects who received a single oral 600 mg dose of Holis 12 PR (Quinine) sulfate with the 15^th dose of ritonavir (200 mg every 12 hours for 9 days), there were 4-fold increases in the mean Holis 12 PR (Quinine) AUC and C_max, and an increase in the mean elimination half-life (13.4 hours versus 11.2 hours), compared to when Holis 12 PR (Quinine) was given alone. Therefore, the concomitant administration of ritonavir with Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) concentrations were about two-fold higher than in 8 patients who received Holis 12 PR (Quinine) monotherapy. Although tetracycline may be concomitantly administered with Holis 12 PR (Quinine), patients should be monitored closely for adverse reactions associated with Holis 12 PR (Quinine) sulfate.

Theophylline or aminophylline: In 20 healthy subjects who received multiple doses of Holis 12 PR (Quinine) (648 mg every 8 hours × 7 days) with a single 300 mg oral dose of theophylline, the Holis 12 PR (Quinine) mean C_max and AUC were increased by 13% and 14% respectively. Although no change in the Holis 12 PR (Quinine) dosage regimen is necessary with concomitant theophylline or aminophylline, patients should be monitored closely for adverse reactions associated with Holis 12 PR (Quinine).

Urinary alkalizers (acetazolamide, sodium bicarbonate): Urinary alkalinizing agents may increase plasma Holis 12 PR (Quinine) concentrations.

7.2 Effects of Holis 12 PR on the Pharmacokinetics of Other Drugs

Results of in vivo drug interaction studies suggest that Holis 12 PR (Quinine) has the potential to inhibit the metabolism of drugs that are substrates of CYP3A4 and CYP2D6. Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) sulfate increased the mean plasma C_max, and AUC_0–24 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 C_max were 56%, 53%, and 4%, respectively. Mean urinary recoveries of the three antiepileptics over 24 hours were also profoundly increased by Holis 12 PR (Quinine). 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 Holis 12 PR (Quinine) sulfate for nocturnal leg cramps concomitantly with chronic astemizole 10 mg/day. The concurrent use of Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine). Holis 12 PR (Quinine) may increase plasma concentrations of atorvastatin, thereby increasing the risk of myopathy or rhabdomyolysis. Thus, clinicians considering combined therapy of Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) 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): Holis 12 PR (Quinine) (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 Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) (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 Holis 12 PR (Quinine) 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, Holis 12 PR (Quinine) was shown to inhibit the metabolism of halofantrine in vitro using human liver microsomes. Therefore, concomitant administration of Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) sulfate 24 hours apart. The concomitant administration of mefloquine and Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) 324 mg three times daily × 7 days with a single oral 2 mg dose of midazolam, the mean AUC and C_max of midazolam and 1-hydroxymidazolam were not significantly affected. This finding indicates that 7-day dosing with Holis 12 PR (Quinine) 324 mg every 8 hours did not induce the metabolism of midazolam.

Neuromuscular blocking agents (pancuronium, succinylcholine, tubocurarine): In one report, Holis 12 PR (Quinine) potentiated neuromuscular blockade in a patient who received pancuronium during an operative procedure, and subsequently (3 hours after receiving pancuronium) received Holis 12 PR (Quinine) 1800 mg daily. Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) sulfate with the 15^th dose of ritonavir (200 mg every 12 hours for 9 days), the mean ritonavir AUC, C_max, 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 Holis 12 PR (Quinine) pharmacokinetics, the concomitant administration of Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) 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 C_max. Therefore, if Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine), 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. Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine).

7.3 Drug/Laboratory Interactions

Holis 12 PR (Quinine) may produce an elevated value for urinary 17-ketogenic steroids when the Zimmerman method is used.

Holis 12 PR (Quinine) 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. Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) in pregnant women. Published data on over 1,000 pregnancy exposures to Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) at doses about 1 to 4 times the human clinical dose. Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) use, particularly in pregnant women.

Holis 12 PR (Quinine) crosses the placenta with measurable blood concentrations in the fetus. In 8 women who delivered live infants 1 to 6 days after starting Holis 12 PR (Quinine) therapy, umbilical cord plasma Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) concentrations was 0.32 ± 0.14. Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) (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 Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) sulfate (3.5%) [OR = 3.1; 95% CI 2.1-4.7]. An epidemiologic survey that included 104 mother-child pairs exposed to Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine).

In animal developmental studies conducted in multiple animal species, pregnant animals received Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) 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 Holis 12 PR causes uterine contractions at the doses recommended for the treatment of malaria. In doses several-times higher than those used to treat malaria, Holis 12 PR (Quinine) may stimulate the pregnant uterus.

8.3 Nursing Mothers

There is limited information on the safety of Holis 12 PR (Quinine) in breastfed infants. No toxicity was reported in infants in a single study where oral Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) base (< 0.4% of the maternal dose) via breast milk [see Clinical Pharmacology (12.3) ].

Although Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) levels may not be therapeutic in infants of nursing mothers receiving Holis 12 PR (Quinine).

8.4 Pediatric Use

The safety and efficacy of Holis 12 PR in pediatric patients under the age of 16 has not been established.

8.5 Geriatric Use

Clinical studies of Holis 12 PR (Quinine) 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 Holis 12 PR 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), Holis 12 PR (Quinine) 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, Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) may be increased relative to subjects with normal liver function [see Clinical Pharmacology (12.3) ].

10 OVERDOSAGE

Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine). A lethal dose of Holis 12 PR (Quinine) has not been clearly defined, but fatalities have been reported after the ingestion of 2 to 8 grams in adults.

Holis 12 PR (Quinine), like quinidine, has Class I antiarrhythmic properties. The cardiotoxicity of Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) 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. Holis 12 PR (Quinine) 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) ].

Holis 12 PR (Quinine) is rapidly absorbed, and attempts to remove residual Holis 12 PR (Quinine) sulfate from the stomach by gastric lavage may not be effective. Multiple-dose activated charcoal has been shown to decrease plasma Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) elimination in a series of 16 patients.

11 DESCRIPTION

Holis 12 PR (Quinine) (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 Holis 12 PR (Quinine) sulfate is:

Holis 12 PR (Quinine) 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.

Holis 12 PR (Quinine) is supplied for oral administration as capsules containing 324 mg of the active ingredient Holis 12 PR (Quinine) 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

Holis 12 PR 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 Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine). 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 Holis 12 PR is 76 to 88% in healthy adults. Holis 12 PR (Quinine) exposure is higher in patients with malaria than in healthy subjects. After a single oral dose of Holis 12 PR (Quinine) sulfate, the mean Holis 12 PR (Quinine) T_max was longer, and mean AUC and C_max were higher in patients with uncomplicated P. falciparum malaria than in healthy subjects, as shown in Table 1 below.

Holis 12 PR (Quinine) capsules may be administered without regard to meals. When a single oral 324 mg capsule of Holis 12 PR (Quinine) was administered to healthy subjects (N=26) with a standardized high-fat breakfast, the mean T_max of Holis 12 PR (Quinine) was prolonged to about 4.0 hours, but the mean C_max and AUC_0-24h were similar to those achieved when Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) sulfate, the mean Vd/F ranged from 2.5 to 7.1 L/kg.

Holis 12 PR (Quinine) is moderately protein-bound in blood in healthy subjects, ranging from 69 to 92%. During active malarial infection, protein binding of Holis 12 PR (Quinine) is increased to 78 to 95%, corresponding to the increase in α₁-acid glycoprotein that occurs with malaria infection.

Intra-erythrocytic levels of Holis 12 PR (Quinine) are approximately 30 to 50% of the plasma concentration.

Holis 12 PR (Quinine) 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, Holis 12 PR (Quinine) concentrations in placental cord blood and breast milk were approximately 32% and 31%, respectively, of Holis 12 PR (Quinine) concentrations in maternal plasma. The estimated total dose of Holis 12 PR (Quinine) secreted into breast milk was less than 2 to 3 mg per day [see Use in Specific Populations (8.1, 8.3) ].

Metabolism

Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine).

Elimination/Excretion

Holis 12 PR (Quinine) is eliminated primarily via hepatic biotransformation. Approximately 20% of Holis 12 PR (Quinine) is excreted unchanged in urine. Because Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) sulfate, the mean total clearance of Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) dosing followed by 3 further doses over the next 12 hours) decreased the mean Holis 12 PR (Quinine) elimination half-life from 8.2 to 4.6 hours, and increased the mean Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) sulfate. Likewise, in 5 symptomatic patients with acute Holis 12 PR (Quinine) poisoning who received multiple-dose activated charcoal (50 grams every 4 hours), the mean Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) poisoning, forced acid diuresis did not change the half-life of Holis 12 PR (Quinine) elimination (25.1 ± 4.6 hours vs. 26.5 ± 5.8 hours), or the amount of unchanged Holis 12 PR (Quinine) recovered in the urine, in comparison to 8 patients not treated in this manner [see Overdosage (10) ].

Specific Populations

Pediatric Patients: The pharmacokinetics of Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) in pediatric patients vs. healthy pediatric controls.

Geriatric Patients: Following a single oral dose of 600 mg Holis 12 PR (Quinine) 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 T_max and C_max were similar in elderly and younger subjects after a single oral dose of Holis 12 PR (Quinine) sulfate 600 mg. The mean oral clearance of Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) sulfate 648 mg given three times daily for 7 days, no difference in the rate and extent of absorption or clearance of Holis 12 PR (Quinine) 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 C_max (±SD) and AUC_0-8 (±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 Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) 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 C_max 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 Holis 12 PR (Quinine) followed 12 hours later by a maintenance dosing regimen of 324 mg every 12 hours will provide adequate systemic exposure to Holis 12 PR (Quinine) [see Dosage and Administration (2.2) ]. The effects of mild and moderate renal impairment on the pharmacokinetics and safety of Holis 12 PR (Quinine) sulfate are not known.

Negligible to minimal amounts of circulating Holis 12 PR (Quinine) in the blood are removed by hemodialysis or hemofiltration. In subjects with chronic renal failure (CRF) on hemodialysis, only about 6.5% of Holis 12 PR (Quinine) is removed in 1 hour. Plasma Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) sulfate, there was no significant difference in Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) sulfate, the mean AUC increased by 55% without a significant change in mean C_max, as compared to healthy volunteer controls (N=6). In subjects with hepatitis, the absorption of Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) [see Use in Specific Populations (8.7) ].

In subjects with severe hepatic impairment (Child-Pugh C; N=10), Holis 12 PR (Quinine) 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, Holis 12 PR (Quinine) is not indicated in this population and alternate therapy should be administered [see Dosage and Administration (2.3) ].

12.4 Microbiology

Mechanism of Action

Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) sulfate is not completely understood.

Activity In Vitro and In Vivo

Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) can be selected in vivo. P. falciparum malaria that is clinically resistant to Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) have not been conducted.

Mutagenesis

Genotoxicity studies of Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) 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

Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine), and from these, 21 randomized, active-controlled studies were identified which evaluated oral Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine). 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 Holis 12 PR (Quinine) monotherapy were at least 80%; while cure rates for 7 days of oral Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) 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 Holis 12 PR (Quinine) has been reported in some areas of South America, Southeast Asia, and Bangladesh, and Holis 12 PR (Quinine) may not be as effective in those areas.

Completion of a 7-day oral Holis 12 PR (Quinine) treatment regimen may be limited by drug intolerance, and shorter courses (3 days) of Holis 12 PR (Quinine) combination therapy have been used. However, the published data from randomized, controlled clinical trials for shorter regimens of oral Holis 12 PR (Quinine) 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

Holis 12 PR capsules USP, 324 mg are available as clear/clear capsules imprinted AR 102:

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

Holis 12 PR (Quinine)^®

(kwol-a-kwin)

(Quinine sulfate) Capsules

Read the Medication Guide that comes with Holis 12 PR (Quinine) ^® 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 Holis 12 PR (Quinine) ^® when you start taking it and at regular checkups. Holis 12 PR (Quinine) ^® is not approved for the treatment of night-time leg cramps.

What is the most important information I should know about Holis 12 PR (Quinine)^®?

Holis 12 PR (Quinine)^® used to treat or prevent leg cramps may cause serious side effects or even death.

• Holis 12 PR (Quinine) ^® may cause your blood cell (platelet) count to drop causing serious bleeding problems. In some people, serious kidney problems can happen.
• Holis 12 PR (Quinine)^® may cause problems with your heart rhythm that can lead to death.
• Holis 12 PR (Quinine)^® may cause serious allergic reactions.

Call your healthcare provider right away if you have:

Taking Holis 12 PR (Quinine)^® 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 Holis 12 PR (Quinine) ^® 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.

Holis 12 PR (Quinine)^® 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 Holis 12 PR (Quinine)^® and cause serious side effects or death. Do not start taking a new medicine without telling your healthcare provider or pharmacist.

What is Holis 12 PR (Quinine)^®?

Holis 12 PR (Quinine) ^® is a prescription medication used to treat malaria (uncomplicated) caused by the parasite Plasmodium falciparum.

Holis 12 PR (Quinine)^® is Not approved to:

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

It is not known if Holis 12 PR (Quinine)^® is safe and works in children younger than 16 years old.

Who should not take Holis 12 PR (Quinine)^®?

Do not take Holis 12 PR (Quinine)^® 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 Holis 12 PR (Quinine), quinidine, or mefloquine (Lariam^®).
• had serious side effects to Holis 12 PR (Quinine) (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 Holis 12 PR (Quinine)^®?

Before you take Holis 12 PR (Quinine)^®, 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 Holis 12 PR (Quinine)^®. This can include sweating, weakness, nausea, vomiting, or confusion. You and your healthcare provider can decide if Holis 12 PR (Quinine) ^® is right for you.
• Are breast-feeding. Small amounts of Holis 12 PR (Quinine) ^® can pass into your breast milk. You and your healthcare provider can decide if you should breastfeed while taking Holis 12 PR (Quinine) ^® .

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

How should I take Holis 12 PR (Quinine)^®?

• Take Holis 12 PR (Quinine) ^® exactly as your healthcare provider tells you to take it.
• Your healthcare provider will tell you how many Holis 12 PR (Quinine)^® capsules to take and when to take them.
• To lower the chance of stomach upset, take Holis 12 PR (Quinine)^® with food.
• Finish all the Holis 12 PR (Quinine) ^® 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 Holis 12 PR (Quinine)^®, 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 Holis 12 PR (Quinine)^®, 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 Holis 12 PR (Quinine)^®.
• If your fever comes back after finishing treatment with Holis 12 PR (Quinine)^®.

What are the possible side effects of Holis 12 PR (Quinine)^®?

Holis 12 PR (Quinine)^® may cause serious side effects.

• See "What is the most important information I should know about Holis 12 PR (Quinine) ^®" section.
• Low blood sugar (hypoglycemia). This can include sweating, weakness, nausea, vomiting, or confusion.

Common side effects with Holis 12 PR (Quinine) ^® include:

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 Holis 12 PR (Quinine) ^® . 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 Holis 12 PR (Quinine)^®?

• 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 Holis 12 PR (Quinine)^® and all medicines out of the reach of children.

General Information about Holis 12 PR (Quinine)^®

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Holis 12 PR (Quinine) ^® for a condition for which it was not prescribed. Do not give Holis 12 PR (Quinine) ^® 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 Holis 12 PR (Quinine) ^® . If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Holis 12 PR (Quinine) ^® 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 Holis 12 PR (Quinine)^®?

Active Ingredients: Holis 12 PR (Quinine) 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

Holis 12 PR (Quinine) ^®

Holis 12 PR (Quinine) sulfate

capsules USP

324 mg

DISPENSE THE ACCOMPANYING

MEDICATION GUIDE TO EACH PATIENT

AR

SCIENTIFIC

Rx only