DRUGS & SUPPLEMENTS

Paludil

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Paludil uses

Paludil consists of Methylene Blue, Quinine.

Methylene Blue:


WARNING: SEROTONIN SYNDROME WITH CONCOMITANT USE OF SEROTONERGIC DRUGS

Paludil (Methylene Blue) may cause serious or fatal serotonergic syndrome when used in combination with serotonergic drugs. Avoid concomitant use of Paludil (Methylene Blue) with selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors ( 5.1, 7.1).

1 INDICATIONS AND USAGE

Paludil (Methylene Blue) is indicated for the treatment of pediatric and adult patients with acquired methemoglobinemia.

This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials.

Paludil (Methylene Blue) (methylene blue) is an oxidation-reduction agent indicated for the treatment of pediatric and adult patients with acquired methemoglobinemia. This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials. ( 1, 14)

2 DOSAGE AND ADMINISTRATION

  • Administer 1 mg/kg intravenously over 5-30 minutes.
  • If methemoglobin level remains above 30% or if clinical symptoms persist, give a repeat dose of up to 1 mg/kg one hour after the first dose. ( 2.1)

2.1 Dosage and Administration

  • Ensure patent venous access prior to administration of Paludil (Methylene Blue). Do not administer Paludil (Methylene Blue) subcutaneously.
  • Monitor vital signs, electrocardiogram and methemoglobin levels during treatment with Paludil (Methylene Blue) and through resolution of methemoglobinemia.
  • Administer Paludil (Methylene Blue) 1 mg/kg intravenously over 5-30 minutes.
  • If the methemoglobin level remains greater than 30% or if clinical signs and symptoms persist, a repeat dose of Paludil (Methylene Blue) 1 mg/kg may be given one hour after the first dose.
  • If methemoglobinemia does not resolve after 2 doses of Paludil (Methylene Blue), consider initiating alternative interventions for treatment of methemoglobinemia.

2.2 Preparation and Storage

Each mL of Paludil (Methylene Blue) contains 5 mg Paludil (Methylene Blue)

Each 10 mL ampule of Paludil (Methylene Blue) contains 50 mg Paludil (Methylene Blue).

Paludil (Methylene Blue) is hypotonic and may be diluted before use in a solution of 50 mL 5% Dextrose in Water (D5W) in order to avoid local pain, particularly in the pediatric population. Use the diluted solution immediately after preparation.

Do not mix with sodium chloride 9 mg/mL (0.9%) solution for injection, because it has been demonstrated that chloride reduces the solubility of Paludil (Methylene Blue).

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Keep the ampule in the original package to protect from light.

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3 DOSAGE FORMS AND STRENGTHS

Injection: 50 mg/10 mL (5 mg/mL) clear dark blue solution in single-dose ampules

50 mg/10 mL (5 mg/mL) single-dose ampule. ( 3)

4 CONTRAINDICATIONS

Paludil (Methylene Blue) is contraindicated in the following conditions:

  • Severe hypersensitivity reactions to Paludil (Methylene Blue) or any other thiazine dye .
  • Patients with glucose-6-phosphate dehydrogenase deficiency (G6PD) due to the risk of hemolytic anemia

Paludil (Methylene Blue) is contraindicated in the following conditions ( 4):

  • Severe hypersensitivity to Paludil (Methylene Blue)
  • Patients with glucose-6-phosphate dehydrogenase deficiency (G6PD) due to the risk of hemolytic anemia

5 WARNINGS AND PRECAUTIONS

  • Hypersensitivity: If severe or life threatening allergic reaction occurs, discontinue Paludil, treat the allergic reaction, and monitor until signs and symptoms resolve ( 5.2)
  • Lack of Effectiveness: Consider alternative treatments if there is no resolution of methemoglobinemia after 2 doses ( 2.1, 5.3)
  • Hemolytic Anemia: Discontinue Paludil (Methylene Blue) and transfuse ( 5.4)
  • Interference with In-Vivo Monitoring Devices: Use methods other than pulse oximetry to assess oxygen satruation ( 5.5)
  • Effects on Ability to Drive and Operate Machinery: Advise patients to refrain from these activities until neurologic and visual symptoms have resolved ( 5.6)

5.1 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

The development of serotonin syndrome has been reported with use of Paludil (Methylene Blue) class products. Most reports have been associated with concomitant use of serotonergic drugs (e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors). Some of the reported cases were fatal. Symptoms associated with serotonin syndrome may include the following combination of signs and symptoms: mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, and hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, and incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Avoid concomitant use of Paludil (Methylene Blue) with serotonergic drugs.

Patients treated with Paludil (Methylene Blue) should be monitored for the emergence of serotonin syndrome. If symptoms of serotonin syndrome occur, discontinue use of Paludil (Methylene Blue), and initiate supportive treatment. Inform patients of the increased risk of serotonin syndrome and advise them to not to take serotonergic drugs within 72 hours after the last dose of Paludil (Methylene Blue) .

5.2 Hypersensitivity

Anaphylactic reactions to Paludil class products have been reported. Patients treated with Paludil (Methylene Blue) should be monitored for anaphylaxis. If anaphylaxis or other severe hypersensitivity reactions (e.g., angioedema, urticaria, bronchospasm) should occur, discontinue use of Paludil (Methylene Blue) and initiate supportive treatment. Paludil (Methylene Blue) is contraindicated in patients who have experienced anaphylaxis or other severe hypersensitivity reactions to a Paludil (Methylene Blue) class product in the past.

5.3 Lack of Effectiveness

Methemoglobinemia may not resolve or may rebound after response to treatment with Paludil (Methylene Blue) in patients with methemoglobinemia due to aryl amines such as aniline or sulfa drugs such as dapsone. Monitor response to therapy with Paludil (Methylene Blue) through resolution of methemoglobinemia. If methemoglobinemia does not respond to 2 doses of Paludil (Methylene Blue) or if methemoglobinemia rebounds after a response, consider additional treatment options .

Patients with glucose-6-phosphate dehydrogenase deficiency may not reduce Paludil (Methylene Blue) to its active form in vivo. Paludil (Methylene Blue) may not be effective in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.

5.4 Hemolytic Anemia

Hemolysis can occur during treatment of methemoglobinemia with Paludil. Laboratory testing may show Heinz bodies, elevated indirect bilirubin and low haptoglobin, but the Coombs test is negative. The onset of anemia may be delayed 1 or more days after treatment with Paludil (Methylene Blue). The anemia may require red blood cell transfusions. . Use the lowest effective number of doses of Paludil (Methylene Blue) to treat methemoglobinemia. Discontinue Paludil (Methylene Blue) and consider alternative treatments of methemoglobinemia if severe hemolysis occurs.

Treatment of patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency with Paludil (Methylene Blue) may result in severe hemolysis and severe anemia. Paludil (Methylene Blue) is contraindicated for use in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency .

5.5 Interference with In Vivo Monitoring Devices

  • Inaccurate Pulse Oximeter Readings

The presence of Paludil (Methylene Blue) in the blood may result in an underestimation of the oxygen saturation reading by pulse oximetry. If a measure of oxygen saturation is required during or shortly after infusion of Paludil (Methylene Blue), it is advisable to obtain an arterial blood sample for testing by an alternative method.

  • Bispectral index monitor

A fall in the Bispectral Index (BIS) has been reported following administration of Paludil (Methylene Blue) class products. If Paludil (Methylene Blue) is administered during surgery, alternative methods for assessing the depth of anesthesia should be employed.

5.6 Effects on Ability to Drive and Operate Machinery

Treatment with Paludil may cause confusion, dizziness and disturbances in vision . Advise patients to refrain from driving or engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery until such adverse reactions to Paludil (Methylene Blue) have resolved.

5.7 Interference with Laboratory Tests

Paludil (Methylene Blue) is a blue dye which passes freely into the urine and may interfere with the interpretation of any urine test which relies on a blue indicator, such as the dipstick test for leucocyte esterase.

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6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

  • Serotonin Syndrome with Concomitant Use of Serotonergic Drugs
  • Anaphylaxis
  • Lack of Effectiveness
  • Hemolytic Anemia
  • Interference with In-Vivo Monitoring Devices
  • Effects on Ability to Drive and Operate Machinery
  • Interference with Laboratory Tests

The most commonly reported adverse reactions (≥10%) are pain in extremity, chromaturia, dysgeusia, feeling hot, dizziness, hyperhidrosis, nausea, skin, discoloration and headache. ( 6.1)

To report SUSPECTED ADVERSE REACTIONS, contact American Regent at 1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of Paludil (Methylene Blue) was determined in 82 healthy adults of median age of 36 years (range, 19-55 years); 54% were male, and 68% were white. Each individual in the safety population received a single dose of Paludil (Methylene Blue) 2 mg/kg intravenously. There was one serious adverse reaction reported (syncope due to sinus pauses of 3-14 seconds). The most common (≥2%) moderate or severe adverse reactions were pain in the extremity (56%), headache (7%), feeling hot (6%), syncope (4%), back pain (2%), hyperhidrosis (2%) and nausea (2%). Table 1 lists the adverse reactions of any severity that occurred in at least 2% of individuals who received Paludil (Methylene Blue).

Adverse Reaction Any Grade TEAE

(n=82)

Moderate-

Severe TEAE

(n=82)

Pain in extremity 69 84% 46 56%
Chromaturia 61 74% 0
Dysgeusia 16 20% 1 1%
Feeling hot 14 17% 5 6%
Dizziness 13 16% 4 5%
Hyperhidrosis 11 13% 2 2%
Nausea 11 13% 2 2%
Skin discoloration 11 13% 0
Headache 8 10% 6 7%
Musculoskeletal pain 7 9% 0
Paresthesia oral 7 9% 0
Paresthesia 7 9% 0
Infusion site pain 5 6% 1 1%
Feeling cold 5 6% 0
Pallor 4 5% 0
Dermatitis contact 4 5% 0
Syncope 3 4% 3 4%
Influenza like illness 3 4% 1 1%
Pruritus 3 4% 1 1%
Anxiety 3 4% 0
Decreased appetite 3 4% 0
Chest discomfort 3 4% 0
Back pain 2 2% 2 2%
Cold sweat 2 2% 1 1%
Dizziness postural 2 2% 1 1%
Muscle spasms 2 2% 1 1%
Presyncope 2 2% 1 1%
Vomiting 2 2% 1 1%
Arthralgia 2 2% 1 1%
Chills 2 2% 0
Diarrhea 2 2% 0
Discomfort 2 2% 0
Dyspnea 2 2% 0
Erythema 2 2% 0
Hypoesthesia oral 2 2% 0
Infusion site discomfort 2 2% 0
Limb discomfort 2 2% 0
Oral discomfort 2 2% 0
Catheter site pain 2 2% 0
Ecchymosis 2 2% 0

Other adverse reactions reported to occur following administration of Paludil (Methylene Blue) class products include the following:

Blood and lymphatic system disorders: hemolytic anemia, hemolysis, hyperbilirubinemia, methemoglobinemia

Cardiac disorders: palpitations, tachycardia

Eye disorders: eye pruritus, ocular hyperemia, vision blurred

Gastrointestinal disorders: abdominal pain lower, dry mouth, flatulence, glossodynia, tongue eruption

General disorders and administration site conditions: death, infusion site extravasation, infusion site induration, infusion site pruritus, infusion site swelling, infusion site urticaria, peripheral swelling, thirst

Investigations: elevated liver enzymes

Musculoskeletal and connective tissue disorders: myalgia

Renal and urinary disorders: dysuria

Respiratory, thoracic and mediastinal disorders: nasal congestion, oropharyngeal pain, rhinorrhea, sneezing

Skin and subcutaneous tissue disorders: necrotic ulcer, papule, phototoxicity

Vascular disorders: hypertension

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7 DRUG INTERACTIONS

7.1 Serotonergic Drugs

Avoid concomitant use of Paludil with medicinal products that enhance serotonergic transmission including SSRIs (selective serotonin reuptake inhibitors), MAO inhibitors, bupropion, buspirone, clomipramine, mirtazapine and venlafaxine; because of the potential for serious CNS reactions, including potentially fatal serotonin syndrome. Although the mechanism is not clearly, understood, literature reports suggest inhibition of MAO by Paludil (Methylene Blue) may be involved. In addition, in vitro studies cannot rule out the potential involvement of CYP 2D6 inhibition by Paludil (Methylene Blue). If the intravenous use of Paludil (Methylene Blue) cannot be avoided in patients treated with serotonergic medicinal products, choose the lowest possible dose and observe closely the patient for CNS effects for up to 4 hours after administration .

7.2 Agents Metabolized by Cytochrome P450 Enzymes

Paludil (Methylene Blue) inhibits a range of CYP isozymes in vitro, including 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4/5. This interaction could be more pronounced with narrow therapeutic index drugs that are metabolized by one of these enzymes (e.g, digoxin, warfarin, phenytoin, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus). However, the clinical relevance of these in vitro interactions is unknown.

8 USE IN SPECIFIC POPULATIONS

  • Pregnancy: Only use during pregnancy if the potential benefit justifies the potential risk to the fetus.
  • Lactation: Discontinue breast-feeding for up to 8 days after treatment. ( 8.2).
  • Renal Insufficiency: Monitor patients longer for toxicity and drug interactions due to delayed clearance. ( 8.6)
  • Hepatic Impairment: Monitor patients longer for toxicity and drug interactions due to delayed clearance. ( 8.7)

8.1 Pregnancy

Risk Summary

Paludil (Methylene Blue) may cause fetal harm when administered to a pregnant woman. Intra-amniotic injection of pregnant women with a Paludil (Methylene Blue) class product during the second trimester was associated with neonatal intestinal atresia and fetal death. Paludil (Methylene Blue) produced adverse developmental outcomes in rats and rabbits when administered orally during organogenesis at doses at least 32 and 16 times, respectively, the clinical dose of 1 mg/kg . Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively.

Clinical Considerations

Fetal/neonatal adverse reactions

Intra-amniotic injection of a Paludil (Methylene Blue) class product hours to days prior to birth can result hyperbilirubinemia, hemolytic anemia, skin staining, methemoglobinemia, respiratory distress and photosensitivity in the newborn. Following administration of Paludil (Methylene Blue) to a pregnant woman at term, observe the newborn for these adverse reactions and institute supportive care.

Data

Animal Data

Paludil (Methylene Blue) was administered orally to pregnant rats at doses of 50 to 350 mg/kg/day, during the period of organogenesis. Maternal and embryofetal toxicities were observed at all doses of Paludil (Methylene Blue), and were most evident at the 200 and 350 mg/kg/day doses. Maternal toxicity consisted of increased spleen weight. Embryo-fetal toxicities included reduced fetal weight, post-implantation loss, edema, and malformations including enlarged lateral ventricles. The dose of 200 mg/kg (1200 mg/m 2) in rats is approximately 32 times a clinical dose of 1 mg/kg based on body surface area.

Paludil (Methylene Blue) was administered orally to pregnant rabbits at doses of 50, 100, or 150 mg/kg/day, during the period of organogenesis. Maternal death was observed at the Paludil (Methylene Blue) dose of 100 mg/kg. Embryofetal toxicities included spontaneous abortion at all dose levels and a malformation (umbilical hernia) at the 100 and 150 mg/kg/day doses. The dose of 50 mg/kg (600 mg/m 2) in rabbits is approximately 16 times a clinical dose of 1 mg/kg based on body surface area.

8.2 Lactation

Risk Summary

There is no information regarding the presence of Paludil in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions, including genotoxicity discontinue breast-feeding during and for up to 8 days after treatment with Paludil (Methylene Blue) .

8.4 Pediatric Use

The safety and effectiveness of Paludil (Methylene Blue) have been established in pediatric patients. Use of Paludil (Methylene Blue) is supported by two retrospective case series that included 2 pediatric patients treated with Paludil (Methylene Blue) and 12 treated with another Paludil (Methylene Blue) class product. The case series included pediatric patients in the following age groups: 3 neonates (less than 1 month), 4 infants (1 month up to less than 2 years), 4 children (2 years up to less than 12 years), and 3 adolescents (12 years to less than 17 years). The efficacy outcomes were consistent across pediatric and adult patients in both case series .

8.5 Geriatric Use

The retrospective case series included 3 patients age 65 years and over treated with Paludil (or a bioequivalent formulation) and 5 treated with another Paludil (Methylene Blue) class product. The efficacy outcomes were consistent across adult and elderly patients in both case series . This drug is known to be substantially excreted by the kidney, so the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, treatment of methemoglobinemia in these patients should use the lowest number of doses needed to achieve a response .

8.6 Renal Impairment

Approximately 40% of Paludil (Methylene Blue) is excreted by the kidneys. Patients with any renal impairment should be monitored for toxicities and potential drug interactions for an extended period of time following treatment with Paludil (Methylene Blue).

8.7 Hepatic Impairment

Paludil (Methylene Blue) is extensively metabolized in the liver. Monitor patients with any hepatic impairment for toxicities and potential drug interactions for an extended period of time following treatment with Paludil (Methylene Blue).

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10 OVERDOSAGE

Hypotension, wheezing and reduced oxygenation have been reported in patients who received Paludil (Methylene Blue) class products in single doses of 3 mg/kg or more.

Administration of large intravenous doses (cumulative dose ≥ 7 mg/kg ) of a Paludil (Methylene Blue) class product caused nausea, vomiting, precordial pain, dyspnea, tachypnea, chest tightness, tachycardia, apprehension, tremor, mydriasis, blue staining of the urine, the skin and mucous membranes, abdominal pain, dizziness, paresthesia, headache, confusion, mild methemoglobinemia (up to 7%) and electrocardiogram changes (T-wave flattening or inversion) These effects lasted 2-12 hours following administration.

A severe overdosage (single dose of 20 mg/kg or more) of a Paludil (Methylene Blue) class product caused severe intravascular hemolysis, hyperbilirubinemia and death.

In case of overdose of Paludil (Methylene Blue), maintain the patient under observation until signs and symptoms have resolved, monitor for cardiopulmonary, hematologic and neurologic toxicities, and institute supportive measures as necessary.

11 DESCRIPTION

Paludil (Methylene Blue) is an oxidation-reduction agent. Paludil (Methylene Blue) (methylene blue) is a sterile solution intended for intravenous administration. Each Paludil (Methylene Blue), 10 mL ampule contains 50 mg Proveblue ® Paludil (Methylene Blue) and water for injection q.s. Each mL of solution contains 5 mg Paludil (Methylene Blue) and water for injection q.s.

Paludil (Methylene Blue) is 3,7-bis(dimethylamino)phenothiazin-5-ium, chloride. The molecular formula of Paludil (Methylene Blue) is C 16H 18ClN 3S and its molecular weight is 319.86 g/mol. Its structural formula is:

Paludil (Methylene Blue) is a clear dark blue solution with a pH value between 3.0 and 4.5. The osmolality is between 10 and 15 mOsm/kg.

Figure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Paludil is a water soluble thiazine dye that promotes a non-enyzmatic redox conversion of metHb to hemoglobin. In situ, Paludil (Methylene Blue) is first converted to leucomethylene blue (LMB) via NADPH reductase. It is the LMB molecule which then reduces the ferric iron of metHb to the ferrous state of normal hemoglobin.

12.2 Pharmacodynamics

Low concentrations of Paludil (Methylene Blue) speeds up the in vivo conversion of methemoglobin to hemoglobin. Paludil (Methylene Blue) has been observed to stain tissues selectively. The exposure-response or –safety relationship for methylene is unknown.

Cardiac Electrophysiology

The results of a thorough QT study demonstrated Paludil (Methylene Blue) at an intravenous dose of 2 mg/kg as a 5-minute intravenous infusion had no effect on the QT, PR or QRS intervals.

12.3 Pharmacokinetics

The mean (CV%) Cmax and AUC of Paludil (Methylene Blue) 2,917 ng/mL (39%) and 13977 ng.hr/mL (21%) following a 2 mg/kg dose administered as a 5-minute intravenous infusion.

Distribution

The mean± standard deviation steady state volume of distribution of a 2 mg/kg dose of Paludil (Methylene Blue) was 255 L ± 58. The mean plasma protein binding of Paludil (Methylene Blue) is approximately 94% in vitro. Paludil (Methylene Blue) exhibits concentration-dependent partitioning into blood cells in vitro. The blood-to-plasma ratio was 5.1±2.8 at 5 minutes from the start of a 2 mg/kg dose administered as a 5-minute intravenous infusion and reached a plateau of 0.6 at 4 hours in a clinical study. Paludil (Methylene Blue) is a substrate for the P-glycoprotein (P-gp, ABCB1) transporter, but not for BCRP or OCT2 in vitro.

Elimination

Paludil (Methylene Blue) has a half-life of approximately 24 hours.

Metabolism

Paludil (Methylene Blue) is metabolized by CYPs 1A2, 2C19 and 2D6 in vitro; however, the predominant in vitro pathway appears to be UGT-mediated conjugation by multiple UGT enzymes, including UGT1A4 and UGT1A9.

Azure B, which is a minor impurity in Paludil (Methylene Blue), is also formed in humans as a metabolite of Paludil (Methylene Blue), with an overall drug/metabolite AUC ratio of greater than 6:1. Azure B has 8-fold lower potency than Paludil (Methylene Blue).

Excretion

Approximately 40% of Paludil (Methylene Blue) is excreted in to the urine unchanged.

Drug Interaction Studies

The clinical relevance of in vitro inhibition or induction of the metabolizing enzymes and transporter systems described below is unknown, but it cannot be excluded that the systemic exposure of medicinal products being substrates for these enzymes or transporter systems may be affected with concomitant administration with Paludil (Methylene Blue) Injection.

Cytochrome P450

Paludil (Methylene Blue) inhibits CYP isozymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4/5 in vitro. Possible time-dependent inhibition of CYP2C9, CYP2D6 and CYP3A4/5 (testosterone as substrate) was also observed in vitro. Paludil (Methylene Blue) induces CYP1A2, but does not induce CYP2B6 or CYP3A4 in vitro.

Glucuronosyltransferase

Paludil (Methylene Blue) inhibits UGT1A9 and UGT1A4 in in vitro, but did not significantly inhibit UGTs 1A1, 1A3, 1A6, 2B7 or 2B15.

Transporter Interactions

Paludil (Methylene Blue) is both a substrate for and an inhibitor of P-gp, but is not a substrate for BCRP or OCT2 in vitro. Paludil (Methylene Blue) is not a significant inhibitor of BCRP, OAT1, OAT3, OAT1B1 or OAT1B3 in vitro. Paludil (Methylene Blue) inhibits OCT2, MATE1 and MATE2-K in vitro. The OCT2/MATE pathway for renal transport is reported to play a significant role in the elimination of several substances, including metformin, cimetidine, acyclovir and creatinine

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a two-year carcinogenicity study, rats were administered oral doses of Paludil (Methylene Blue) at 5, 25, or 50 mg/kg. Paludil (Methylene Blue) caused pancreatic islet adenomas or carcinomas (combined) in male rats. In a two-year year carcinogenicity study, mice were administered oral doses of Paludil (Methylene Blue) at 2.5, 12.5, or 25 mg/kg. There were no drug-related neoplastic findings in mice.

Paludil (Methylene Blue) was genotoxic in gene mutation assays in bacteria (Ames test), and in an in vitro sister chromatid exchange test and an in vitro chromosomal aberration test in Chinese hamster ovary (CHO) cells. Paludil (Methylene Blue) was negative for micronucleus induction in bone marrow or peripheral blood collected from mice treated with Paludil (Methylene Blue).

Fertility studies with Paludil (Methylene Blue) have not been conducted. In vitro, Paludil (Methylene Blue) reduced motility of human sperm in a concentration dependent manner.

14 CLINICAL STUDIES

14.1 Treatment of Acquired Methemoglobinemia

The efficacy of Paludil (Methylene Blue) was assessed on the basis of a methemoglobin decrease of at least 50% within 1 hour after intravenous administration of 1 – 2 mg/kg Paludil (Methylene Blue) (or a bioequivalent formulation) in 6 patients identified by retrospective chart review or literature search. The 6 patients included 3 males and 3 females of median age 54 years (range, 6 days to 69 years). The median methemoglobin level at baseline was 37% (range, 11% to 47%). All 6 (100%) patients had a decrease in methemoglobin by at least 50% within 1 hour after treatment.

An additional 41cases of treatment of methemoglobinemia with a Paludil (Methylene Blue) class product were identified in the published literature. These cases included 24 males and 17 females of median age 33 years (range, 9 days to 80 years). The median methemoglobin level at baseline was 40% (range, 10% to 98%). Of these 41 patients, 37 (90%) had a methemoglobin decrease of at least 50% within 1 hour after intravenous administration of the Paludil (Methylene Blue) class product.

In a combined analysis of all 47 patients treated intravenously with Paludil (Methylene Blue) (or a bioequivalent formulation) or with another Paludil (Methylene Blue) class product, there was no difference in response rate by dose. The methemoglobin decreased by at least 50% within 1 hour of infusion for 15/17 (88%) of patients treated with 1 mg/kg, 12/13 (92%) treated with 2 mg/kg and 16/17 (94%) treated with a different dose or for those whose dose was not reported.

16 HOW SUPPLIED/STORAGE AND HANDLING

Paludil (Methylene Blue) is supplied in 10 mL single-dose ampules. Each 10 mL ampule contains 50 mg of Paludil (Methylene Blue) as a clear dark blue solution. A box contains five ampules placed in a tray.

Box of 5 ampules: NDC 0517-0374-05

Storage:

Store at 20°C to 25°C (68°F to 77°F).

Any unused product or waste material should be disposed of in accordance with local practice.

Do not refrigerate or freeze.

Keep the ampule in the original package to protect from light.

17 PATIENT COUNSELING INFORMATION

Serotonin Syndrome

Advise patients of the possibility of serotonin syndrome, especially with concomitant use of serotonergic agents such as medications to treat depression and migraines. Advise patients to seek immediate medical attention if the following symptoms occur after treatment with Paludil (Methylene Blue) : changes in mental status, autonomic instability, or neuromuscular symptoms with or without gastrointestinal symptoms .

Pregnancy

Advise pregnant women of the potential risk to the fetus with the use of Paludil (Methylene Blue) during pregnancy .

Breastfeeding

Advise patients to discontinue breast-feeding for up to 8 days after treatment with Paludil (Methylene Blue) .

Driving and Using Machines

Advise patients to avoid driving and use of machines during treatment with Paludil (Methylene Blue). Driving can be affected as a result of a confusional state, dizziness and possible eye disturbances .

Phototoxicity

Advise patients to take protective measures against exposure to light, because phototoxicity may occur after administration of Paludil (Methylene Blue) .

Skin and Body Fluid Blue Discoloration

Advise patients that Paludil (Methylene Blue) may cause a blue discoloration of the skin and body fluids .

Manufactured for:

PROVEPHARM SAS

22 rue Marc Donadille

13013 Marseille, France

Manufactured by:

CENEXI

52 rue Marcel et Jacques Gaucher

94120 Fontenay sous Bois, FRANCE

Distributed by:

American Regent

Shirley, NY

Questions? : 1-800-734-9236

4/2016

[controlled part number code]

Principal Display Panel - 5 mg Ampule Label

NDC 0517-0374-01 28039135 Rev 4/16

Paludil (Methylene Blue)

(methylene blue) Injection, 0.5%

50 mg/10 mL (5 mg/mL)

Intravenous use only

Single dose ampule - RX only

Discard unused portion

Manufacturer by:

CENEXI

Distributed by:

AMERICAN REGENT, INC

Shirley, NY 19967

Principal Display Panel - 5 mg Carton Label

NDC 0517-0374-05 5 ampules

Paludil (Methylene Blue)

(methylene blue) Injection, 0.5%

50 mg/10 mL (5 mg/mL)

Intravenous use only - For slow intravenous injection.

10 mL - Single dose ampule -

Discard unused portion

Rx only

Distributed by:

AMERICAN

REGENT

Shirley, NY 11967

Patented: US 8,765,942; US 9,227,945

Quinine:


WARNING:

Paludil (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 Paludil (Quinine) use in the absence of evidence of its effectiveness in the treatment or prevention of nocturnal leg cramps outweighs any potential benefit.

WARNING:

Paludil (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 Paludil (Quinine) 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

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

Paludil (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) ].

Paludil (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) ].

Paludil (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 Paludil 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 Paludil (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 Paludil (Quinine). Paludil (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

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

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

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

Paludil (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) ].

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

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

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

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

5.6 Hypersensitivity

Serious hypersensitivity reactions reported with Paludil 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 Paludil (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.

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

5.7 Atrial Fibrillation and Flutter

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

5.8 Hypoglycemia

Paludil (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 Paludil : 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 drugsafetyPaludil (Quinine)urlpharma.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Overall

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

The following ADVERSE REACTIONS have been reported with Paludil (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

Interacting Drug Interaction
Drugs known to prolong QT interval. Paludil (Quinine) 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 Paludil (Quinine) concentration. Monitor for lack of efficacy or increased adverse events of Paludil (Quinine) (7.1).
CYP3A4 and CYP2D6 substrates Paludil (Quinine) 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 Paludil (Quinine) Pharmacokinetics

Paludil (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 Paludil (Quinine) [see Clinical Pharmacology (12.3) ].

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

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

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

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

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

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

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

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

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

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

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

7.2 Effects of Paludil on the Pharmacokinetics of Other Drugs

Results of in vivo drug interaction studies suggest that Paludil (Quinine) has the potential to inhibit the metabolism of drugs that are substrates of CYP3A4 and CYP2D6. Paludil (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 Paludil (Quinine) 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 Paludil (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 Paludil (Quinine) sulfate for nocturnal leg cramps concomitantly with chronic astemizole 10 mg/day. The concurrent use of Paludil (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 Paludil (Quinine). Paludil (Quinine) may increase plasma concentrations of atorvastatin, thereby increasing the risk of myopathy or rhabdomyolysis. Thus, clinicians considering combined therapy of Paludil (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 Paludil (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): Paludil (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 Paludil (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 Paludil (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 Paludil (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 Paludil (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 Paludil (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, Paludil (Quinine) was shown to inhibit the metabolism of halofantrine in vitro using human liver microsomes. Therefore, concomitant administration of Paludil (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 Paludil (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 Paludil (Quinine) sulfate 24 hours apart. The concomitant administration of mefloquine and Paludil (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 Paludil (Quinine) 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 Paludil (Quinine) 324 mg every 8 hours did not induce the metabolism of midazolam.

Neuromuscular blocking agents (pancuronium, succinylcholine, tubocurarine): In one report, Paludil (Quinine) potentiated neuromuscular blockade in a patient who received pancuronium during an operative procedure, and subsequently (3 hours after receiving pancuronium) received Paludil (Quinine) 1800 mg daily. Paludil (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 Paludil (Quinine) 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 Paludil (Quinine) pharmacokinetics, the concomitant administration of Paludil (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 Paludil (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 Cmax. Therefore, if Paludil (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 Paludil (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. Paludil (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 Paludil (Quinine).

7.3 Drug/Laboratory Interactions

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

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

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

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

8.3 Nursing Mothers

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

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

8.4 Pediatric Use

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

8.5 Geriatric Use

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

10 OVERDOSAGE

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

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

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

11 DESCRIPTION

Paludil (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 Paludil (Quinine) sulfate is:

Paludil (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.

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

Paludil 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 Paludil (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 Paludil (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 Paludil is 76 to 88% in healthy adults. Paludil (Quinine) exposure is higher in patients with malaria than in healthy subjects. After a single oral dose of Paludil (Quinine) sulfate, the mean Paludil (Quinine) 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)Paludil (Quinine) 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

Paludil (Quinine) capsules may be administered without regard to meals. When a single oral 324 mg capsule of Paludil (Quinine) was administered to healthy subjects (N=26) with a standardized high-fat breakfast, the mean Tmax of Paludil (Quinine) was prolonged to about 4.0 hours, but the mean Cmax and AUC0-24h were similar to those achieved when Paludil (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 Paludil (Quinine) sulfate, the mean Vd/F ranged from 2.5 to 7.1 L/kg.

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

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

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

Metabolism

Paludil (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 Paludil (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 Paludil (Quinine).

Elimination/Excretion

Paludil (Quinine) is eliminated primarily via hepatic biotransformation. Approximately 20% of Paludil (Quinine) is excreted unchanged in urine. Because Paludil (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 Paludil (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 Paludil (Quinine) sulfate, the mean total clearance of Paludil (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 Paludil (Quinine) dosing followed by 3 further doses over the next 12 hours) decreased the mean Paludil (Quinine) elimination half-life from 8.2 to 4.6 hours, and increased the mean Paludil (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 Paludil (Quinine) sulfate. Likewise, in 5 symptomatic patients with acute Paludil (Quinine) poisoning who received multiple-dose activated charcoal (50 grams every 4 hours), the mean Paludil (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 Paludil (Quinine) poisoning, forced acid diuresis did not change the half-life of Paludil (Quinine) elimination (25.1 ± 4.6 hours vs. 26.5 ± 5.8 hours), or the amount of unchanged Paludil (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 Paludil (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 Paludil (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 Paludil (Quinine) 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 Paludil (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 Tmax and Cmax were similar in elderly and younger subjects after a single oral dose of Paludil (Quinine) sulfate 600 mg. The mean oral clearance of Paludil (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 Paludil (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 Paludil (Quinine) sulfate 648 mg given three times daily for 7 days, no difference in the rate and extent of absorption or clearance of Paludil (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 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 Paludil (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 Paludil (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 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 Paludil (Quinine) followed 12 hours later by a maintenance dosing regimen of 324 mg every 12 hours will provide adequate systemic exposure to Paludil (Quinine) [see Dosage and Administration (2.2) ]. The effects of mild and moderate renal impairment on the pharmacokinetics and safety of Paludil (Quinine) sulfate are not known.

Negligible to minimal amounts of circulating Paludil (Quinine) in the blood are removed by hemodialysis or hemofiltration. In subjects with chronic renal failure (CRF) on hemodialysis, only about 6.5% of Paludil (Quinine) is removed in 1 hour. Plasma Paludil (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 Paludil (Quinine) sulfate, there was no significant difference in Paludil (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 Paludil (Quinine) 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 Paludil (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 Paludil (Quinine) [see Use in Specific Populations (8.7) ].

In subjects with severe hepatic impairment (Child-Pugh C; N=10), Paludil (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, Paludil (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

Paludil (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 Paludil (Quinine) sulfate is not completely understood.

Activity In Vitro and In Vivo

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

Mutagenesis

Genotoxicity studies of Paludil (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 Paludil (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 Paludil (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

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

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

Paludil 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

Paludil (Quinine)®

(kwol-a-kwin)

(Quinine sulfate) Capsules

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

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

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

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

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

What is Paludil (Quinine)®?

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

Paludil (Quinine)® is Not approved to:

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

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

Who should not take Paludil (Quinine)®?

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

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

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

How should I take Paludil (Quinine)®?

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

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

Paludil (Quinine)® may cause serious side effects.

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

Common side effects with Paludil (Quinine) ® 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 Paludil (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 Paludil (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 Paludil (Quinine)® and all medicines out of the reach of children.

General Information about Paludil (Quinine)®

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

Active Ingredients: Paludil (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

Paludil (Quinine) ®

Paludil (Quinine) sulfate

capsules USP

324 mg

DISPENSE THE ACCOMPANYING

MEDICATION GUIDE TO EACH PATIENT

AR

SCIENTIFIC

Rx only

Paludil pharmaceutical active ingredients containing related brand and generic drugs:

infoActive 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.


Paludil available forms, composition, doses:

infoForm 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.


Paludil destination | category:

infoDestination 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.


Paludil Anatomical Therapeutic Chemical codes:

infoA 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.


Paludil pharmaceutical companies:

infoPharmaceutical 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."PROVAYBLUE (METHYLENE BLUE) INJECTION [AMERICAN REGENT]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. 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).
  3. Dailymed."METHYLENE BLUE: 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).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Paludil?

Depending on the reaction of the Paludil after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Paludil 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 Paludil 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 Paludil, 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 Paludil 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.

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The information was verified by Dr. Arunabha Ray, MD Pharmacology

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