Togal

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Togal uses

Togal consists of Aspirin, Lithium Citrate, Quinine Dihydrochloride.

Aspirin:


Pharmacological action

Togal is a NSAIDs. It has anti-inflammatory, analgesic and antipyretic effect, and inhibits platelet aggregation. The mechanism of action is associated with inhibition of COX activity - the main enzyme metabolism of arachidonic acid which is a precursor of prostaglandins which play a major role in the pathogenesis of inflammation, pain and fever. Reduction of prostaglandins (mainly E1) in the thermoregulation center leads to a decrease in body temperature due to expansion of blood vessels of the skin and increase perspiration. Analgesic effect of Togal (Aspirin) is due to both central and peripheral effects. Reduces aggregation, platelet adhesion and thrombus formation through suppression of synthesis of thromboxane A2 in platelets.

Reduces mortality and risk of myocardial infarction in unstable stenocardia. It is effective in primary prevention of cardio-vascular system and secondary prevention of myocardial infarction. At a daily dose of 6 g or more inhibits the synthesis of prothrombin in the liver and increases the prothrombin time. Togal (Aspirin) increases fibrinolytic activity of plasma and reduces the concentration of vitamin K-dependent coagulation factors (II, VII, IX, X). Increases the rate of hemorrhagic complications in carrying out surgical procedures, increases the risk of bleeding during therapy with anticoagulants. It stimulates the excretion of uric acid (violating its reabsorption in the renal tubules) but in high doses. The blockade of COX-1 in the mucosa of the stomach leads to inhibition of gastroprotective prostaglandins, which may lead to ulceration of the mucous membrane and subsequent bleeding.

Pharmacokinetics

When administered orally Togal (Aspirin) is rapidly absorbed mainly from the proximal small intestine and to a lesser extent from the stomach. The presence of food in the stomach significantly affects the absorption of Togal (Aspirin).

Metabolised in the liver by hydrolysis with the formation of salicylic acid with subsequent conjugation with glycine or two drugs. The concentration of salicylates in blood plasma is variable.

About 80% of salicylic acid binds to plasma proteins. Salicylates easily penetrate into many tissues and body fluids, including the cerebrospinal, peritoneal and synovial fluid. In small quantities salicylates are found in brain tissue, traces - in bile, sweat and feces. Quickly penetrates the placental barrier in small amounts excreted in breast milk.

For newborns salicylates may displace bilirubin from its association with albumin and promote bilirubin encephalopathy.

Penetration into the joint cavity is accelerated in the presence of hyperemia and edema, and slows down in the proliferative phase of inflammation.

If you have acidosis most of salicylate becomes unionized acid, good penetration into the tissue, including in the brain.

Togal (Aspirin) withdraws mainly by active secretion in the tubules of the kidneys in unchanged form (60%) and in the form of metabolites. The withdraw of unchanged salicylate is dependent on the pH of urine (for alkalinization of urine increases ionized salicylates, worsening their reabsorption and increases excretion). T1/2 of Togal (Aspirin) is approximately 15 minutes. T1/2 of salicylate at a reception in low doses is 2-3 h, with an increase in dose may increase to 15-30 hours. Newborns' elimination of salicylate is much slower than in adults.

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Why is Togal prescribed?

Rheumatism, rheumatoid arthritis, infectious-allergic myocarditis, fever during infectious and inflammatory diseases, pain syndrome, weak and medium intensity of various origins (including neuralgia, myalgia, headache); based prevention of thrombosis and embolism, primary and secondary prevention of myocardial infarction, prevention of violations of cerebral circulation by ischemic type.

In the clinical immunology and allergy: a gradually increasing doses for a prolonged "aspirin" desensitization and the formation of stable tolerance to NSAIDs in patients with "aspirin asthma" and "aspirin triad."

Dosage and administration

Individual. For oral administration dosing of Togal regimen depends on indication for use. Usual adult dose when used as antipyretic and analgesic is 500-1000 mg / day (up to 3 g) were divided into 3 admission.

In myocardial infarction, as well as for secondary prevention in patients after myocardial infarction - 40-325 mg 1 time a day (usually 160 mg). As an inhibitor of platelet aggregation - a dose of 300-325 mg / day, for a long time. At the dynamic circulatory disorders in men, cerebral thromboembolism, including to prevent a recurrence - 325 mg / day with gradual increase to a maximum of 1 g / day. For prevention of thrombosis or occlusion of the aortic shunt - by 325 mg every 7 h after intranasal gastric tube set, and then - through the mouth to 325 mg 3 times a day (usually in combination with dipyridamole, which abolished after 1 week, continuing the long-term treatment with Togal (Aspirin)).

Togal (Aspirin) side effects, adverse reactions

Digestive system: nausea, vomiting, anorexia, epigastric pain, diarrhea; rarely - occurrence of erosive and ulcerative lesions, bleeding from the gastrointestinal tract, abnormal liver function.

Central nervous system: long-term use may be dizziness, headache, reversible visual disturbances, tinnitus, aseptic meningitis.

Hemopoietic system: rarely - thrombocytopenia, anemia.

Blood coagulation system: rarely - haemorrhagic syndrome, prolongation of bleeding time.

Urinary system: rarely - renal dysfunction, with prolonged use - acute kidney failure, nephrotic syndrome.

Allergic reactions: rarely - skin rash, Quincke's edema, bronchospasm, "aspirin triad" (a combination of bronchial asthma, recurrent nasal polyposis, and paranasal sinuses and intolerance of Togal (Aspirin) and medicines pirazolonic series).

Other: in some cases - Reye syndrome, long-term use - increased symptoms of chronic heart failure.

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Togal contraindications

Exacerbation phase of erosive-ulcerative lesions in the gastrointestinal tract, gastro-intestinal bleeding, "aspirin triad", a history of indications urticaria, rhinitis, caused by taking Togal (Aspirin) and other NSAIDs, hemophilia, hemorrhagic diathesis, gipoprotrombinemii, dissecting aneurysm of the aorta, portal hypertension, deficiency of vitamin K, liver and / or renal failure, deficiency of glucose-6-phosphate dehydrogenase, Reye syndrome, children's age (under 15 years - the risk of developing Reye syndrome in children with hyperthermia on a background of viral diseases), I and III trimester of pregnancy, lactation, hypersensitivity to Togal (Aspirin) and other salicylates.

Using during pregnancy and breastfeeding

Togal (acetylsalicylic acid) is contraindicated in I and III trimester of pregnancy. In pregnancy trimester II can a one-off reception on the strict condition.

This medication has a teratogenic effect: when used in the I trimester leads to top palatoschisis, in the III trimester - cause inhibition of labor (inhibition of prostaglandin synthesis), premature closure of the ductus arteriosus in the fetus, pulmonary vascular hyperplasia and hypertension in the pulmonary circulation.

Togal (Aspirin) (acetylsalicylic acid) is excreted in breast milk, which increases the risk of bleeding in a child due to dysfunction of platelets, and therefore should not be applied Togal (Aspirin) in the mother during lactation.

Special instructions

Togal (Aspirin) with caution used in patients with liver diseases and kidney, bronchial asthma, erosive and ulcerative lesions, and bleeding from the digestive tract in history, with increased bleeding or while holding anticoagulant therapy, decompensated congestive heart failure.

Togal (Aspirin) even in small doses reduces the excretion of uric acid from the organism that can cause an acute attack of gout in predisposed patients. When conducting long-term therapy and / or use of Togal (Aspirin) in high doses required medical supervision and regular monitoring of hemoglobin levels.

The use of Togal (Aspirin) as anti-inflammatory drugs in a daily dose of 5-8 g is limited due to the high probability of adverse effects from the gastrointestinal tract.

Before surgery to reduce bleeding during surgery and postoperative period should stop taking salicylates for 5-7 days.

During prolonged therapy is necessary to conduct a general analysis of blood and study of occult blood.

The use of Togal (Aspirin) is contraindicated in pediatrics, as in the case of viral infection in children under the influence of Togal (Aspirin) increases the risk of developing Reye syndrome. Symptoms of Reye syndrome are prolonged vomiting, acute encephalopathy, liver enlargement.

Duration of treatment (without consulting a doctor) with Togal (Aspirin) should not exceed 7 days when administered as analgesic and more than 3 days as an antipyretic.

During treatment the patient should abstain from alcohol.

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Precautionary measures

Undesirable combined use with other NSAIDs and glucocorticoids. For 5-7 days before surgery should stop taking.

The probability of NSAID-gastropathy decreases in the appointment after a meal, use of tablets with buffer additives or coated with a special enteric-soluble shell. The risk of hemorrhagic complications is minimal when used in doses less than 100 mg / day.

Note that in predisposed patients Togal (Aspirin) (even in small doses) reduces the excretion of uric acid from the body and can cause the development of acute attack of gout.

During prolonged therapy should regularly carry out the analysis of blood and to investigate faeces for occult blood. In connection with the observed cases hepatogenic encephalopathy is not recommended for relief of fever syndrome in children.

Togal (Aspirin) drug interactions

With simultaneous use of antacids containing magnesium and / or aluminum hydroxide, slow down and reduce the absorption of Togal (Aspirin).

With simultaneous use of calcium channel blockers, means limiting intake of calcium or increasing the excretion of calcium from the body, increases the risk of bleeding.

With simultaneous use with Togal (Aspirin) enhances the action of heparin and indirect anticoagulants, hypoglycemic funds derived sulfonylureas, insulin, methotrexate, phenytoin, valproic acid.

With simultaneous use of Togal (Aspirin) with SCS increases the risk of ulcerogenic effect and occurrence of gastrointestinal bleeding.

With simultaneous use of decreasing the effectiveness of diuretics (spironolactone, furosemide).

With simultaneous use of other NSAIDs increases the risk of side effects. Togal (Aspirin) may reduce plasma concentrations indomethacin, piroxicam.

With simultaneous use of gold drugs Togal (Aspirin) can induce liver damage.

With simultaneous use decreases effectiveness of uricosuric medications (including probenecid, sulfinpirazon, benzbromarone).

With simultaneous use of Togal (Aspirin) and alendronate sodium may develop severe esophagitis.

With simultaneous use of griseofulvin may be in breach Absorption of Togal (Aspirin).

There is one case of spontaneous hemorrhage in the iris while taking Ginkgo Biloba extract on the background of prolonged use of Togal (Aspirin) in a dose of 325 mg / day. It is believed that this may be due to additive inhibitory effect on platelet aggregation.

With simultaneous use of dipyridamole may increase Cmax of salicylate in plasma and AUC.

When applied simultaneously with Togal (Aspirin) increased concentration of digoxin, barbiturates and lithium salts in the blood plasma.

With simultaneous use of salicylates in high doses with carbonic anhydrase inhibitors can intoxication salicylates.

Togal (Aspirin) in doses of less than 300 mg have little effect on the effectiveness of captopril and enalapril. When Togal (Aspirin) (acetylsalicylic acid) is admistered in high doses may decrease the effectiveness of captopril and enalapril.

With simultaneous application of caffeine increases the rate of absorption, plasma concentrations and bioavailability of Togal (Aspirin).

With simultaneous use of Togal (Aspirin) with metoprolol may increase Cmax of salicylate in blood plasma.

In the application of pentazocine on the background of long-term use of Togal (Aspirin) in high doses there is a risk of severe adverse reactions in the kidneys.

With simultaneous application phenylbutazone reduces uricosuria caused by Togal (Aspirin).

With simultaneous application of ethanol may exacerbate the effects of Togal (Aspirin) on the gastrointestinal tract.

Togal in case of emergency / overdose

May occur after receiving a single large dose or prolonged use. If a single dose of less than 150 mg / kg, acute poisoning feel light, 150-300 mg / kg - moderate, when using higher doses - heavy.

Symptoms: salicylism syndrome (nausea, vomiting, tinnitus, blurred vision, dizziness, severe headache, malaise, fever - a poor prognostic sign in adults). More severe poisoning - stupor, convulsions and coma, noncardiogenic pulmonary edema, abrupt dehydration, violations ABE (initially - respiratory alkalosis, then - metabolic acidosis), renal failure and shock.

In chronic overdose concentration determined in plasma are poorly correlated with the severity of intoxication. The greatest risk of chronic intoxication is found among elderly people at reception for a few days more than 100 mg / kg / day. In children and elderly patients the initial signs of salicylism are not always visible, and therefore desirable to periodically determine the concentration of salicylates in the blood. Level above 70 mg% indicates moderate or severe poisoning; above 100 mg% - on extremely heavy, a poor prognosis. If poisoning moderate require hospitalization for at least 24 hours.

Treatment: the provocation of vomiting, the appointment of activated charcoal and laxatives, monitoring ABE and electrolyte balance, depending on the state of metabolism - the introduction of sodium bicarbonate, solution of sodium citrate or sodium lactate. Raising reserve alkalinity increases the excretion of Togal (Aspirin) by alkalinization of urine. Alkalinization of urine is shown at the level of salicylates above 40 mg%, is provided in / by infusion of sodium bicarbonate - 88 mEq in 1 liter of 5% glucose solution, the rate of 10-15 ml / kg / h. Restoring BCC and induction of diuresis (achieved by introducing a bicarbonate in the same dose and dilution, repeat 2-3 times); should be aware that intense infusion fluid elderly patients may lead to pulmonary edema. Not recommended the use of acetazolamide for alkalinization of urine (may cause acidemia and enhance the toxic effect of salicylates). Hemodialysis is shown at the level of salicylates over 100-130 mg%, and in patients with chronic poisoning - 40 mg% or lower in the presence of witnesses (refractory acidosis, progressive deterioration, severe damage of the CNS, pulmonary edema and renal failure). When pulmonary edema - a mixture of artificial ventilation, oxygen enriched, in the mode of positive end-expiratory pressure, to treat cerebral edema apply hyperventilation and osmotic diuresis.

Lithium Citrate:


Rx only

WARNING

Togal (Lithium Citrate) toxicity is closely related to serum Togal (Lithium Citrate) levels, and can occur at doses close to therapeutic levels. Facilities for prompt and accurate serum Togal (Lithium Citrate) determinations should be available before initiating therapy.

DESCRIPTION

Togal (Lithium Citrate) Carbonate Extended-release Tablets USP contain Togal (Lithium Citrate) carbonate USP, a white granular powder with molecular formula Li2CO3 and molecular weight 73.89. Togal (Lithium Citrate) is an element of the alkali-metal group with atomic number 3, atomic weight 6.94 and an emission line at 671 nm on the flame photometer. The tablets meet the requirements of USP Dissolution Test 2 in the USP monograph for Togal (Lithium Citrate) Carbonate Extended-release Tablets USP.

Togal (Lithium Citrate) Carbonate Extended-release Tablets USP are available for oral administration containing 450 mg of Togal (Lithium Citrate) carbonate USP. Each tablet contains the following inactive ingredients: iron oxide (yellow), magnesium stearate, povidone, sodium alginate and sodium starch glycolate.

Togal (Lithium Citrate) Carbonate Extended-release Tablets USP, 450 mg are designed to release a portion of the dose initially and the remainder gradually; the release pattern of the controlled release tablets reduces the variability in Togal (Lithium Citrate) blood levels seen with the immediate release dosage forms.

ACTIONS

Preclinical studies have shown that Togal (Lithium Citrate) alters sodium transport in nerve and muscle cells and effects a shift toward intraneuronal metabolism of catecholamines, but the specific biochemical mechanism of Togal (Lithium Citrate) action in mania is unknown.

INDICATIONS

Togal (Lithium Citrate) carbonate is indicated in the treatment of manic episodes of manic-depressive illness. Maintenance therapy prevents or diminishes the intensity of subsequent episodes in those manic-depressive patients with a history of mania.

Typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, elation, poor judgment, aggressiveness and possibly hostility. When given to a patient experiencing a manic episode, Togal (Lithium Citrate) carbonate may produce a normalization of symptomatology within 1 to 3 weeks.

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WARNINGS

Togal Toxicity

Togal (Lithium Citrate) toxicity is closely related to serum Togal (Lithium Citrate) levels, and can occur at doses close to therapeutic levels.

Outpatients and their families should be warned that the patient must discontinue Togal (Lithium Citrate) carbonate therapy and contact his physician if such clinical signs of Togal (Lithium Citrate) toxicity as diarrhea, vomiting, tremor, mild ataxia, drowsiness or muscular weakness occur.

Togal (Lithium Citrate) carbonate may impair mental and/or physical abilities. Caution patients about activities requiring alertness (e.g., operating vehicles or machinery).

Togal (Lithium Citrate) should generally not be given to patients with significant renal or cardiovascular disease, severe debilitation or dehydration, or sodium depletion, since the risk of Togal (Lithium Citrate) toxicity is very high in such patients. If the psychiatric indication is life-threatening, and if such a patient fails to respond to other measures, Togal (Lithium Citrate) treatment may be undertaken with extreme caution, including daily serum Togal (Lithium Citrate) determinations and adjustment to the usually low doses ordinarily tolerated by these individuals. In such instances, hospitalization is a necessity.

Unmasking of Brugada Syndrome

There have been postmarketing reports of a possible association between treatment with Togal and the unmasking of Brugada Syndrome. Brugada Syndrome is a disorder characterized by abnormal electrocardiographic (ECG) findings and a risk of sudden death. Togal (Lithium Citrate) should generally be avoided in patients with Brugada Syndrome or those suspected of having Brugada Syndrome. Consultation with a cardiologist is recommended if: (1) treatment with Togal (Lithium Citrate) is under consideration for patients suspected of having Brugada Syndrome or patients who have risk factors for Brugada Syndrome, e.g., unexplained syncope, a family history of Brugada Syndrome, or a family history of sudden unexplained death before the age of 45 years, (2) patients who develop unexplained syncope or palpitations after starting Togal (Lithium Citrate) therapy.

Renal Effects

Chronic Togal (Lithium Citrate) therapy may be associated with diminution of renal concentrating ability, occasionally presenting as nephrogenic diabetes insipidus, with polyuria and polydipsia. Such patients should be carefully managed to avoid dehydration with resulting Togal (Lithium Citrate) retention and toxicity. This condition is usually reversible when Togal (Lithium Citrate) is discontinued.

Morphologic changes with glomerular and interstitial fibrosis and nephron atrophy have been reported in patients on chronic Togal (Lithium Citrate) therapy. Morphologic changes have also been seen in manic-depressive patients never exposed to Togal (Lithium Citrate). The relationship between renal functional and morphologic changes and their association with Togal (Lithium Citrate) therapy have not been established.

When kidney function is assessed, for baseline data prior to starting Togal (Lithium Citrate) therapy or thereafter, routine urinalysis and other tests may be used to evaluate tubular function (e.g., urine specific gravity or osmolality following a period of water deprivation, or 24-hour urine volume) and glomerular function (e.g., serum creatinine or creatinine clearance). During Togal (Lithium Citrate) therapy, progressive or sudden changes in renal function, even within the normal range, indicate the need for reevaluation of treatment.

Encephalopathic Syndrome

An encephalopathic syndrome has occurred in a few patients treated with Togal (Lithium Citrate) plus a neuroleptic. In some instances, the syndrome was followed by irreversible brain damage. Because of a possible causal relationship between these events and the concomitant administration of Togal (Lithium Citrate) and neuroleptics, patients receiving such combined therapy should be monitored closely for early evidence of neurologic toxicity and treatment discontinued promptly if such signs appear. This encephalopathic syndrome may be similar to or the same as neuroleptic malignant syndrome (NMS).

Concomitant Use With Neuromuscular Blocking Agents

Togal (Lithium Citrate) may prolong the effects of neuromuscular blocking agents. Therefore, neuromuscular blocking agents should be given with caution to patients receiving Togal (Lithium Citrate).

Usage in Pregnancy

Adverse effects on implantation in rats, embryo viability in mice and metabolism in vitro of rat testes and human spermatozoa have been attributed to Togal, as have teratogenicity in submammalian species and cleft palates in mice.

In humans, Togal (Lithium Citrate) carbonate may cause fetal harm when administered to a pregnant woman. Data from Togal (Lithium Citrate) birth registries suggest an increase in cardiac and other anomalies, especially Ebstein's anomaly. If this drug is used in women of childbearing potential, or during pregnancy, or if a patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Usage in Nursing Mothers

Togal (Lithium Citrate) is excreted in human milk. Nursing should not be undertaken during Togal (Lithium Citrate) therapy except in rare and unusual circumstances where, in the view of the physician, the potential benefits to the mother outweigh possible hazards to the child.

Usage in Pediatric Patients

Since information regarding the safety and effectiveness of Togal carbonate in children under 12 years of age is not available, its use in such patients is not recommended.

There has been a report of a transient syndrome of acute dystonia and hyperreflexia occurring in a 15 kg child who ingested 300 mg of Togal (Lithium Citrate) carbonate.

Usage in the Elderly

Elderly patients often require lower Togal (Lithium Citrate) dosages to achieve therapeutic serum levels. They may also exhibit adverse reactions at serum levels ordinarily tolerated by younger patients.

PRECAUTIONS

General

The ability to tolerate Togal is greater during the acute manic phase and decreases when manic symptoms subside.

The distribution space of Togal (Lithium Citrate) approximates that of total body water. Togal (Lithium Citrate) is primarily excreted in urine with insignificant excretion in feces. Renal excretion of Togal (Lithium Citrate) is proportional to its plasma concentration. The half-life of elimination of Togal (Lithium Citrate) is approximately 24 hours. Togal (Lithium Citrate) decreases sodium reabsorption by the renal tubules which could lead to sodium depletion. Therefore, it is essential for the patient to maintain a normal diet, including salt, and an adequate fluid intake (2500 to 3000 mL) at least during the initial stabilization period. Decreased tolerance to Togal (Lithium Citrate) has been reported to ensue from protracted sweating or diarrhea and, if such occur, supplemental fluid and salt should be administered under careful medical supervision and Togal (Lithium Citrate) intake reduced or suspended until the condition is resolved.

In addition to sweating and diarrhea, concomitant infection with elevated temperatures may also necessitate a temporary reduction or cessation of medication.

Previously existing underlying thyroid disorders do not necessarily constitute a contraindication to Togal (Lithium Citrate) treatment; where hypothyroidism exists, careful monitoring of thyroid function during Togal (Lithium Citrate) stabilization and maintenance allows for correction of changing thyroid parameters, if any; where hypothyroidism occurs during Togal (Lithium Citrate) stabilization and maintenance, supplemental thyroid treatment may be used.

Information for the Patients

A condition known as Brugada Syndrome may pre-exist and be unmasked by Togal (Lithium Citrate) therapy. Brugada Syndrome is a heart disorder characterized by abnormal electrocardiographic (ECG) findings and risk of sudden death. Patients should be advised to seek immediate emergency assistance if they experience fainting, lightheadedness, abnormal heart beats, or shortness of breath.

Drug Interactions

Caution should be used when Togal (Lithium Citrate) and diuretics are used concomitantly because diuretic-induced sodium loss may reduce the renal clearance of Togal (Lithium Citrate) and increase serum Togal (Lithium Citrate) levels with risk of Togal (Lithium Citrate) toxicity. Patients receiving such combined therapy should have serum Togal (Lithium Citrate) levels monitored and the Togal (Lithium Citrate) dosage adjusted if necessary.

Togal (Lithium Citrate) levels should be closely monitored when patients initiate or discontinue NSAID use. In some cases, Togal (Lithium Citrate) toxicity has resulted from interactions between an NSAID and Togal (Lithium Citrate). Indomethacin and piroxicam have been reported to increase significantly steady-state plasma Togal (Lithium Citrate) concentrations. There is also evidence that other nonsteroidal anti-inflammatory agents, including the selective cyclooxygenase-2 (COX-2) inhibitors, have the same effect. In a study conducted in healthy subjects, mean steady-state Togal (Lithium Citrate) plasma levels increased approximately 17% in subjects receiving Togal (Lithium Citrate) 450 mg b.i.d. with celecoxib 200 mg b.i.d. as compared to subjects receiving Togal (Lithium Citrate) alone.

Concurrent use of metronidazole with Togal (Lithium Citrate) may provoke Togal (Lithium Citrate) toxicity due to reduced renal clearance. Patients receiving such combined therapy should be monitored closely.

There is evidence that angiotensin-converting enzyme inhibitors, such as enalapril and captopril, and angiotension II receptor antagonists, such as losartan, may substantially increase steady-state plasma Togal (Lithium Citrate) levels, sometimes resulting in Togal (Lithium Citrate) toxicity. When such combinations are used, Togal (Lithium Citrate) dosage may need to be decreased, and plasma Togal (Lithium Citrate) levels should be measured more often.

Concurrent use of calcium channel blocking agents with Togal (Lithium Citrate) may increase the risk of neurotoxicity in the form of ataxia, tremors, nausea, vomiting, diarrhea and/or tinnitus. Caution is recommended.

The concomitant administration of Togal (Lithium Citrate) with selective serotonin reuptake inhibitors should be undertaken with caution as this combination has been reported to result in symptoms such as diarrhea, confusion, tremor, dizziness and agitation.

The following drugs can lower serum Togal (Lithium Citrate) concentrations by increasing urinary Togal (Lithium Citrate) excretion: acetazolamide, urea, xanthine preparations and alkalinizing agents such as sodium bicarbonate.

The following have also been shown to interact with Togal (Lithium Citrate): methyldopa, phenytoin and carbamazepine.

ADVERSE REACTIONS

The occurrence and severity of adverse reactions are generally directly related to serum Togal (Lithium Citrate) concentrations as well as to individual patient sensitivity to Togal (Lithium Citrate), and generally occur more frequently and with greater severity at higher concentrations.

Adverse reactions may be encountered at serum Togal (Lithium Citrate) levels below 1.5 mEq/L. Mild to moderate adverse reactions may occur at levels from 1.5 to 2.5 mEq/L, and moderate to severe reactions may be seen at levels of 2 mEq/L and above.

Fine hand tremor, polyuria and mild thirst may occur during initial therapy for the acute manic phase, and may persist throughout treatment. Transient and mild nausea and general discomfort may also appear during the first few days of Togal (Lithium Citrate) administration.

These side effects usually subside with continued treatment or a temporary reduction or cessation of dosage. If persistent, cessation of Togal (Lithium Citrate) therapy may be required.

Diarrhea, vomiting, drowsiness, muscular weakness and lack of coordination may be early signs of Togal (Lithium Citrate) intoxication, and can occur at Togal (Lithium Citrate) levels below 2 mEq/L. At higher levels, ataxia, giddiness, tinnitus, blurred vision and a large output of dilute urine may be seen. Serum Togal (Lithium Citrate) levels above 3 mEq/L may produce a complex clinical picture, involving multiple organs and organ systems. Serum Togal (Lithium Citrate) levels should not be permitted to exceed 2 mEq/L during the acute treatment phase.

The following reactions have been reported and appear to be related to serum Togal (Lithium Citrate) levels, including levels within the therapeutic range:

Neuromuscular/Central Nervous System: tremor, muscle hyperirritability (fasciculations, twitching, clonic movements of whole limbs), hypertonicity, ataxia, choreo-athetotic movements, hyperactive deep tendon reflex, extrapyramidal symptoms including acute dystonia, cogwheel rigidity, blackout spells, epileptiform seizures, slurred speech, dizziness, vertigo, downbeat nystagmus, incontinence of urine or feces, somnolence, psychomotor retardation, restlessness, confusion, stupor, coma, tongue movements, tics, tinnitus, hallucinations, poor memory, slowed intellectual functioning, startled response, worsening of organic brain syndromes, myasthenia gravis (rarely).

Cardiovascular: cardiac arrhythmia, hypotension, peripheral circulatory collapse, bradycardia, sinus node dysfunction with severe bradycardia (which may result in syncope), unmasking of Brugada Syndrome (See WARNINGS: Unmasking of Brugada Syndrome and PRECAUTIONS: Information for the Patients ).

Gastrointestinal: anorexia, nausea, vomiting, diarrhea, gastritis, salivary gland swelling, abdominal pain, excessive salivation, flatulence, indigestion.

Genitourinary: glycosuria, decreased creatinine clearance, albuminuria, oliguria, and symptoms of nephrogenic diabetes insipidus including polyuria, thirst and polydipsia.

Dermatologic: drying and thinning of hair, alopecia, anesthesia of skin, acne, chronic folliculitis, xerosis cutis, psoriasis or its exacerbation, generalized pruritus with or without rash, cutaneous ulcers, angioedema.

Autonomic: blurred vision, dry mouth, impotence/sexual dysfunction.

Thyroid Abnormalities: euthyroid goiter and/or hypothyroidism (including myxedema) accompanied by lower T3 and T4. I131 uptake may be elevated. Paradoxically, rare cases of hyperthyroidism have been reported.

EEG Changes: diffuse slowing, widening of the frequency spectrum, potentiation and disorganization of background rhythm.

EKG Changes: reversible flattening, isoelectricity or inversion of T-waves.

Miscellaneous: fatigue, lethargy, transient scotomata, exophthalmos, dehydration, weight loss, leukocytosis, headache, transient hyperglycemia, hypercalcemia, hyperparathyroidism, excessive weight gain, edematous swelling of ankles or wrists, metallic taste, dysgeusia/taste distortion, salty taste, thirst, swollen lips, tightness in chest, swollen and/or painful joints, fever, polyarthralgia, dental caries.

Some reports of nephrogenic diabetes insipidus, hyperparathyroidism and hypothyroidism which persist after Togal (Lithium Citrate) discontinuation have been received.

A few reports have been received of the development of painful discoloration of fingers and toes and coldness of the extremities within one day of the starting of treatment with Togal (Lithium Citrate). The mechanism through which these symptoms (resembling Raynaud's syndrome) developed is not known. Recovery followed discontinuance.

Cases of pseudotumor cerebri (increased intracranial pressure and papilledema) have been reported with Togal (Lithium Citrate) use. If undetected, this condition may result in enlargement of the blind spot, constriction of visual fields and eventual blindness due to optic atrophy. Togal (Lithium Citrate) should be discontinued, if clinically possible, if this syndrome occurs.

OVERDOSAGE

The toxic levels for Togal are close to the therapeutic levels. It is therefore important that patients and their families be cautioned to watch for early toxic symptoms and to discontinue the drug and inform the physician should they occur. Toxic symptoms are listed in detail under ADVERSE REACTIONS.

Treatment

No specific antidote for Togal (Lithium Citrate) poisoning is known. Early symptoms of Togal (Lithium Citrate) toxicity can usually be treated by reduction or cessation of dosage of the drug and resumption of the treatment at a lower dose after 24 to 48 hours. In severe cases of Togal (Lithium Citrate) poisoning, the first and foremost goal of treatment consists of elimination of this ion from the patient. Treatment is essentially the same as that used in barbiturate poisoning: 1) gastric lavage, 2) correction of fluid and electrolyte imbalance, and 3) regulation of kidney function. Urea, mannitol and aminophylline all produce significant increases in Togal (Lithium Citrate) excretion. Hemodialysis is an effective and rapid means of removing the ion from the severely toxic patient. Infection prophylaxis, regular chest X-rays and preservation of adequate respiration are essential.

DOSAGE AND ADMINISTRATION

Doses of extended-release tablets are usually given b.i.d.. When initiating therapy with immediate-release or extended-release Togal (Lithium Citrate), dosage must be individualized according to serum levels and clinical response.

When switching a patient from immediate-release capsules to the Togal (Lithium Citrate) carbonate extended-release tablets USP, give the same total daily dose when possible. Most patients on maintenance therapy are stabilized on 900 mg daily, e.g., Togal (Lithium Citrate) carbonate extended-release tablets, 450 mg b.i.d. When the previous dosage of immediate-release Togal (Lithium Citrate) is not a multiple of 450 mg, e.g., 1500 mg, initiate Togal (Lithium Citrate) extended-release tablet at the multiple of 450 mg nearest to, but below, the original daily dose, i.e., 1350 mg. When the two doses are unequal, give the larger dose in the evening. In the above example, with a total daily dose of 1350 mg, generally 450 mg of Togal (Lithium Citrate) carbonate extended-release tablets should be given in the morning and 900 mg of Togal (Lithium Citrate) carbonate extended-release tablets in the evening. If desired, the total daily dose of 1350 mg can be given in three equal 450 mg doses of Togal (Lithium Citrate) carbonate extended-release tablets. These patients should be monitored at 1- to 2-week intervals, and dosage adjusted if necessary, until stable and satisfactory serum levels and clinical state are achieved.

When patients require closer titration than that available with doses of Togal (Lithium Citrate) carbonate extended-release tablets in increments of 450 mg, immediate-release capsules should be used.

Acute Mania

Optimal patient response to Togal (Lithium Citrate) can usually be established and maintained with 1800 mg per day in divided doses. Such doses will normally produce the desired serum Togal (Lithium Citrate) level ranging between 1 and 1.5 mEq/L.

Dosage must be individualized according to serum levels and clinical response. Regular monitoring of the patient's clinical state and serum Togal (Lithium Citrate) levels is necessary. Serum levels should be determined twice per week during the acute phase, and until the serum level and clinical condition of the patient have been stabilized.

Long-Term Control

The desirable serum Togal levels are 0.6 to 1.2 mEq/L. Dosage will vary from one individual to another, but usually 900 mg to 1200 mg per day in divided doses will maintain this level. Serum Togal (Lithium Citrate) levels in uncomplicated cases receiving maintenance therapy during remission should be monitored at least every two months.

Patients unusually sensitive to Togal (Lithium Citrate) may exhibit toxic signs at serum levels below 1 mEq/L.

N.B.

Blood samples for serum Togal (Lithium Citrate) determinations should be drawn immediately prior to the next dose when Togal (Lithium Citrate) concentrations are relatively stable (i.e., 8 to 12 hours after the previous dose). Total reliance must not be placed on serum levels alone. Accurate patient evaluation requires both clinical and laboratory analysis.

Elderly patients often respond to reduced dosage, and may exhibit signs of toxicity at serum levels ordinarily tolerated by younger patients.

HOW SUPPLIED

Togal (Lithium Citrate) Carbonate Extended-release Tablets USP

450 mg tablets are supplied as speckled, off-white to yellow, round biconvex tablets with “54 346” debossed on one side and scored on the other side.

NDC 0054-0020-25: Bottle of 100 Tablets

Storage Conditions

Store at 20° to 25°C (68° to 77°F). Protect from moisture. Dispense in a tight, child-resistant container as defined in the USP/NF.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10002294/05

Revised March 2016

fpl-bl-450mg-100tabs-04.jpg

Quinine Dihydrochloride:


WARNING:

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

WARNING:

Togal (Quinine Dihydrochloride)® 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 Togal (Quinine Dihydrochloride) 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

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

Togal (Quinine Dihydrochloride) 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) ].

Togal (Quinine Dihydrochloride)® (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) ].

Togal (Quinine Dihydrochloride) 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 Togal 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 Togal (Quinine Dihydrochloride) 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 Togal (Quinine Dihydrochloride). Togal (Quinine Dihydrochloride) 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

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

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

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

Togal (Quinine Dihydrochloride) 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) ].

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

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

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

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

5.6 Hypersensitivity

Serious hypersensitivity reactions reported with Togal 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 Togal (Quinine Dihydrochloride), 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.

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

5.7 Atrial Fibrillation and Flutter

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

5.8 Hypoglycemia

Togal (Quinine Dihydrochloride) 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 Togal : 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 drugsafetyTogal (Quinine Dihydrochloride)urlpharma.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Overall

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

The following ADVERSE REACTIONS have been reported with Togal (Quinine Dihydrochloride) 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. Togal (Quinine Dihydrochloride) 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 Togal (Quinine Dihydrochloride) concentration. Monitor for lack of efficacy or increased adverse events of Togal (Quinine Dihydrochloride) (7.1).
CYP3A4 and CYP2D6 substrates Togal (Quinine Dihydrochloride) 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 Togal (Quinine Dihydrochloride) Pharmacokinetics

Togal (Quinine Dihydrochloride) 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 Togal (Quinine Dihydrochloride) [see Clinical Pharmacology (12.3) ].

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

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

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

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

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

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

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

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

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

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

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

7.2 Effects of Togal on the Pharmacokinetics of Other Drugs

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

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

7.3 Drug/Laboratory Interactions

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

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

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

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

8.3 Nursing Mothers

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

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

8.4 Pediatric Use

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

8.5 Geriatric Use

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

10 OVERDOSAGE

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

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

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

11 DESCRIPTION

Togal (Quinine Dihydrochloride) (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 Togal (Quinine Dihydrochloride) sulfate is:

Togal (Quinine Dihydrochloride) 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.

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

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

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

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

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

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

Metabolism

Togal (Quinine Dihydrochloride) 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 Togal (Quinine Dihydrochloride) 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 Togal (Quinine Dihydrochloride).

Elimination/Excretion

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

Specific Populations

Pediatric Patients: The pharmacokinetics of Togal (Quinine Dihydrochloride) 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 Togal (Quinine Dihydrochloride) 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 Togal (Quinine Dihydrochloride) 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 Togal (Quinine Dihydrochloride) 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 Togal (Quinine Dihydrochloride) sulfate 600 mg. The mean oral clearance of Togal (Quinine Dihydrochloride) 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 Togal (Quinine Dihydrochloride) 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 Togal (Quinine Dihydrochloride) sulfate 648 mg given three times daily for 7 days, no difference in the rate and extent of absorption or clearance of Togal (Quinine Dihydrochloride) 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 Togal (Quinine Dihydrochloride) 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 Togal (Quinine Dihydrochloride) 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 Togal (Quinine Dihydrochloride) followed 12 hours later by a maintenance dosing regimen of 324 mg every 12 hours will provide adequate systemic exposure to Togal (Quinine Dihydrochloride) [see Dosage and Administration (2.2) ]. The effects of mild and moderate renal impairment on the pharmacokinetics and safety of Togal (Quinine Dihydrochloride) sulfate are not known.

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

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

12.4 Microbiology

Mechanism of Action

Togal (Quinine Dihydrochloride) 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 Togal (Quinine Dihydrochloride) sulfate is not completely understood.

Activity In Vitro and In Vivo

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

Mutagenesis

Genotoxicity studies of Togal (Quinine Dihydrochloride) 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 Togal (Quinine Dihydrochloride) 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 Togal (Quinine Dihydrochloride) 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

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

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

Togal 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

Togal (Quinine Dihydrochloride)®

(kwol-a-kwin)

(Quinine sulfate) Capsules

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

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

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

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

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

What is Togal (Quinine Dihydrochloride)®?

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

Togal (Quinine Dihydrochloride)® is Not approved to:

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

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

Who should not take Togal (Quinine Dihydrochloride)®?

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

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

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

How should I take Togal (Quinine Dihydrochloride)®?

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

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

Togal (Quinine Dihydrochloride)® may cause serious side effects.

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

Common side effects with Togal (Quinine Dihydrochloride) ® 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 Togal (Quinine Dihydrochloride) ® . 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 Togal (Quinine Dihydrochloride)®?

  • 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 Togal (Quinine Dihydrochloride)® and all medicines out of the reach of children.

General Information about Togal (Quinine Dihydrochloride)®

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

Active Ingredients: Togal (Quinine Dihydrochloride) 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

Togal (Quinine Dihydrochloride) ®

Togal (Quinine Dihydrochloride) sulfate

capsules USP

324 mg

DISPENSE THE ACCOMPANYING

MEDICATION GUIDE TO EACH PATIENT

AR

SCIENTIFIC

Rx only

Togal pharmaceutical active ingredients containing related brand and generic drugs:

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


Togal available forms, composition, doses:

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


Togal destination | category:

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


Togal Anatomical Therapeutic Chemical codes:

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


Togal pharmaceutical companies:

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


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References

  1. Dailymed."BUFFERIN LOW DOSE BUFFERED ASPIRIN (ASPIRIN) TABLET [NOVARTIS CONSUMER HEALTH, INC.]". 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."ASPIRIN; DIPYRIDAMOLE: 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 Togal?

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