Quinine Sulfate
Quinine DHL Injection is indicated for the treatment of acute attacks of malaria, including attacks due to chloroquine-resistant or multi-drug-resistant strains of Plasmodium falciparum. Quinine is used parenterally for cerebral, severe or complicated malaria, or when vomiting prevents retention of an orally administered drug.
DESCRIPTION:
Quinine sulfate is available as tablets or capsules for oral administration. Each tablet contains 260 mg quinine sulfate. Also Contains, as Inactive Ingredients: Corn starch, pregelatinized starch, sodium starch glycolate, sucrose, and zinc stearate.
Neuromuscular Agent.
Quinine sulfate occurs as a white, crystalline powder, which darkens on exposure to light. It is odorless and has a persistent, very bitter taste. It is slightly soluble in water, alcohol, chloroform, and ether.
CLINICAL PHARMACOLOGY:
Quinine sulfate is effective as a malarial suppressant and in control of overt clinical attacks. Its primary action is schizontocidal. No lethal effect is exerted on sporozoites or preerythrocitic tissue forms.
Quinine sulfate is readily absorbed when given orally. Absorption occurs mainly from the upper part of the small intestine, and is almost complete even in patients with marked diarrhea.
The cinchona alkaloids in large measure are metabolically degraded in the body, especially in the liver; less than 5% of an administered dose is excreted unaltered in the urine. It is reported that there is no accumulation of the drugs in the body upon continued administration. The metabolic degradation products are excreted in the urine, where many of them have been identified as hydroxy derivatives, but small amounts also appear in the feces, gastric juice, bile, and saliva. Renal excretion of quinine sulfate is twice as rapid when the urine is acidic as when it is alkaline, due to the greater tubular reabsorption of the alkaloidal base that occurs in an alkaline media. Excretion is also limited by the binding of a large fraction of cinchona alkaloids to plasma proteins.
Peak plasma concentrations of cinchona alkaloids occur within 1 to 3 hours after a single oral dose. The half-life is 4 to 5 hours. After chronic administration of total daily doses of 1 g of drug, the average plasma quinine sulfate concentration is approximately 7 mug/ml. After termination of quinine sulfate therapy, the plasma level falls rapidly and only a negligible concentration is detectable after 24 hours.
A large fraction (approximately 70%) of the plasma quinine sulfate is bound to proteins. This explains in part why the concentration of the alkaloid in cerebrospinal fluid is only 2-5% of that in the plasma. However, it can traverse the placental membrane and readily reach fetal tissues.
Tinnitus and impairment of hearing rarely should occur at plasma quinine sulfate concentrations of less than 10 mug/ml. While this level would not be anticipated from use of 1 or 2 tablets of quinine sulfate daily, an occasional patient may have some evidence of cinchonism on this dosage, such as tinnitus. (See WARNINGS.)
INDICATIONS AND USAGE:
For the treatment of malaria as a supplement to other antimalarial drugs (e.g., with primaquine in relapsing vivax malaria) or the treatment of malaria due to strains of P. falciparum resistant to chloroquine and other antimalarial drugs.
CONTRAINDICATIONS:
Quinine sulfate may cause fetal harm when administered to a pregnant woman. Congenital malformations in the human have been reported with the use of quinine sulfate, primarily with large doses (up to 30 g) for attempted abortion. In about half of these reports, the malformation was deafness related to auditory nerve hypoplasia. Among the other abnormalities reported were limb anomalies, visceral defects, and visual changes. In animal tests, teratogenic effects were found in rabbits and guinea pigs and were absent in mice, rats, dogs, and monkeys. Quinine sulfate is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Because of the quinine content, quinine sulfate is contraindicated in patients with known quinine hypersensitivity and in patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.
Since thrombocytopenic purpura may follow the administration of quinine sulfate in highly sensitive patients, a history of this occurrence associated with previous quinine sulfate ingestion contraindicates its further use. Recovery usually occurs following withdrawal of the medication and appropriate therapy.
This drug should not be used in patients with tinnitus or optic neuritis or in patients with a history of blackwater fever.
WARNINGS:
Repeated doses or overdosage of quinine sulfate in some individuals may precipitate a cluster of symptoms referred to as cinchonism. Such symptoms, in the mildest form, include ringing in the ears, headache, nausea, and slightly disturbed vision; however, when medication is continued or after large single doses, symptoms also involve the gastrointestinal tract, the nervous and cardiovascular systems, and the skin.
Hemolysis (with the potential for hemolytic anemia) has been associated with a G-6-PD deficiency in patients taking quinine sulfate. Quinine sulfate should be stopped immediately if evidence of hemolysis appears.
If symptoms occur, drug should be discontinued and supportive measures instituted. In case of overdosage, see OVERDOSAGE.
PRECAUTIONS:
General
Quinine sulfate should be discontinued if there is any evidence of hypersensitivity. (See CONTRAINDICATIONS.) Cutaneous flushing, pruritus, skin rashes, fever, gastric distress, dyspnea, ringing in the ears, and visual impairment are the usual expressions of hypersensitivity, particularly if only small doses of quinine sulfate have been taken. Extreme flushing of the skin accompanied by intense, generalized pruritus is the most common form. Hemoglobinuria and asthma from quinine sulfate are rare types of idiosyncrasy.
In patients with atrial fibrillation, the administration of quinine sulfate requires the same precautions as those for quinidine. (See DRUG INTERACTIONS.)
Drug/Laboratory Test Interactions
Quinine sulfate may produce an elevated value for urinary 17-ketogenic steroids when the Zimmerman method is used.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
A study of quinine sulfate administered in drinking water (0.1%) to rats for periods up to 20 months showed no evidence of neoplastic changes.
Mutation studies of quinine (dihydrochloride) in male and female mice gave negative results by the micronucleus test. Intraperitoneal injections (0.5 mM/kg) were given twice, 24 hours apart. Direct Salmonella typhimurium tests were negative; when mammalian liver homogenate was added, positive results were found.
No information relating to the effect of quinine sulfate upon fertility in animal or in man has been found.
Pregnancy Category X
See CONTRAINDICATIONS.
Nonteratogenic Effects: Because quinine sulfate crosses the placenta in humans, the potential for fetal effects is present. Stillbirths in mothers taking quinine sulfate have been reported in which no obvious cause for the fetal deaths was shown. Quinine sulfate in toxic amounts has been associated with abortion. Whether this action is always due to direct effect on the uterus is questionable.
Nursing Mothers
Caution should be exercised when quinine sulfate is given to nursing women because quinine sulfate is excreted in breast milk (in small amounts).
DRUG INTERACTIONS:
Increased plasma levels of digoxin and digitoxin have been demonstrated in individuals after concomitant quinine administration. Because of possible similar effects from use of quinine sulfate, it is recommended that plasma levels of digoxin and digitoxin be determined for those individuals taking these drugs and quinine sulfate concomitantly.
Concurrent use of aluminum-containing antacids may delay or decrease absorption of quinine sulfate.
Cinchona alkaloids, including quinine sulfate, have the potential to depress the hepatic enzyme system that synthesizes the vitamin K-dependent factors. The resulting hypoprothrombinemic effect may enhance the action of warfarin and other oral anticoagulants.
The effects of neuromuscular blocking agents (particularly pancuronium, succinylcholine, and tubocurarine) may be potentiated with quinine sulfate, and result in respiratory difficulties.
Urinary alkalizers (such as acetazolamide and sodium bicarbonate) may increase quinine sulfate blood levels with potential for toxicity.
ADVERSE REACTIONS:
The following adverse reactions have been reported with quinine sulfate in therapeutic or excessive dosage. (Individual or multiple symptoms may represent cinchonism or hypersensitivity.)
Hematologic: Acute hemolysis, thrombocytopenic purpura, agranulocytosis, hypoprothrombinemia.
CNS: Visual disturbances, including blurred vision with scotomata, photophobia, diplopia, diminished visual fields, and disturbed color vision; tinnitus, dizziness, deafness, and vertigo; headache, nausea, vomiting, fever, apprehension, restlessness, confusion, and syncope.
Dermatologic/Allergic: Cutaneous rashes (urticarial, the most frequent type of allergic reaction, papular, or scarlatinal), pruritus, flushing of the skin, sweating, occasional edema of the face.
Respiratory: Asthmatic symptoms.
Cardiovascular: Anginal symptoms.
Gastrointestinal: Nausea and vomiting (may be CNS-related), epigastric pain.
DRUG ABUSE AND DEPENDENCE:
Tolerance, abuse, or dependence with quinine sulfate has not been reported.
OVERDOSAGE:
The more common signs and symptoms of quinine sulfate overdosage are tinnitus, dizziness, skin rash, and gastrointestinal disturbance (intestinal cramping). With higher doses, cardiovascular and CNS effects may occur, including headache, fever, vomiting, apprehension, confusion, and convulsions. Other effects are listed in ADVERSE REACTIONS.
A fatal oral dose of quinine in adults has been reported as 8 grams. Tinnitus and impaired hearing may occur at plasma quinine concentrations over 10 mug/ml. This level would not be normally attained with the use of 1 or 2 quinine sulfate capsules daily, but in a hypersensitive patient, as little as 0.3 grams (less than 1 capsule) of quinine sulfate may produce tinnitus.
Treatment: Treatment for overdosage should include initially efforts to remove any residual quinine sulfate from the stomach by gastric lavage or by emesis induced with syrup of ipecac. The blood pressure should be supported and measures used to maintain renal function. Artificial respiration may be needed. Sedatives, oxygen, and other supportive measures should be used as necessary.
Fluid and electrolyte balance with intravenous fluids should be maintained. Acidification of the urine will promote renal excretion of quinine sulfate. In the presence of hemoglobinuria, however, acidification of the urine may augment renal blockade. Quinine sulfate should be readily dialyzable by hemodialysis and/or hemoperfusion procedures.
Evidence of angioedema or asthma may require the use of epinephrine, corticosteroids, and antihistamines. In the acute phase of toxic amaurosis caused by quinine sulfate, vasodilators administered intravenously may have a salutary effect. Stellate block has also been used effectively for quinine-associated blindness. Residual visual impairment occassionally yields to vasodilators.
DOSAGE AND ADMINISTRATION:
Tablets: One tablet upon retiring. If needed, 2 tablets may be taken nightly--1 following the evening meal and 1 upon retiring.
Capsules: In adults, for use as a component of a malarial suppressant regimen, 2 capsules 3 times per day for 7 days.
After several consecutive nights in which recumbency leg cramps do not occur, Quinamm may be discontinued in order to determine whether continued therapy is needed.