Milnacipran Hydrochloride and Quinine Sulfate

• Generic Name: milnacipran
• Dosage Forms: n.a.
• Other Brand Names: Savella, Savella Titration Pack

Management of fibromyalgia.

Has been used in the treatment of major depressive disorder and is approved for treating depression in some countries; this indication is not an FDA-labeled use.

Insufficient data, to date, to determine if efficacy and tolerability of milnacipran as an antidepressant are superior, inferior, or equal to that of other antidepressants for acute treatment of major depressive disorder. Some studies indicate improved tolerability with milnacipran when compared with tricyclic antidepressants.

• Generic Name: quinine
• Dosage Forms: n.a.
• Other Brand Names: Qualaquin, QM-260, Quinamm

Treatment of uncomplicated malaria caused by Plasmodium falciparum. Also used for treatment of uncomplicated malaria caused by chloroquine-resistant P. vivax and treatment of uncomplicated malaria when plasmodial species not identified.

Designated an orphan drug by FDA for treatment of malaria. Since malaria is a life-threatening infection, FDA states that potential benefits of the drug outweigh associated risks and justify its use for treatment of malaria.

For treatment of uncomplicated malaria caused by chloroquine-resistant P. falciparum or treatment of uncomplicated malaria when plasmodial species not identified, CDC recommends fixed combination of atovaquone and proguanil (atovaquone/proguanil), fixed combination of artemether and lumefantrine (artemether/lumefantrine), or regimen of quinine in conjunction with doxycycline, tetracycline, or clindamycin. If quinine regimen used, concomitant doxycycline or tetracycline generally preferred instead of concomitant clindamycin since more efficacy data exist regarding antimalarial regimens that include tetracyclines.

For treatment of uncomplicated malaria caused by chloroquine-susceptible P. falciparum, P. malariae, or P. knowlesi or treatment of uncomplicated malaria when plasmodial species not identified and infection acquired in areas where chloroquine resistance not reported, CDC recommends chloroquine (or hydroxychloroquine). Alternatively, CDC states that any of the regimens recommended for treatment of uncomplicated chloroquine-resistant P. falciparum malaria may be used if preferred, more readily available, or more convenient.

For treatment of uncomplicated malaria caused by chloroquine-resistant P. vivax, CDC recommends regimen of quinine and doxycycline (or tetracycline) given in conjunction with primaquine, atovaquone/proguanil given in conjunction with primaquine, or mefloquine given in conjunction with primaquine. Because quinine, doxycycline (or tetracycline), atovaquone/proguanil, and mefloquine active only against asexual erythrocytic forms of Plasmodium (not exoerythrocytic stages), 14-day regimen of primaquine indicated to prevent delayed primary attacks or relapse and provide a radical cure whenever any of these drugs used for treatment of P. vivax or P. ovale malaria.

Pediatric patients with uncomplicated malaria generally can receive same treatment regimens recommended for adults using age- and weight-appropriate drugs and dosages. For treatment of uncomplicated chloroquine-resistant P. falciparum in children <8 years of age, atovaquone/proguanil or artemether/lumefantrine usually recommended; mefloquine can be considered if no other options available. If a quinine regimen used in children <8 years of age, CDC states a 7-day regimen of quinine alone can be used (regardless of where infection was acquired) or quinine can be given in conjunction with clindamycin, since children <8 years of age generally should not receive tetracyclines. In rare instances, doxycycline or tetracycline can be used in conjunction with quinine in children <8 years of age if other treatment options not available or not tolerated and if potential benefits of including a tetracycline outweigh risks. For treatment of chloroquine-resistant P. vivax malaria in children <8 years of age, CDC recommends mefloquine given in conjunction with primaquine. Alternatively, if mefloquine not available or not tolerated and if potential benefits outweigh risks, atovaquone/proguanil or artemether/lumefantrine can be used for treatment of chloroquine-resistant P. vivax in this age group.

Pregnant women with uncomplicated malaria caused by P. malariae, P. vivax, P. ovale, or chloroquine-susceptible P. falciparum should receive prompt treatment with chloroquine (or hydroxychloroquine). CDC recommends that pregnant women with uncomplicated malaria caused by chloroquine-resistant P. falciparum receive prompt treatment with mefloquine or a regimen of quinine and clindamycin; mefloquine recommended for those with uncomplicated malaria caused by chloroquine-resistant P. vivax. Although tetracyclines generally contraindicated in pregnant women, in rare circumstances when other treatment options not available or not tolerated and if potential benefits outweigh risks, CDC states that regimen of quinine and doxycycline (or tetracycline) may be used. Alternatively, atovaquone/proguanil or artemether/lumefantrine can be considered for treatment of uncomplicated malaria caused by chloroquine-resistant P. falciparum in pregnant women when other treatment options not available or not tolerated and if potential benefits outweigh risks. Pregnant women with P. vivax or P. ovale malaria should receive chloroquine prophylaxis for the duration of the pregnancy and receive primaquine after delivery to provide a radical cure.

Assistance with diagnosis or treatment of malaria available from CDC Malaria Hotline at 770-488-7788 or 855-856-4713 from 9:00 a.m. to 5:00 p.m. Eastern Standard Time or CDC Emergency Operation Center at 770-488-7100 after hours and on weekends and holidays.

Treatment of Severe Malaria

Used in conjunction with doxycycline, tetracycline, or clindamycin for follow-up treatment of severe or complicated malaria.

Severe malaria usually caused by P. falciparum and requires initial aggressive treatment with a parenteral antimalarial regimen initiated as soon as possible after diagnosis.

For treatment of severe malaria in adults and children, CDC recommends an initial regimen of IV quinidine in conjunction with doxycycline, tetracycline, or clindamycin (administered orally or IV as tolerated). After parasitemia reduced to <1% and oral therapy tolerated, IV quinidine can be discontinued and oral quinine initiated to complete 7 or 3 days of total quinidine and quinine therapy as determined by geographic origin of infecting parasite (7 days if malaria was acquired in Southeast Asia or 3 days if acquired elsewhere).

If IV quinidine unavailable or cannot be used for initial treatment because of adverse effects or contraindications, parenteral artesunate may be available from CDC under an investigational new drug (IND) protocol for emergency initial treatment of severe malaria.

Assistance with diagnosis or treatment of malaria and assistance obtaining quinidine or artesunate for treatment of severe malaria is available by contacting CDC Malaria Hotline at 770-488-7788 or 855-856-4713 from 9:00 a.m. to 5:00 p.m. Eastern Standard Time or CDC Emergency Operation Center at 770-488-7100 after hours and on weekends and holidays.

Presumptive Self-treatment of Malaria

Regimen of quinine in conjunction with doxycycline has been recommended by some clinicians for presumptive self-treatment of malaria in travelers.

Not approved by FDA for presumptive self-treatment of malaria in travelers and not recommended by CDC for such treatment.

For presumptive self-treatment of malaria in travelers, CDC and other experts recommend atovaquone/proguanil or artemether/lumefantrine.

Prevention of Malaria

Not approved by FDA for prevention (prophylaxis) of malaria and not included in current CDC recommendations for prevention of malaria.

CDC and other clinicians recommend other antimalarials (e.g., chloroquine [or hydroxychloroquine], atovaquone/proguanil, doxycycline, mefloquine) for prevention of malaria caused by susceptible plasmodia.

Information on risk of malaria in specific countries and mosquito avoidance measures and recommendations regarding whether prevention of malaria indicated and choice of antimalarials for prevention are available from CDC.

Babesiosis

Treatment of babesiosis caused by Babesia microti.

IDSA states that all patients with active babesiosis (i.e., symptoms of viral-like infection and identification of babesial parasites in blood smears or by polymerase chain reaction [PCR] amplification of babesial DNA) should receive anti-infective treatment because of the risk of complications; however, symptomatic patients whose serum contains antibody to babesia but whose blood lacks identifiable babesial parasites on smear or babesial DNA by PCR should not receive treatment. Treatment not recommended initially for asymptomatic individuals, regardless of results of serologic examination, blood smears, or PCR, but should be considered if parasitemia persists for >3 months.

When anti-infective treatment of babesiosis indicated, IDSA and other clinicians recommend a regimen of quinine and clindamycin or a regimen of atovaquone and azithromycin.

The quinine and clindamycin regimen may be preferred for severe babesiosis. However, there is some evidence that, in patients with mild or moderate illness, the atovaquone and azithromycin regimen may be as effective and better tolerated than the quinine and clindamycin regimen. Consider use of exchange transfusions, especially in severely ill patients with high levels of parasitemia (≥10%), significant hemolysis, or compromised renal, hepatic, or pulmonary function.

B. microti is transmitted by Ixodes scapularis ticks, which also may be simultaneously infected with and transmit Borrelia burgdorferi (causative agent of Lyme disease) and Anaplasma phagocytophilum (causative agent of human granulocytotropic anaplasmosis [HGA, formerly known as human granulocytic ehrlichiosis]). Consider possibility of coinfection with B. burgdorferi and/or A. phagocytophilum in patients who have severe or persistent symptoms despite appropriate anti-infective treatment for babesiosis.

Nocturnal Recumbency Leg Muscle Cramps

Not approved by FDA for the treatment or prevention of nocturnal leg cramps. Should not be used in the management of this or related conditions (e.g. restless legs syndrome).

Although quinine has been used in the past for the prevention and treatment of nocturnal recumbency leg muscle cramps (night cramps), there are no adequate and well-controlled studies evaluating efficacy and safety for this use.

Quinine has a narrow margin of safety and may cause unpredictable serious and life-threatening hypersensitivity reactions, QT interval prolongation, serious cardiac arrhythmias (including torsades de pointes), serious hematologic reactions (including thrombocytopenia and HUS/TTP), and other serious adverse events (e.g., blindness, deafness) requiring medical intervention and hospitalization. Fatalities associated with use of the drug have been reported. The known risks associated with the use of quinine, in the absence of evidence of safety and efficacy of the drug for the treatment or prevention of nocturnal leg cramps, outweigh any potential benefits for this benign, self-limiting condition.

FDA has determined that quinine preparations (including preparations containing any quinine salt alone or in fixed combination with vitamin E) are not generally recognized as safe and effective for treatment or prevention of nocturnal leg muscle cramps. Promotion of quinine for self-medication of nocturnal leg cramps has been prohibited in the US since February 1995 because of safety concerns. In addition, FDA ordered that marketing of all unapproved quinine preparations be discontinued as of December 11, 2006.