Calcium Levofolinate
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Oseltamivir Phosphate

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(Treatmeant for bird influenza)

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Roch's Trademark: Tamiflu

Product information please click here and get information from Roch in PDF form

Chemical synthesis

The synthesis commences from naturally available (?)-shikimic acid. The 3,4-pentylidene acetal mesylate is prepared in three steps: esterification with ethanol and thionyl chloride; ketalization with para-toluenesulfonic acid and 3-pentanone; and mesylation with triethylamine and methanesulfonyl chloride. Reductive opening of the ketal under modified Hunter conditions (JOC 1993, 58, 6756) in dichloromethane yields an inseparable mixture of isomeric mesylates. The corresponding epoxide is formed under basic conditions with potassium bicarbonate. Using the inexpensive Lewis acid magnesium bromide diethyl etherate (commonly prepared fresh by the addition of magnesium turnings to 1,2-dibromoethane in benzene:diethyl ether), the epoxide is opened with allyl amine to yield the corresponding 1,2-amino alcohol. The water-immiscible solvents methyl tert-butyl ether and acetonitrile are used to simplify the workup procedure, which involved stirring with 1 M aqueous ammonium sulfate. Reduction on palladium, promoted by ethanolamine, followed by acidic workup yielded the deprotected 1,2-aminoalcohol. The aminoalcohol was converted directly to the corresponding allyl-diamine in an interesting cascade sequence that commences with the unselective imination of benzaldehyde with azeotropic water removal in methyl tert-butyl ether. Mesylation, followed by removal of the solid byproduct triethylamine hydrochloride, results in an intermediate that was poised to undergo aziridination upon transimination with another equivalent of allylamine. With the librated methanesulfonic acid, the aziridine opens cleanly to yield a diamine that immediately undergoes a second transimination. Acidic hydrolysis then removed the imine. Selective acylation with acetic anhydride (under buffered conditions, the 5-amino group is protonated owing to a considerable difference in pKa, 4.2 vs 7.9, preventing acetylation) yields the desired N-acetylated product in crystalline form upon extractive workup. Finally, deallylation as above, yielded the freebase of oseltamivir, which was converted to the desired oseltamivir phosphate by treatment with phosphoric acid. The final product is obtained in high purity (99.7%) and an overall yield of 17-22% from (?)-shikimic acid. It is noted that the synthesis avoids the use of potentially explosive azide reagents and intermediates; however, the synthesis actually used by Roche uses azides. Roche has other routes to Tamiflu that do not involve the use of (?)-shikimic acid as a chiral pool starting material, such as a Diels-Alder route involving furan and ethyl acrylate or a isophthalic acid route, which involves catalytic hydrogenation and enzymatic desymmetrization.

The reported azide-free Roche synthesis of tamiflu is summarized graphically below:

Oseltamivir ( Oh¨Csel¨CTAM¨Ci¨Cveer) belongs to the family of medicines called antivirals, which are used to treat infections caused by viruses. Oseltamivir is used in the treatment of the infection caused by the flu virus (influenza A and influenza B). Oseltamivir may reduce flu symptoms (weakness, headache, fever, cough, and sore throat) by 1 day. Oseltamivir has also been shown to prevent influenza infection if you have come into close contact with someone who has the flu.

If you receive the flu vaccine every year, continue to do so.

Before Using This Medicine:

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For oseltamivir, the following should be considered:

Allergies¡ªTell your doctor if you have ever had any unusual or allergic reaction to oseltamivir. Also tell your health care professional if you are allergic to any other substances, such as foods, preservatives, or dyes.

Pregnancy¡ªOseltamivir has not been studied in pregnant women. However, studies in animals have shown that oseltamivir causes problems. Before taking this medicine, make sure your doctor knows if you are pregnant or if you may become pregnant.

Breast-feeding¡ªIt is not known whether oseltamivir passes into human breast milk. Although most medicines pass into breast milk in small amounts, many of them may be used safely while breast-feeding. Mothers who are using this medicine and who wish to breast-feed should discuss this with their doctor.

Children¡ªThis medicine has not been tested in children younger than 1 year of age.

Older adults¡ªThis medicine has been tested in older adults and has not been shown to cause different side effects or problems in older adults than it does in younger adults.

Other medicines¡ª Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking oseltamivir it is especially important that your doctor and pharmacist know if you are taking any of the following:

Probenecid (e.g., Benemid)¡ªCo-administration may result in higher blood levels of the active metabolite of oseltamivir

Other medical problems¡ªThe presence of other medical problems may affect the use of oseltamivir. Make sure to tell your doctor if you have any other medical problems, especially:
Kidney disease
Heart disease
Illnesses caused by viruses other than influenza Type A or B
Liver disease
Lung disease
Serious medical problems that may need admission to a hospital

Proper Use of This Medicine

Talk to your doctor about the possibility of getting a flu shot if you have not had one yet. Patient information about oseltamivir is available. Read this information carefully.

For patients taking oseltamivir for treatment of the flu: This medicine works best if taken within 2 days of having flu symptoms (weakness, headache, fever, cough, and sore throat). Oseltamivir capsules may be taken with meals or on an empty stomach. Taking oseltamivir with food may lessen the possibility of stomach upset. This medicine should be taken for 5 days. Continue taking this medicine for the full time of treatment even if you begin to feel better after a few days. This will help to clear up your infection completely. If you stop taking this medicine too soon, your symptoms may return.

For patients taking oseltamivir for prevention of the flu after exposure: The medicine should be taken within 2 days of being exposed to the flu. Oseltamivir capsules may be taken with meals or on an empty stomach. Taking oseltamivir with food may lessen the possibility of stomach upset. This medicine should be taken for at least 7 days.

For patients taking the oral suspension form of this medicine:

This medicine is to be taken only by mouth. Use the specially marked measuring device that is given to you with the medicine to measure each dose accurately. The average household spoon may not hold the right amount of liquid.
Do not use after the expiration date on the label. The medicine may not work properly after that date. If you have any questions about this, check with your pharmacist.


The dose of oseltamivir will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of oseltamivir. If your dose is different, do not change it unless your doctor tells you to do so.

For oral dosage forms (capsules and oral suspension):
For treatment of the flu:
Adults: 75 milligrams (mg) two times a day for five days.
Children 1 year of age or older: Dose is based on body weight and must be determined by your doctor. It is usually between 30 and 75 mg two times a day for five days.
Children up to 1 year of age: Use and dose must be determined by your doctor.
For prevention of the flu:
Adults and teenagers 13 years of age or older: 75 mg once a day for at least seven days.
Children up to 13 years of age: Use and dose must be determined by your doctor.
Missed dose¡ª

This medicine works best when there is a constant amount in the body. To help keep the amount constant, do not miss any doses. If you miss a dose, take as soon as possible, except if it is near the next dose (within 2 hours). Then go back to your regular dosing schedule. Do not double doses. If you have missed several doses, inform your doctor and follow the advice given to you.


To store this medicine:

Keep out of the reach of children.
Do not store the capsules in the bathroom, near the kitchen sink, or in other damp places. Heat or moisture may cause the medicine to break down.
Store the oral suspension at room temperature or in the refrigerator. However, keep the medicine from freezing.
Do not keep outdated medicine or medicine no longer needed. Be sure that any discarded medicine is out of the reach of children.

Side Effects of This Medicine
Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Stop using this medicine and get emergency help immediately if either of the following side effects occur:

Less common
Phlegm producing cough or wheezing

Other side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. However, check with your doctor if any of the following side effects continue or are bothersome:

More common
Diarrhea; nausea; vomiting

Less common
Abdominal or stomach pain; bloody nose or unexplained nosebleeds (occurs mainly in children); burning, dry or itching eyes, redness, pain, swelling of eye or eyelid, or excessive tearing (occurs mainly in children); cough; dizziness; ear disorder (occurs mainly in children); fatigue ; headache; trouble in sleeping

Other side effects not listed above may also occur in some patients. If you notice any other effects, check with your doctor.

Safety Information:

There is no evidence for the efficacy of TAMIFLU in any illness other than influenza types A and B. Treatment efficacy in high-risk patients (chronic cardiac disease and/or respiratory disease) has not been established, and there were no differences in the incidence of complications between treatment and placebo groups in this population. The safety and efficacy of repeated treatment or prophylaxis courses have not been established.

In treatment studies in adult patients, adverse events occurring more frequently in patients taking TAMIFLU compared with placebo (incidence >1%) were nausea, vomiting, bronchitis, insomnia and vertigo.

In treatment studies in pediatric patients, the most frequently reported adverse event occurring in >1% of patients receiving TAMIFLU was vomiting. Other events reported more frequently by pediatric patients treated with TAMIFLU included abdominal pain, epistaxis, ear disorder and conjunctivitis. These events generally occurred once and resolved despite continued dosing.

In prophylaxis studies in adult patients and adolescents aged 13 years and older, adverse events were qualitatively very similar to those seen in the treatment studies, despite a longer duration of dosing. Events reported more frequently in subjects receiving TAMIFLU compared to subjects receiving placebo in prophylaxis studies included nausea, vomiting, diarrhea, abdominal pain, dizziness, headache, insomnia, vertigo and fatigue.