Pocket Drug Guide

Posts Tagged ‘US’

(British Approved Name, US Adopted Name, rINN)

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Description. Dactinomycin is an antineoplastic antibiotic produced by Streptomyces parvulus and other species of Streptomyces.

Cactinomycin (actinomycin C; HBF-386; NSC-18268) is a mixture of dactinomycin (actinomycin D) (10%), actinomycin C2 (45%), and actinomycin C3 (45%) produced by Streptomyces chrysomallus.

Pharmacopoeias. In China, International, Japan, Poland, and US.

The United States Pharmacopeia 31, 2008 (Dactinomycin). A bright red, somewhat hygroscopic, crystalline powder, affected by light and heat. It has a potency of not less than 950 and not more than 1030 micrograms/mg, calculated on the dried basis. Soluble in water at 10° and slightly soluble in water at 37°; freely soluble in alcohol; very slightly soluble in ether. Store at a temperature not exceeding 40° in airtight containers. Protect from light.

Adsorption. Dactinomycin binds to cellulose ester filters, and such filtration should be avoided. Although it has been suggested that significant amounts of drug may be adsorbed to glass or plastic, dactinomycin is reportedly compatible with glass and PVC infusion containers, and giving into the tubing of a fast-running intravenous infusion is recommended — see Uses and Administration, below.

Adverse Effects, Treatment, and Precautions

For general discussions see Antineoplastics.

Apart from nausea and vomiting adverse effects are often delayed, beginning 2 to 4 days after the completion of a course of treatment and reaching a maximum after 1 to 2 weeks. Fatalities have occurred. Bone-marrow depression and gastrointestinal effects (particularly stomatitis and diarrhoea) may prove dose-limiting. Bone-marrow depression is apparent 1 to 7 days after therapy and may be manifest first as thrombocytopenia; the nadir of the platelet and white cell counts usually occurs within 14 to 21 days, with recovery in 21 to 25 days. Other adverse effects include oral and gastrointestinal effects such as cheilitis, oesophagitis, gastrointestinal ulceration, and proctitis; fever, malaise, hypocalcaemia, erythema, myalgia, alopecia, pneumonitis, and kidney and liver abnormalities. Anaphylactoid reactions have occurred. Dactinomycin is very irritant and extravasation results in severe tissue damage.

The effects of radiotherapy are enhanced by dactinomycin and severe reactions may follow the use of high doses. Erythema and pigmentation of the skin may occur in areas previously irradiated. An increase in incidence of second primary tumours has been seen in patients treated with radiation and dactinomycin.

Dactinomycin should not be given to patients with varicella or herpes zoster, as severe and even fatal systemic disease may occur. Its use is best avoided in infants under 1 year as they are reported to be highly susceptible to the toxicity of dactinomycin. Blood counts and renal and hepatic function should be monitored frequently

Effects on the liver. Although doses less than about 50 micrograms/kg or 1.5 mg/m do not seem to be associated with an unacceptable degree of hepatotoxicity, giving dactinomycin as a single dose of 60 micrograms/kg (about 1.8 mg/m) every 3 weeks to children with Wilms’ tumour was associated with a high incidence of severe hepatotoxicity; reduction of the dose to 45 micrograms/kg every 3 weeks reduced this incidence to levels comparable with a standard regimen of 15 micrograms/kg daily for 5 successive days. Others have not seen such a high incidence of hepatotoxicity with doses of 60 micrograms/kg (despite some raised liver enzyme values), but in this case the high dose was given only every 6 weeks In general, dactinomycin should be given with caution to children with a history of antecedent liver damage, including abdominal irradiation or recent halothane anaesthesia.

Reversible veno-occlusive disease has been seen particularly in children with Wilms’ tumour who have received dactinomycin and vincristine. One study found age of less than 1 year to be a risk factor and a study in children with rhabdomyosarcoma given dactinomycin, vincristine, and eye lop hosp hamide also found that young age (under 3 years) was associated with a greater risk of severe hepatic toxicity. A literature review noted a significant predominance of veno-occlusive disease in right-sided Wilms’ tumour, possibly because the tumour mass could interfere with blood flow in the hepatic veins, which might make the liver more susceptible to the effects of dactinomycin.

Handling. Dactinomycin is irritant; avoid contact with skin and mucous membranes.

Interactions

For a general outline of antineoplastic drug interactions.

Pharmacokinetics

Intravenous doses of dactinomycin are rapidly distributed with high concentrations in bone marrow and nucleated cells. It undergoes only minimal metabolism and is slowly excreted in urine and bile. The terminal plasma half-life is reported to be about 36 hours. It does not cross the blood-brain barrier but is thought to cross the placenta.

In children. A study involving 31 patients aged between 1 and 20 years given dactinomycin in intravenous doses of 0.7 to 1.5 mg/m found that the pharmacokinetics of the drug were variable, but could be described by a 3-compartment model. Peak plasma concentrations varied from 3.2 to 99.2nanograms/mL, and both peak plasma concentration and exposure were inversely related to body-weight. Since there was evidence that exposure was also related to more severe toxicity, younger patients might be at greater risk with a regimen based on surface area; conversely the practice of capping the dose at 2 mg in older patients might result in underdosage.

For evidence that younger patients do experience more liver toxicity with dactinomycin, see Effects on the Liver, above.

Uses and Administration

Dactinomycin is a highly toxic antibiotic with antineoplastic properties. It inhibits the proliferation of cells in a cell-cycle non-specific way by forming a stable complex with DNA and interfering with DNA-dependent RNA synthesis. It may enhance the cytotoxic effects of radiotherapy (see also Adverse Effects, above). Dactinomycin also has immunosuppressant properties.

It has been used, usually with other drugs or radiotherapy, in the treatment of Wilms’ tumour, gestational trophoblastic tumours, nonseminomatous testicular cancer, and sarcomas such as rhabdomyosarcoma and Ewing’s sarcoma.

In the treatment of Wilms’ tumour, childhood rhabdomyosarcoma, or Ewing’s sarcoma, an intravenous dose of 15 micrograms/kg daily for 5 days has been used in combination regimens. In adults, gestational trophoblastic tumours have been treated with 12 micrograms/kg daily for 5 days as a single agent, or 500 micrograms on days 1 and 2 of combination regimens. Metastatic nonseminomatous testicular cancer has been treated with 1 mg/m on day 1 of combination regimens. The dose intensity for adults or children should not exceed 15 micrograms/kg or 400 to 600 micrograms/m daily for 5 days per 2-week cycle, and lower doses may need to be used in some chemotherapy combinations or with radiotherapy. Using a regional perfusion technique to localise the drug has permitted the use of higher doses, 50 micrograms/kg being suggested for an isolated lower extremity or pelvis and 35 micrograms/kg for an upper extremity.

Great care must be taken to avoid extravasation and it should be given, for preference, into the tubing of a fast-running intravenous infusion. Platelet and white cell counts should be performed frequently to detect bone-marrow depression; if either count shows a marked decrease the drug should be withheld until recovery occurs, which may take up to 3 weeks (see also Bone-marrow Depression.

Preparations

The United States Pharmacopeia 31, 2008: Dactinomycin for Injection.

Proprietary Preparations

Argentina: Cosmegen;

Australia: Cosmegen;

Austria: Cosmegen;

Belgium: Lyovac Cosmegen;

Brazil: Cosmegen;

Canada: Cosmegen;

Finland: Cosmegen;

France: Cosmegen;

Germany: Lyovac Cosmegen;

Greece: Cosmegen;

Hong Kong: Cosmegen;

India: Dacmozen;

Ireland: Cosmegen;

Italy: Cosmegen;

Malaysia: Cosmegen †;

Mexico: Ac-De;

The Netherlands: Lyovac Cosmegen;

Norway: Cosmegen;

New Zealand: Cosmegen;

Philippines: Cosmegen; Trepar;

Singapore: Cosmegen;

Sweden: Cosmegen;

Switzerland: Cosmegen;

Thailand: Cosmegen †; Lyovac Cosmegen;

Turkey: Cosmegen;

United Kingdom (UK): Cosmegen;

United States of America (US and USA): Cosmegen.

(British Approved Name, rINN)

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Pharmacopoeias. In China, Europe, International, Japan, and US.

European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Busulfan). A white or almost white, crystalline powder. Very slightly soluble in water and in alcohol; freely soluble in acetone and in acetonitrile. Store in airtight containers. Protect from light.

The United States Pharmacopeia 31, 2008 (Busulfan). A white, crystalline powder. Very slightly soluble in water; slightly soluble in alcohol; soluble 1 in 45 of acetone. Store in airtight containers.

Adverse Effects and Treatment

For a general outline see Antineoplastics.

The major adverse effect of busulfan with standard doses is bone-marrow depression, manifest as leucopenia, thrombocytopenia, and sometimes, anaemia. The nadir of the granulocyte count usually occurs after about 10 to 30 days with recovery occurring over up to 5 months, but busulfan has sometimes caused irreversible or extremely-prolonged bone-marrow depression. Hyperpigmentation is common, and in a few cases after long-term therapy may be part of a syndrome simulating Addison’s disease.

Rarely, progressive interstitial pulmonary fibrosis, known as ‘busulfan lung’, can occur on prolonged treatment. Gastrointestinal disturbances are rare at usual therapeutic doses but may be dose-limiting where high doses are given before bone marrow transplantation. Other rare adverse effects include dry skin and other skin reactions, liver damage, gynaecomastia, cataract formation, and, at high doses, CNS effects including convulsions.

Busulfan may result in impaired fertility and gonadal function. As with other alkylating agents, it is potentially carcinogenic, mutagenic, and teratogenic.

Effects on the bladder. Haemorrhagic cystitis occurred in a patient who had received prolonged therapy with busulfan. High-dose busulfan used in conditioning regimens for haematopoietic stem cell transplantation may increase the risk of lateonset haemorrhagic cystitis.

Effects on the liver. Jaundice in the terminal phase of chronic myeloid leukaemia in a 31 -year-old man was attributed to busulfan which had been taken for 6 years. Busulfan toxicity involving the liver was also reported in a patient who had taken busulfan for 54 months, while hepatitis possibly associated with busulfan therapy has also been described. Dose-dependent veno-occlusive disease (VOD) has been reported in 20 to 40% of patients receiving high-dose busulfan before bone marrow transplantation. Licensed product information from 1 manufacturer (Pierre Fabre, UK) states that previous radiotherapy, progenitor cell transplantation, or three cycles of chemotherapy or more, can increase the risk of hepatic VOD; another (GSK) lists concurrent use of multiple alkylating agents, or total doses of busulfan in excess of 16 mg/kg, as possible risk factors. A reduced incidence of hepatic VOD has been seen in those patients given high-dose busulfan and cyclophosphamide when the first dose of cyclophosphamide has been delayed for more than 24 hours after the last dose of busulfan.

Effects on the nervous system. High-dose busulfan, used in conditioning regimens for bone marrow transplantation, has been associated with the development of convulsions, both generalised and myoclonic. As a result, the use of prophylactic antiepileptic therapy has been suggested as a component of such regimens. However, some do not consider the routine use of prophylactic antiepileptics justified, and the potential for phenytointo increase the metabolism of busulfan, thereby possibly decreasing its myeloablative efficacy, has been pointed out. In addition, phenytoin plasma concentrations have been found to be subtherapeutic in patients who developed convulsions despite a standard prophylactic dose, and the regimen was subsequently adjusted to take account of plasma concentrations. Clobazam has been suggested as an alternative to phenytoin for prophylaxis of busulfan-induced seizures. Licensed product information from one manufacturer (GSK, UK) recommends the use of prophylactic antic onvulsants, and prefers a benzodiazepine to phenytoin. However, other manufacturers suggest use with phenytoin; Otsuka in the United States of America state that the recommended dose of their parenteral product is based on studies in which phenytoin was given, and that if other anticonvulsants are used exposure should be monitored, as a 15% increase in plasma-busulfan may be expected, with increased risk of toxicity.

Effects on the skin and hair. For the effect of radiotherapy in activating skin lesions in busulfan-treated patients, see under Precautions, below.

Precautions

For reference to the precautions necessary with antineoplastics. Careful attention should be given to monitoring blood counts during therapy. This should be done at least weekly at the start of standard dose therapy. With high dose therapy blood counts should be monitored daily, as should liver function. Prophy lactic anticonvulsants should be used during high dose therapy (see Effects on the Nervous System, above). Busulfan should be stopped if lung toxicity develops. The use of oxygen may exacerbate possible lung toxicity; if anaesthesia is required the concentration of oxygen should be minimised.

Handling. Busulfan is irritant; avoid contact with skin and mucous membranes.

Porphyria. Busulfan is considered to be unsafe in patients with porphyria because it has been shown to be porphyrinogenic in animals.

Radiotherapy. Severe cutaneous reactions occurred in patients given radiotherapy at least 30 days after combined chemotherapy with high-dose busulfan.

It is possible that radiotherapy could worsen subclinical lung injury caused by busulfan.

Interactions

For a general outline of antineoplastic drug interactions. Phenytoin increases the clearance of busulfan (see Effects on the Nervous System, above).

Antifungals. Giving itraconazole with busulfan resulted in a decrease in the clearance of busulfan; fluconazole had no such effect. Busulfan doses may need to be decreased if itraconazole is also given.

Antineoplastics. When tioguanine was given with busulfan for chronic myeloid leukaemia, a number of cases of hepatic nodular regenerative hyperplasia, with abnormal liver function tests, portal hypertension, and oesophageal varices were noted. There were no cases in patients treated with busulfan alone, and the mechanism of this possible interaction is unclear.

Antiprotozoals. In a study of patients who received high-dose busulfan as part of a myeloablative regimen before stem cell transplantation, the use of metronidazole significantly increased plasma concentrations of busulfan and the degree of associated toxicity, including elevation of liver function tests, veno-occlusive disease, and mucositis.

Pharmacokinetics

Busulfan is readily absorbed from the gastrointestinal tract and rapidly disappears from the blood with a half-life of 2 to 3 hours. It is extensively metabolised, and excreted in the urine almost entirely as sulfur-containing metabolites. It crosses the blood-brain barrier.

Metabolism. In a study of the pharmacokinetics of high-dose busulfan in 5 patients receiving 1 mg/kg orally every six hours for 4 days, the mean elimination half-life decreased from about 3.4 hours after the first dose to about 2.3 hours after the final dose, suggesting that busulfan may induce its own metabolism.

Therapeutic drug monitoring. A review concluded that therapeutic drug monitoring of busulfan would maximise en-graftment and minimise toxicity and relapse in haematopoietic stem cell transplantation. In regimens using busulfan with cyclophosphamide, steady-state plasma concentrations of busulfan above 600 micrograms/litre appeared to favour engraftment. A pharmacokinetic analysis found that in patients with graft rejections, busulfan trough concentrations were below 150 nanograms/mL; steady state concentrations also tended to be lower in this group but not significantly so. The bioavailability of oral busulfan is variable, particularly in children; intravenous conditioning regimens, adjusted on the basis of first-dose pharmacokinetics and therapeutic drug monitoring, have been used to overcome this problem. A study found a significant correlation between busulfan concentration in plasma and saliva after oral dosing in children; busulfan saliva analysis may therefore be a useful, non-invasive alternative to plasma analysis.

Uses and Administration

Busulfan is an antineoplastic with a cell-cycle non-specific alkylating action unlike that of the nitrogen mustards, and having a selective depressant action on bone marrow. In small doses, it depresses granulocytopoiesis and to a lesser extent thrombocytopoiesis but has little effect on lymphocytes. With larger doses, severe bone-marrow depression eventually ensues. Because of its selective action, busulfan has been used in the palliative treatment of chronic myeloid leukaemia. It provides symptomatic relief with a reduction in spleen size and a general feeling of well-being. The fall in leucocyte count is usually accompanied by a rise in the haemoglobin concentration. Permanent remission is not induced and resistance to its beneficial effects gradually develops.

Busulfan may be used in patients with polycythaemia vera and in some patients with myelofibrosis and primary thrombocythaemia. It is also used at high doses as part of a conditioning regimen to prepare patients for bone marrow transplantation, a procedure discussed on site under Haematopoietic Stem Cell Transplantation.

The licensed initial oral dosage ofbusulfan in chronic myeloid leukaemia is 60 micrograms/kg daily, with a usual maximum single daily dose of 4 mg. This is continued until the white cell count has fallen to between 15 000 and 25 000 cells/mm (typically 12 to 20 weeks). It should be stopped earlier if the platelet count falls below 100 000 cells/mm. Higher doses may be given if the response after 3 weeks is inadequate but this increases the risk of irreversible damage to the bone marrow and calls for special vigilance. Complete blood counts should be made at least every week and the trends followed closely; if haemorrhagic tendencies occur or there is a steep fall in the white cell count indicating severe bone-marrow depression, busulfan should be withdrawn until marrow function has returned.

Once an initial remission has been attained treatment is stopped and not resumed until the white cell count returns to 50 000 cells/mm. If this occurs within 3 months continuous maintenance treatment with a usual dose of 0.5 to 2 mg daily may be given. In patients with polycythaemia vera the usual oral dose is 4 to 6 mg daily, continued for 4 to 6 weeks with careful monitoring of blood counts. Further courses are given when relapse occurs; alternatively, maintenance therapy may be given at half the dose required for induction. Doses of 2 to 4 mg daily have been given for essential thrombocythaemia or myelofibrosis. In conditioning regimens for bone marrow transplantation busulfan has been given in usual doses of 3.5 to 4mg/kg daily in divided doses for 4 days orally (total dose 14 to 16 mg/kg), with cyclo-phosphamide, for ablation of the recipient’s bone marrow. When given by intravenous infusion in a regimen with phenytoin (see Effects on the Nervous System, above), a recommended dose is 3.2 mg/kg ideal body-weight daily for 4 days (total dose 12.8 mg/kg); actual body-weight is used for the calculation if it is less than the ideal weight. The daily dose is given as 4 infusions of 800 micrograms/kg at intervals of 6 hours; each dose should be diluted in sodium chloride 0.9% or glucose 5% to a final concentration of about 500 micrograms/mL, and given over 2 hours through a central venous catheter using an infusion pump. UK licensed product information states that cyclophosphamide dosing should not be started for at least 24 hours after the last dose ofbusulfan; US information permits use no sooner than 6 hours after the last busulfan dose.

In the UK, busulfan is licensed for use with cyclophosphamide or melphalan as a conditioning regimen prior to haematopoietic stem cell transplantation in children. The recommended dose for children up to 17 years of age is weight-based as follows: • less than 9 kg: busulfan 1 mg/kg

• 9 to 16 kg: busulfan 1.2 mg/kg

• 16 to 23 kg: busulfan 1.1 mg/kg

• 23 to 34 kg: busulfan 950 micrograms/kg

• greater than 34 kg: busulfan 800 micrograms/kg This dose is given every 6 hours over 4 days to a total of 16 doses, diluted and infused as for adults. Cyclophosphamide or melphalan should not be started for at least 24 hours after the last dose ofbusulfan.

Preparations

British Pharmacopoeia 2008: Busulfan Tablets;

The United States Pharmacopeia 31, 2008: Busulfan Tablets.

Proprietary Preparations

Argentina: Myleran;

Australia: Myleran;

Austria: Myleran;

Belgium: Myleran;

Brazil: Myleran;

Canada: Busulfex; Myleran;

Chile: Myleran;

Czech Republic: Busilvex; Myleran;

Denmark: Busilvex;

France: Busilvex; Myleran;

Germany: Busilvex; Myleran;

Greece: Busilvex; Myleran;

Hong Kong: Busulfex; Myleran;

India: Myleran;

Ireland: Myleran;

Israel: Busulfex; Myleran;

Italy: Busilvex; Myleran;

Malaysia: Myleran;

Mexico: Myleran;

The Netherlands: Busilvex; Myleran;

Norway: Busilvex;

New Zealand: Myleran;

Poland: Busilvex; Myleran;

Portugal: Busilvex; Myleran;

Russia: Myleran;

South Africa: Myleran;

Singapore: Myleran;

Spain: Busilvex;

Sweden: Busilvex; Myleran;

Switzerland: Busilvex; Myleran †;

Thailand: Myleran;

Turkey: Busulfex; Myleran;

United Kingdom (UK): Busilvex; Myleran;

United States of America (US and USA): Busulfex; Myleran

(British Approved Name, US Adopted Name, rINN)

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Pharmacopoeias. In China and US.

The United States Pharmacopeia 31, 2008 (Altretamine). A white crystalline powder. Insoluble in water; soluble in chloroform. Store in airtight containers.

Adverse Effects, Treatment, and Precautions

For a general outline see Antineoplastics.

Bone-marrow depression is usually moderate, manifesting as leucopenia, thrombocytopenia, and anaemia, and may require dosage reduction; blood counts should be monitored regularly. Nausea and vomiting are common and usually moderate although they may be dose-limiting. Prolonged or high-dose therapy may be associated with neurotoxicity, both peripheral (neuropathies) and central (ataxia, depression, confusion, drowsiness, and hallucinations); neurological examination should be performed regularly and treatment interrupted or the dose reduced as appropriate. Renal toxicity may also be dose-limiting. Other rare adverse effects include rashes, alopecia, and hepatic toxicity.

Handling. Altretamine is irritant; avoid contact with skin and mucous membranes.

Interactions

For a general outline of antineoplastic drug interactions. Pyridoxine appears to reduce the activity of altretamine.

Antidepressants. Severe and potentially life-threatening orthostatic hypotension developed in 3 patients who took amitriptyline or imipramine with altretamine and in a fourth patient who took phenelzine and altretamine. One patient was able to tolerate the antineoplastic with nortriptyline.

Pharmacokinetics

Altretamine is well absorbed from the gastrointestinal tract after oral doses, but is rapidly demethylated in the liver producing variation in plasma-altretamine concentrations. The principal metabolites are pentamethylmelamine and tetramethylmelamine, which are excreted in urine. The elimination half-life has been reported to be 4 to 10 hours.

Uses and Administration

Altretamine is an antineoplastic agent structurally similar to the alkylating agent tretamine (triethylenemelamine) although its mode of action may be different. It is given orally and is licensed for use as a single agent in the palliative treatment of ovarian carcinoma. Altretamine has also been tried in lung cancer. The usual dose as a single agent in ovarian cancer is 260 mg/m daily in four divided doses, for 14 or 21 consecutive days out of a 28-day cycle. Up to 12 cycles may be given. Therapy should be interrupted for at least 14 days, and subsequently restarted at a lower dose of 200 mg/m daily, if the white cell count falls below 2000 cells/mm or the platelet count below 75 000 cells/mm or if neurotoxic or intolerable gastrointestinal symptoms occur. Lower doses are also used in combination regimens.

Preparations

Single-ingredient Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.

Australia: Hexalen; Canada: Hexalen¤; Hexastat¤; Czech Republic: Tretax; France: Hexastat¤; Hong Kong: Hexastat¤; Israel: Hexalen¤; Italy: Hexastat¤; Netherlands: Hexastat¤; Norway: Hexalen; Hexastat¤; New Zealand: Hexalen; Russia: Hexalen (Гексален); Spain: Hexinawas¤; Sweden: Hexalen; Thailand: Hexalen; United Kingdom: Hexalen¤; United States: Hexalen;

Pharmacopoeial Preparations

The United States Pharmacopeia 31, 2008, and Supplements 1 and 2.: Altretamine Capsules

Drug Approvals

(British Approved Name, rINN)

Pharmacopoeias. In China, and US. Europe includes the hemihydrate.

European Pharmacopoeia, 6th ed. (Estradiol Hemihydrate). A white or almost white crystalline powder or colourless crystals. Practically insoluble in water sparingly soluble in alcohol soluble in acetone slightly soluble in dichloromethane.

The United States Pharmacopeia 31, 2008 (Estradiol). White or creamy-white, odourless, hygroscopic small crystals or crystalline powder. Practically insoluble in water soluble 1 in 28 of alcohol, 1 in 435 of chloroform, and 1 in 150 of ether soluble in acetone, in dioxan, and in solutions of fixed alkali hydroxides sparingly soluble in vegetable oils. Store in airtight containers at a temperature of 25°, excursions permitted between 15° and 30°. Protect from light.

Estradiol Acetate

(British Approved Name Modified, US Adopted Name, rINNM)

Drug Nomenclature

Estradiol Benzoate

(British Approved Name Modified, rINNM)

Drug Nomenclature

Pharmacopoeias. In China, Europe, Japan, and US.

European Pharmacopoeia, 6th ed. (Estradiol Benzoate). An almost white crystalline powder or colourless crystals. It exhibits polymorphism. Practically insoluble in water sparingly soluble in acetone freely soluble in dichloromethane slightly soluble in methyl alcohol.

The United States Pharmacopeia 31, 2008 (Estradiol Benzoate). A white to off-white, crystalline powder. Insoluble in water soluble in alcohol and in acetone slightly soluble in ether. Store in airtight containers. Protect from light.

Estradiol Cipionate

Drug Approvals

(British Approved Name Modified, rINNM)

Pharmacopoeias. In US.

The United States Pharmacopeia 31, 2008 (Estradiol Cypionate). A white to practically white crystalline powder, odourless or has a slight odour. Insoluble in water soluble 1 in 40 of alcohol, 1 in 7 of chloroform, and 1 in 2800 of ether soluble in acetone and in dioxan sparingly soluble in vegetable oils. Store in airtight containers. Protect from light.

Estradiol Dipropionate

Drug Approvals

(British Approved Name Modified, rINNM)

Estradiol Enantate

(British Approved Name Modified, rINNM)

Drug Nomenclature

Estradiol Hexahydrobenzoate

Drug Approvals

(British Approved Name Modified, rINNM)

Estradiol Phenylpropionate

Drug Approvals

(British Approved Name Modified, rINNM)

Estradiol Valerate

(British Approved Name Modified, rINNM)

Drug Nomenclature

Pharmacopoeias. In China, Europe, and US.

European Pharmacopoeia, 6th ed. (Estradiol Valerate). A white or almost white, crystalline powder or colourless crystals. Practically insoluble in water soluble in alcohol. Protect from light.

The United States Pharmacopeia 31, 2008 (Estradiol Valerate). A white crystalline powder which is usually odourless or may have a faint fatty odour. Practically insoluble in water soluble in benzyl benzoate, in dioxan, in methyl alcohol, and in castor oil sparingly soluble in arachis oil and in sesame oil. Store in airtight containers. Protect from light.

Adverse Effects

The adverse effects of estradiol and other oestrogens are related, in part, to dose and duration of therapy, and to the gender and age of the recipient. In addition, adverse effects may be modified by a progestogen in combined oral contraceptives or menopausal HRT. Whether adverse effects of natural and synthetic oestrogens differ, and whether the dosage route has an effect, is less clear.

The adverse effects of oestrogens used in hormonal contraceptives are considered in detail starting. Those of oestrogens used in HRT are considered in detail starting. The use of oestrogens in children may cause premature closure of the epiphyses resulting in decreased final adult height.

Large doses of oestrogens used in palliation of cancers have also been associated with nausea, fluid retention, venous and arterial thrombosis, and cholestatic jaundice. In men, they cause impotence and feminising effects such as gynaecomastia. In women, they may cause withdrawal bleeding, and, when used for breast cancer, they have caused hypercalcaemia and bone pain.

Effects on the skin. Transdermal patches in which estradiol is dissolved in the adhesive matrix may cause fewer skin reactions than those releasing estradiol from an alcoholic reservoir.

Precautions

The precautions for the use of estradiol and other oestrogens used as menopausal HRT are considered in detail starting. Those for oestrogens used in hormonal contraceptives are considered in detail starting.

High doses of oestrogen used in treating malignant disease should be used cautiously in patients with cere-brovascular disorders, coronary artery disease, or venous thromboembolism. They may exacerbate hypercalcaemia of malignancy. Oestrogens should be used with caution in children because premature closure of the epiphyses may occur resulting in inhibited linear growth and small stature. Oestrogens have been reported to interfere with some diagnostic tests such as those for thyroid function and glucose tolerance.

Breast feeding. Estradiol has been detected in breast milk after the use of pessaries containing 50 or 100 mg of estradiol. The American Academy of Pediatrics considers that estradiol is usually compatible with breast feeding.

Cosmetic use. Use of cosmetic products containing oestrogens has led to adverse effects such as precocious puberty in children and gynaecomastia or postmenopausal bleeding in adults. Such products have been used by a greater proportion of African Americans than any other ethnic group in the USA, and it has been hypothesised that this may have contributed to the observations of earlier onset of puberty in girls’ and increased risk of breast cancer in young women

Porphyria. Oestrogens are considered to be unsafe in patients with porphyria although there is conflicting experimental evidence of porphyrfnogenicity.

Pregnancy. Although gross abnormalities of the genito-urinary tract have been reported in the male offspring of women who took diethylstilbestrol during pregnancy there is conflicting evidence as to whether the oestrogen produced an increased risk of abnormalities, infertility, or testicular cancer in such offspring. The male fetus is normally protected from the feminising effects of the natural oestrogens in the uterine environment by the early development of the testes and the secretion of male hormones. However, there has been considerable concern about a rising incidence of disorders of the male reproductive tract, and a reduction in sperm counts, which has been noted in the last 20 to 30 years. It has been hypothesised that overexpo-sure of male fetuses to environmental oestrogens derived from pollutants such as pesticides and plastics may be responsible for this decline, although some dispute this A systematic review of epidemiological data found no strong evidence to link fetal exposure to oestrogens (as pharmaceuticals or pollutants) with reduced sperm count, cryptorchidism, or hypospadias, although there was some evidence to support a possible link with testicular cancer.

For discussion of the lack of effects of hormonal contraceptives on the fetus, including evidence that they are unlikely to increase the risk of hypospadia in the male fetus, see Pregnancy, under Precautions of Hormonal Contraceptives.

Veterinary use. An FAO/WHO expert committee examining the risks from residues of veterinary drugs in foodstuffs established an acceptable daily intake for estradiol, but concluded that there would be no need to specify a numerical maximum residue limit for estradiol in the edible tissues of cattle when products are used as growth promotors according to good practice.^l However, it should be noted that in the EU the use of steroidal hormones such as oestrogens in veterinary practice is restricted, and their use as growth promotors is banned.

There is concern about the effect of environmental oestrogens on male fertility and development, see Pregnancy, above.

Interactions

Interactions involving estradiol and other oestrogens used in menopausal HRT are covered. Interactions for oestrogens used in hormonal contraceptives are covered.

Pharmacokinetics

In general, estradiol and other oestrogens are readily absorbed from the gastrointestinal tract and through the skin or mucous membranes. However, the natural unconjugated oestrogens such as estradiol undergo extensive first-pass metabolism in the gastrointestinal tract and liver after oral doses. They are, therefore, generally not orally active, although a micronised preparation of estradiol has sufficient bioavailability (3 to 5%) to be orally active. Estradiol is metabolised in part to less active oestrogens such as estriol and estrone. Synthetic oestrogens produced by alkylation of the C17 position, such as ethinylestradiol, are more slowly metabolised and are therefore orally active. Conjugated oestrogens, which are essentially oestrogen metabolites, are also orally active because they are hydrolysed by enzymes in the lower gastrointestinal tract allowing absorption of the active oestrogen. Vaginal, transdermal, intranasal, or parenteral use of oestrogens also avoids first-pass hepatic metabolism. Plasma-estradiol concentrations are reported to reach a peak 1.5 to 2 hours after an oral dose, and again at about 8 hours due to enterohepatic recycling. Estradiol esters are rapidly hydrolysed to free estradiol when given orally. After intramuscular injection of the esters, absorption is prolonged.

Oestrogens are extensively bound to plasma proteins. Naturally occurring oestrogens such as estradiol are principally bound to sex-hormone binding globulin. Conversely, ethinylestradiol is mostly bound to albumin.

Oestrogens are metabolised in the liver. A variety of sulfate and glucuronide conjugates are formed, and these are excreted in the urine and the bile. Those excreted in the bile undergo enterohepatic recycling or are excreted in the faeces.

Uses and Administration

Estradiol is the most active of the naturally occurring oestrogens (for further details). Estradiol and its semisynthetic esters and other natural oestrogens are primarily used as menopausal HRT whereas synthetic derivatives such as ethinylestradiol and mestranol have a major role as components of combined oral contraceptives (see Hormonal Contraceptives). Estradiol may also be used as replacement therapy for female hypogonadism or primary ovarian failure. Replacement therapy (‘add-back’ therapy) may also be given to women in whom the pituitary-ovarian axis is suppressed by therapy with gonadorelin or its analogues.

Estradiol hemihydrate 1.03 mg is equivalent to about 1 mg of the anhydrous substance.

For menopausal HRT oral preparations or transdermal patches of estradiol are commonly used. Other transdermal formulations, subcutaneous implants, and a nasal spray are also available. Intramuscular injections were formerly used. In women with a uterus, a progestogen is also required, given cyclically or continuously, usually by mouth although some combined transdermal preparations are available. Local vaginal estradiol preparations are used specifically for the treatment of menopausal atrophic vaginitis these are generally recommended for short-term use only, if given without a progestogen in women with a uterus, although specific recommendations vary between products.

For use by mouth estradiol or estradiol valerate are normally given doses are 1 or 2 mg daily cyclically or more often continuously. Estradiol acetate may be given in an initial dose of 450 micrograms daily, increasing if necessary to 0.9 or 1.8 mg once daily.

Estradiol may be used topically as transdermal skin patches to provide a systemic effect a variety of patch-es are available which release between 25 and 100 micrograms of estradiol every 24 hours. A low-dose patch supplying 14 micrograms daily is also available specifically for the prevention of postmenopausal osteoporosis in women at significant risk with this low dose, the addition of a 14-day course of progestogen in women with a uterus is only required once every 6 to 12 months. Depending on the preparation, patches are replaced once or twice weekly. Each new patch is applied to a different area of skin in rotation, usually below the waistline patches should not be applied on or near the breasts. Topical gel preparations are also used for systemic effect. The usual applied dose is 0.25 to 1.5 mg of estradiol daily, depending on the preparation, but up to 3 mg daily may be required for control of menopausal symptoms in some women. The gel should not be applied on the face or on or near the breasts, vagina, or vulval region. A topical emulsion is also available estradiol hemihydrate 8.7 mg is applied daily to provide a systemic estradiol dose of about 50 micrograms. A transdermal spray has also been developed, delivering a single dose of estradiol 1.53 mg onto the skin. It should be applied to the skin of the inner surface of the forearm, and the dose may be increased up to 3 sprays once daily in the morning, at separate sites on the forearm, according to response.

A nasal spray is available, delivering 150 micrograms of estradiol hemihydrate per spray. The usual initial dose is 150 micrograms daily (1 spray in 1 nostril). After 2 or 3 cycles the dose may be adjusted according to response the usual maintenance dose is 300 micrograms daily (1 spray in each nostril once daily) but may range from 150 micrograms once daily up to 450 to 600 micrograms daily in 2 divided doses.

In order to prolong the duration of action subcutaneous implants of estradiol may be used. The dose of estradiol is generally 25 to 100 mg with a new implant being given after about 4 to 8 months according to oestrogen concentrations.

Estradiol may be used locally either as 25-microgram vaginal tablets, at an initial dose of one tablet daily for 2 weeks followed by a maintenance dose of one tablet twice a week, or as a 0.01% vaginal cream, in initial amounts of 2 to 4 g of cream daily for 1 to 2 weeks followed by half the initial dose for a similar period, then a maintenance dose of 1 g up to 3 times weekly. A local delivery system using a 3-month vaginal ring contains 2 mg of estradiol hemihydrate, and delivers about 7.5 micrograms of estradiol per 24 hours. Another 3-month vaginal ring system, which contains estradiol acetate, releases either 50 or 100 micrograms of estradiol daily, and is used for the relief of both local and systemic postmenopausal symptoms. Intramuscular injections of estradiol benzoate or valer-ate esters have been used as oily depot solutions, usually given once every 3 to 4 weeks. The cipionate, di-propionate, enantate, hexahydrobenzoate, phenylpropionate, and undecylate esters have been used similarly. The enantate and cipionate esters are used as the oestrogen component of combined injectable contraceptives.

Estradiol and other oestrogens have sometimes been used in higher doses for palliative treatment in prostate cancer and breast cancer in men and postmenopausal women.

Administration, buccal and sublingual administration.

Estradiol is absorbed through the buccal route, and has been reported to improve postmenopausal vasomotor symptoms. A pharmacokinetic study of micronised estradiol found the sublingual route resulted in more rapid absorption, a higher peak concentration, and more rapid elimination, than oral dosage. Sublingual micronised estradiol has been studied for the management of postpartum depression.

IMPLANTS. There may be a striking interpatient variation in blood-estradiol concentrations in women receiving estradiol implants, and symptoms of oestrogen deficiency have re-appeared in some patients even though serum-estradiol concentrations were within or above the physiological range. After debate on the appropriateness of using serum concentrations of estradiol as a guide to implant use, rather than symptoms, it is now recommended that estradiol concentration should be monitored during therapy.

Cyclical progestogen may be required for a prolonged period after removal of estradiol implants in women with a uterus.

INTRANASAL ADMINISTRATION. The intranasal route for estradiol HRT has been reviewed. It appears to be comparable in efficacy to oral or transdermal use in the treatment of meno-pausal symptoms. As with transdermal application, the intranasal route avoids intestinal and hepatic first-pass metabolism.

TRANSDERMAL ADMINISTRATION. Transdermal estradiol given via patches applied to the skin has been reviewed. This method of delivery has certain advantages over the oral route in that gastrointestinal and hepatic first-pass metabolism is

avoided, liver enzymes are not stimulated (although this may also mean that beneficial effects on serum lipids are absent), and the prolonged drug release from the patch means less frequent application is necessary and hence patient compliance may be improved. For oestrogen replacement in menopausal and postmenopausal women estradiol patches are used continuously or in a cyclical manner, with added progestogen for part of the cycle in those women with an intact uterus. This does not lead to drug accumulation and produces blood-estradiol concentrations and estradiol to estrone ratios similar to those normally observed in premenopausal women. The patch is well tolerated with skin irritation being the main problem. Patches are as effective as oral oestrogens in treating menopausal and postmenopausal symptoms such as flushing and vaginal atrophy and in preventing osteoporosis. Combined HRT patches, providing both estradiol and a progestogen, have also been developed.

Estradiol is also effective when applied topically to the skin as a gel or emulsion.

Depression. The use of oestrogen therapy in the treatment of premenopausal women with postnatal depression has been shown to be effective. However, although such therapy could be a useful adjunct to conventional treatment (see Depression), the risk of serious adverse effects including thrombosis may limit its value.

Whether oestrogens are of benefit in older women, typically with depression associated with the menopause, is less clear. Some studies of transdermal estradiol have reported benefit, whereas other studies of transdermal or oral dosage have not found it to be effective. Whether the presence of a progestogen in combination HRT would reduce any purported benefit is also unclear. Antidepressants remain the standard of care in perimen-opausal or postmenopausal women with clinical depression.

Gender reassignment. Oestrogens are used in male-to-female transsexuals to develop and maintain secondary sexual characteristics. Although ethinylestradiol and conjugated oestrogens have been used for this purpose, and there is some evidence that such use can improve vascular function, others consider ethinylestradiol too thrombogenic at the doses required [typically 50 to 100 micrograms daily or more] and suggest that estradiol, as the valerate in oral doses of 2 to 4 mg daily, or transdermally as a patch supplying 100 micrograms daily, is the oestrogen of choice. Cyproterone acetate is usually also given for its anti-androgenic effect.

Growth disorders. Supraphysiological doses of oestrogens inhibit somatic growth and have been used, with a cyclical progestogen, to reduce final height in girls with constitutional tall stature, although such treatment has declined markedly with changing social norms. In early reports, diethylstilbestrol was used, but this is an unsuitable choice because of the increased risk of cancer. Ethinylestradiol has been given in the past in doses of up to 500 micrograms daily, but doses of 50 to 100 micrograms daily came to be preferred, although lower doses may be equally effective. Conjugated oestrogens have also been used, and a study reported that doses of 7.5 to 11.25 mg daily resulted in an average decrease of about 5 cm from final predicted height. In practice, doses as low as 625 micrograms daily have been used. Reported height reductions have ranged from 2 to 10 cm but studies are difficult to compare. Treatment has generally been continued until closure of the epiphyses, but the effects of oestrogen therapy may be influenced by both chronological and bone age at the onset of treatment, duration of treatment, the oestrogen used and its dose, and the point of final height assessment. High-dose oestrogen therapy is also associated with adverse effects such as weight gain, headache, nausea, and pigmentation of the areolae or nipples, and there can be adverse changes to haemostatic and lipid measures. A retrospective cohort review has also reported that girls who had been treated with high-dose oestrogens were more likely to report fertility problems in later life than similar girls who had not been treated.

Oestrogen therapy has occasionally been used to help promote growth in girls with constitutional delayed puberty.

Haemorrhagic disorders. Limited evidence supports the use of oestrogens in various bleeding disorders. There have been mixed results from small studies of oestrogens, given alone or with a progestogen, in patients with hereditary haemorrhagic telangiectasia the use of a combined oral contraceptive has been suggested as a suitable option for fertile women with symptomatic epistaxis. There are also some reports of bleeding being reduced in patients with gastrointestinal vascular malformations from other causes. Conjugated oestrogens have been used in haemorrhagic disorders associated with chronic renal failure and haemorrhagic cystitis.

Lactation inhibition. Synthetic oestrogens (e.g. quinestrol) and nonsteroidal oestrogens (e.g. diethylstilbestrol) were historically used to suppress lactation. However, this use is now considered inappropriate because of an increased risk of puerperal thromboembolism.

Premenstrual syndrome. Premenstrual syndrome (PMS) presents as a variable combination of psychological and somatic symptoms occurring during the luteal phase of the menstrual cycle, which resolve during, and immediately after, menstruation. Another term, premenstrual dysphoric disorder, has been proposed to cover severe cyclical mood disorder that is functionally incapacitating. Whereas about 20 to 40% of women have complaints that may be classified as PMS, only 3 to 8% meet criteria for premenstrual dysphoric disorder. The term premenstrual tension (PMT) has sometimes been applied to the psychological symptoms. Many symptoms of PMS are the same as normal premenstrual symptoms, but are more severe. The aetiology of PMS is not fully understood, although it is thought that affected women may be more sensitive to the effects of normal hormonal fluctuations on CNS neurotransmitter function.

Initial management includes non-medical interventions such as education and support, counselling, stress management, relaxation techniques, and exercise caffeine and salt restriction are of unproven benefit. The herbal remedy agnus castus has been found to be of benefit For patients with moderate to severe symptoms, a number of drugs have been tried with varying degrees of success objective assessment of efficacy has been hampered by varying diagnostic criteria, a marked placebo response, and difficulties in obtaining reproducible responses. Treatment may be aimed at modifying the menstrual cycle or treating specific symptoms.

In women with mainly psychological symptoms, SSRIs can be helpful. Fluoxetine and sertraline have been shown in controlled studies to alleviate both psychological and somatic symptoms in women with PMS, and may be given intermittently (only in the luteal phase) or continuously. If treatment with one SSRI is ineffective or not tolerated, another SSRI or venlafaxine may be substituted. ‘^e There is limited information on the use of S S-RIs for PMS in adolescents, and precautions regarding suicidal ideation in young adults should be considered. Clomipramine, a nonselective serotonin reuptake inhibitor, has been tried for PMS with some success. The anxiolytic alprazolam has also been used, but use of this and other benzodiazepines should be restricted to the luteal phase of the cycle in selected patients to minimise the risk of dependence and tolerance.

Abdominal bloating and swelling associated with PMS has traditionally been thought to be due to sodium and water retention. However, in most women with these symptoms there is no evidence of an increase in body-weight or in body sodium or total water, and use of diuretics is therefore not justified. Nevertheless, in women with appreciable weight gain and abdominal bloating in the luteal phase, the aldosterone antagonist spironol-actone may be useful. Another symptom of PMS, cyclical mastalgia, is discussed.

Pyridoxine has been tried on the basis that it is a cofactor in neu-rotransmitter (specifically serotonin) synthesis, and has been found to relieve depression induced by oral contraceptives in selected patients. However, its efficacy in PMS is equivocal, and high daily doses have been associated with neurotoxicity. Calcium supplementation may relieve symptoms of PMS.

Treatments that modify the menstrual cycle have often been used in women with PMS. In general, drugs with proven efficacy such as danazol, oestrogen implants, and gonadorelin analogues are reserved for women with severe PMS unresponsive to other treatments, because of their adverse effects. Progestogen therapy was once popular, but beneficial responses have not been universally achieved and the theory that progesterone was necessary to correct a hormone imbalance is now losing ground. In addition, a systematic review of clinical trials found no evidence to support the use of progesterone or progestogens for PMS. Combined oral contraceptives have met with limited success. They may be useful in some women for the control of somatic symptoms, but in others, PMS is caused or exacerbated by them. There is some suggestion that combined contraceptives containing dros-pirenone may be more effective in managing PMS than those containing progestogens such as levonorgestrel or norethister-one. Consideration should be given to continuous rather than cyclical use. Perimenopausal women may benefit from oestrogen delivered from transdermal patches. In women with a uterus, use with a cyclical progestogen is required to avoid endometrial hyperplasia unfortunately, the progestogen may be associated with the return of symptoms. Possible strategies to minimise this include the use of a less androgenic progestogen, reducing the frequency with which it is given, or using an intra-uterine device to deliver the progestogen locally. Danazol can be useful, but there is concern over its adverse effects on lipids during long-term use and over the risk of masculinisation of a female fetus should pregnancy occur. For patients with severe symptoms not amenable to other treatments, gonadorelin analogues such as goserelin can be used to eliminate ovarian function, ‘add-back’ treatment with oestrogen plus progestogen being given to protect against the adverse effects of oestrogen deficiency including osteoporosis. This treatment is very effective for both physical and psychological symptoms. Short-term use (3 months) of a gonadorelin analogue alone has been used to confirm the diagnosis of PMS, or to predict the response to bilateral oophorectomy.

Preparations

British Pharmacopoeia 2008: Estradiol and Norethisterone Acetate Tablets; Estradiol and Norethisterone Tablets; Estradiol Injection; Estradiol Transdermal Patches

The United States Pharmacopeia 31, 2008: Estradiol and Norethindrone Acetate Tablets; Estradiol Cypionate Injection; Estradiol Injectable Suspension; Estradiol Pellets; Estradiol Tablets; Estradiol Transdermal System; Estradiol Vaginal Cream; Estradiol Valerate Injection.

Proprietary Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.

Argentina: Aerodiol; Climaderm¤; Disequens; Estraderm; Estradot; Estreva; Estring¤; Estrofem; Etrosteron; Eutocol; Evorel; Fem 7; Ginatex; Hormodiol; Lindisc; Oestro Gel; Progynon; Progynova; Replasyn; Ronfase; Rontagel; Transdiol¤; Trial Gel; Trial Sat; Australia: Aerodiol; Climara; Dermestril; Estraderm; Estradot; Estring¤; Estrofem; Femtran; Menorest; Primogyn Depot; Progynova; Sandrena; Vagifem; Zumenon; Austria: Aerodiol; Climara; Cycloderm; Dermestril; Duokliman; Estracutan; Estraderm; Estradot; Estramon; Estring¤; Estrofem; Estrogel; FemSeven; FemSieben; Klimapur; Klimareduct; Linoladiol; Menorest; Merimono; Oesclim¤; Progynon; Progynova; Sandrena¤; Sterigin; Substitol¤; Systen; Vagifem; Zerella; Zumenon; Belgium: Aerodiol; Climara; Dermestril; Estraderm; Estreva; Estrofem; Feminova; Meno-Implant; Oestrogel; Progynova; Systen; Vagifem; Vivelle; Zumenon; Brazil: Aerodiol; Avicis; Benzo-Ginoestril; Climaderm; Estradelle; Estraderm; Estradot; Estreva; Estrofem; Fem 7; Ginedisc¤; Hormodose; Lindisc; Menorest¤; Merimono; Natifa; Oesclim¤; Oestrogel¤; Primogyna; Reglovar¤; Riselle; Sandrena; Systen; Canada: Climara; Delestrogen; Estrace; Estraderm; Estradot; Estring; Estrogel; Femogex¤; Oesclim; Vagifem; Vivelle¤; Chile: Climaderm; Cyclobiol; Dermatrans; Enadiol; Epiestrol; Estranova E; Estreva; Farlutes; Fem 7; Femalon; Femiderm; Femidott; Ginoderm; Mirion; Oesclim¤; Primaquin; Primofol Depot¤; Primogyna¤; Progynova; Sandrena; Transvital; Vagifem; Czech Republic: Agofollin; Climara; Dermestril; Divigel; Elleste; Estrace; Estraderm; Estrahexal; Estreva; Estrimax; Estring; Estrofem; Fem 7; Linoladiol N; Menorest; Neofollin; Octodiol; Oesclim; Oestrogel; Riselle; Systen; Vagifem; Denmark: Aerodiol; Climara; Divigel; Estraderm; Estring; Estrofem; Estrogel; Evorel; Femanest; FemSeven¤; Menorest¤; Progynon; Sandrena; Vagifem; Vivelle Dot; Finland: Climara; Dermestril; Divigel; Estraderm; Estradot; Estrena; Estring; Estrofem; Estrogel; Evorel; FemSeven; Menorest¤; Merimono; Progynova; Vagifem; Zumenon; France: Aerodiol; Benzo-Gynoestryl¤; Climara; Delidose; Dermestril; Estraderm; Estrapatch; Estrofem; Evafilm¤; Femsept; Menorest; Oesclim; Oestrodose; Oestrogel; Oromone; Progynova; Provames; Systen; Thais; Vivelledot; Germany: Aerodiol; Cerella¤; Cutanum; Dermestril; Ephelia; Estrabeta; Estraderm; Estradot; Estramon; Estreva; Estrifam; Estring; Estronorm; Evorel; Fem 7; Femoston mono; Gynokadin; GynPolar; Linoladiol N; Menorest; Merimono; Pantostin; Progynon B¤; Progynon Depot 100¤; Progynon Depot 10; Progynon Depot 40¤; Progynova; Sandrena; Sisare mono; Tradelia; Vagifem; Greece: Aerodiol; Dermestril; Estraderm TTS¤; Estradot; Estramon; Estring¤; Estrofem; Estrogel; Menorest; Oesclim¤; Oestrogel; Vagifem; Hong Kong: Aerodiol¤; Bisteron¤; Dermestril; Estraderm; Estreva; Estrofem; Fem 7¤; Oestrogel; Progynova; Hungary: Calidiol; Dermestril; Divigel; Estraderm; Estradot; Estramon; Estrimax; Estrofem; Linoladiol N; Oesclim; Oestrogel; Systen; Triaklim; Vagifem; India: Estraderm; Ireland: Aerodiol; Climara; Dermestril; Divigel; Epiestrol¤; Estraderm; Estradot; Estramon¤; Estrofem; Evorel; Fematab; Fematrix¤; Menorest¤; Oestrogel; Progynova¤; Vagifem; Israel: Climara¤; Dermestril; Estraderm; Estrofem; Evorel; Meno-Patch¤; Oestrodose; Oestrogel; Progynova; Vagifem; Italy: Aerodiol; Armonil; Benztrone¤; Climara; Dermestril; Ephelia; Epiestrol; Esclima; Estraderm; Estroclim; Estrodose; Estrofem; FemSeven; Gelestra; Ginaikos; Menorest; Progynon B¤; Progynon Depot¤; Progynova; Sandrena; Sprediol; Systen; Vagifem; Zerella; Malaysia: Divigel; Estrofem; Oestrogel; Progynova; Trisequens; Mexico: Armistor; Benzo-Ginestryl; Climaderm; Essventia; Estraderm; Estramon; Estreva; Evorel; Fem 7; Ginedisc; Oestrogel; Primogyn; Sandrena; Systen; Monaco: Estreva; Netherlands: Aerodiol; Climara; Dermestril; Dimenformon¤; Estraderm; Estradot; Estring¤; Estrofem; Fem 7; Femring; Meno-Implant; Menorest; Progynon Depot 100¤; Progynon Depot 10¤; Progynova; Sandrena; Systen; Vagifem; Zumenon; Norway: Climara; Estraderm; Estradot; Estring; Evorel; Menorest¤; Progynova; Vagifem; New Zealand: Aerodiol; Climara; Estraderm; Estring¤; Estrofem; Femtran; Progynova; Sandrena¤; Vagifem¤; Portugal: Climara; Dermestril; Estraderm; Estradot; Estrofem; Estronar¤; Menorest; Vagifem; Zumenon; Russia: Climara (Климара); Divigel (Дивигель); Estrimax (Естримакс); Estrofem (Естрофем); Oestrogel (Естрожель); South Africa: Climara; Estraderm; Estring; Estro-Pause; Estrofem; Evorel; Femigel; Menorest¤; Primogyn Depot; Progynova; Vagifem; Singapore: Divigel; Estraderm; Estreva; Estrofem; Fem 7¤; Oestrogel; Progynova; Vagifem; Spain: Absorlent; Alcis; Cliogan; Dermestril; Endomina; Esotran¤; Esprasone; Estraderm; Estradot; Estroffik; Evopad; Menorest¤; Meriestra; Oestraclin; Oestrodose¤; Progynon Depot¤; Progynova; Vagifem; Sweden: Climara; Divigel; Estraderm; Estradot; Evorel; Femanest; FemSeven; Menorest¤; Oesclim; Oestring; Progynon; Vagifem; Switzerland: Aerodiol; Cerina; Climara; Dermestril; Divigel; Epiestrol¤; Estraderm; Estradot; Estramon; Estreva; Estring; Estrofem N; Fem 7; FemSeven¤; Menorest; Oestrogel; Progynon Depot 100¤; Progynon Depot 10¤; Progynova; Sandrena; Systen; Vagifem; Zumenon; Thailand: Climara; Divigel; Estrofem; Oestrogel; Progynon; Progynova; Vagifem; United Kingdom: Adgyn Estro¤; Aerodiol; Bedol; Benztrone¤; Climaval; Dermestril¤; Elleste-Solo; Estraderm; Estradot; Estring; Evorel; Fematrix; FemSeven; FemTab; Menorest¤; Menoring¤; Oestrogel; Progynova; Sandrena; Vagifem; Zumenon; United States: Alora; Climara; Deladiol¤; Delestrogen; depGynogen; Depogen; Dioval¤; Dura-Estrin¤; Duragen¤; E-Cypionate¤; Esclim; Estra-D¤; Estra-L¤; Estrace; Estraderm; Estrasorb; Estring; Estro-Cyp¤; Estrogel; Estroject¤; FemPatch; Femring; Femtrace; Gynodiol; Gynogen¤; Menaval¤; Menostar; Vagifem; Valergen; Vivelle; Venezuela: Aerodiol; Climaderm; Estraderm; FemSeven

Multi-ingredient Preparations

Argentina: Activelle; Angeliq; Atrimon; Ciclocur; Climene; Cristerona; Dilena; Dos Dias N; Estalis Sequi; Estalis; Estracomb; Estragest; Evorel Conti; Evorel Sequi; Farludiol Ciclo; Farludiol; Fem 7 Combi; Fempack; Gynodian Depot; Hosterona; Kliogest; Lubriderm; Menstrogen; Mesigyna; Perlutal; Plenifem¤; Prefest; Primosiston; Supligol NF; Supligol¤; Totelle Ciclico; Totelle Continuo; Trial Combi; Trial Gest; Trial Pack¤; Trisequens; Australia: Angeliq; Climen; Divina¤; Estalis Continuous; Estalis Sequi; Estracombi; Estrapak¤; Femoston; Kliogest; Kliovance; Primodian Depot¤; Trisequens; Austria: Activelle; Climabelle; Climen; Climodien; Cyclacur; Estalis Sequens; Estalis; Estandron¤; Estracomb; Estragest¤; Femipak; Femoston Conti; Femoston; Femphascyl conti; Femphascyl; FemSeven Combi; Filena; Gravibinon¤; Gynodian Depot; Ichth-Oestren¤; Kliogest; Lafamme; Liseta; Mericomb; Merigest; Minique; Novofem; Ostrolut¤; Perikliman; Primodian Depot¤; Totelle cyclo¤; Tri-Filena¤; Trisequens; Belgium: Activelle; Climen; Climodien; Cyclocur; Dimenformon; Diviplus¤; Diviva¤; Estracombi; Feminova Plus; Femoston Conti; Femoston; Kliogest; Novofem; Totelle Cycle; Trisequens; Trivina¤; Brazil: Activelle; Cicloprimogyna; Ciclovular¤; Cliane; Climene; Cyclofemina; Dilena; Elamax; Estalis SQ; Estalis; Estandron P; Estracomb; Estragest; Evitas¤; Femineo; Femoston Conti; Femoston; Gestadinona; Ginecoside¤; Ginedisc 50 Plus¤; Hormoginase¤; Kliogest; Lindisc Duo¤; Mericomb; Merigest; Mesigyna; Natifa Pro; Normomensil¤; Perlutan; Postoval; Prefest; Preg-Less; Progest¤; Suprema; Systen Conti; Systen Sequi; Trinestril; Trisequens; Unalmes; Uno-Ciclo; Canada: Climacteron; Duogex LA¤; Estalis Sequi; Estalis; Estracomb; Estrand¤; Neo-Pause¤; Chile: Activelle; Agurin; Avaden; Cliane; Climene; Cyclofem; Enadiol CC; Enadiol MP; Enadiol Neta; Estandron Prolongado; Estracomb; Estragest; Estranova 30 Simple; Estranova CC; Farlupost; Fem 7 Combi; Femoston Conti; Femoston; Ginefolin; Gravidinona¤; Gynodian Depot; Kilios; Kliogest; Mesigyna; Novafem; Postoval; Primaquin MP Continuo; Primaquin MP; Progyluton; Totelle Continuo; Totelle; Trisequens; Unalmes¤; Czech Republic: Activelle; Aknefug; Alpicort F; Avaden; Climara Duo; Climen; Convaden; Cyclo-Menorette; CycloOstrogynal; Divina; Diviseq; Estalis Sequi; Estalis; Estrace Plus; Estrace-C; Estracomb; Estragest; Femoston; Folivirin; Gynodian Depot; Indivina; Kliane; Klimodien; Klimonorm; Kliogest; Linoladiol-H N; Pausogest; Systen Conti; Systen Sequi; Triaklim; Trisequens; Denmark: Activelle; Climen; Climodien; Cyclo-Progynon; Divina Plus; Divina; Estracomb; Evo-Conti; Evo-Sequi; Femanor; Femasekvens; Indivina; Klimalet; Klimaxil¤; Kliogest; Novofem; Nuvelle; Ostranorm¤; Totelle; Trevina; Trinorm¤; Trisekvens; Finland: Activelle; Climara Duo¤; Cyclabil; Divina; Divitren; Estalis Sekvens; Estalis; Estracomb¤; Evorel Conti; Evorel Sequi; Femilar; Femoston Conti; Femoston; FemSeven Combi; Indivina; Kliogest; Mericomb; Merigest; Novofem; Senikolp¤; Totelle Sekvens; Trisekvens; France: Activelle; Avadene; Climaston; Climaston; Climene; Climodiene; Divina; Diviseq; Duova; FemseptCombi; Gravibinan¤; Gynodian Depot¤; Kliogest; Naemis; Novofemme; Successia¤; TOM¤; Trisequens; Germany: Acetonal Vaginale¤; Activelle; Aknefug-Emulsion¤; Alpicort F; Androfemon¤; Climen; Climodien; Clionara; Crinohermal fem; Cyclo-Menorette; Cyclo-Progynova; CycloOstrogynal; CycloPolar¤; Ell-Cranell¤; Estalis Sequi; Estracomb; Estrafemol; Estragest; Fem 7 Combi; Femoston Conti; Femoston; Fissan-Brustwarzensalbe¤; Gianda; Gravibinon¤; Gynamon; Gynodian Depot; Ichth-Oestren¤; Indivina; Jephagynon¤; Klimonorm; Kliogest N; Lafamme; Linoladiol-H N; Lynandron¤; Malun¤; Mericomb; Merigest; NeoOstrogynal; NeyNormin N (Revitorgan-Dilutionen N Nr 65); Novofem; Osmil; Ostronara; Ovatest¤; Primodian Depot¤; Primosiston¤; Procyclo; Sebohermal¤; Sisare 28; Sisare; Syngynon¤; Trisequens; Vitrena; Greece: Activelle; Angeliq; Climodien; Cyclacur; Divina; Estalis; Estopause; Estracomb TTS; Femaston; Kliogest; Nuvelle¤; Systen Conti; Systen Sequi; Trisequens; Hong Kong: Activelle; Climen 28; Dilena; Estracomb; Femoston; Hormonin; Klimonorm¤; Kliogest; Progestrol¤; Trisequens; Hungary: Activelle; Alpicort F; Climen; Cyclo-Menorette; Divina; Divitren; Estracomb; Estragest; Femoston; Klimodien; Klimonorm; Kliogest; Linoladiol-H N; Pausogest; Trisequens; India: Kemicetine Antiozena; Mixogen; Ireland: Activelle; Cyclo-Progynova¤; Diviseq¤; Estalis Sequi; Estalis; Estracombi; Estrapak¤; Evorel Conti; Femoston Conti; Femoston; Femplan-MA¤; Indivina; Kliogest; Novofem; Nuvelle; Tridestra¤; Trisequens; Israel: Activelle; Evorel Conti; Evorel Sequi; Kliogest; Meno-MPA¤; Meno-Net¤; Novofem; Progyluton; Trisequens; Italy: Ablacton¤; Activelle; Biormon¤; Climen; Clym-Depositum¤; Combiseven; Cyclacur¤; Duo-Ormogyn¤; Estalis Sequi; Estandron¤; Estiamen B¤; Estiamen¤; Estracomb; Femoston Conti; Femoston; Filena; Gravibinan; Gynodian Depot; Kliogest; Menovis; Nuvelle TS¤; Nuvelle; Pausene; Primodian Depot¤; Tesor-C¤; Totelle; Trisequens; Malaysia: Activelle; Climen; Femoston; Klimonorm; Kliogest; Progyluton; Mexico: Anafertin; Binodian; Cliane; Climene; Cyclofemina; Damax; Despamen; Dilena; Estracomb; Estrapak¤; Evorel Conti; Ginoplan¤; Gravidinona; Lutalmin; Lutoginestryl F; Mesigyna; Metrigen Fuerte; Ominol¤; Patector; Perludil; Perlutal; Prefest; Primosiston; Primoson-F; Progediol; Proger-F; Progyluton; Totelle Continuo; Totelle Secuencial; Yectames; Monaco: Trioestrine-Retard¤; Netherlands: Activelle; Angeliq; Avaden; Climene; Cyclocur; Dimenformon Prolongatum¤; Divina¤; Estandron Prolongatum; Estracomb; Fem 7 Sequi; Femoston; Kliogest; Naemis; Novofem; Trisequens; Zumeston¤; Norway: Activelle; Climen; Climodien; Cyclabil; Diviseq¤; Estalis Sekvens; Estalis; Estracomb¤; Indivina; Kliogest; Novofem; Totelle Sekvens; Trisekvens; New Zealand: Cliane; Estrapak¤; Kliogest; Kliovance; Nuvelle; Trisequens; Portugal: Activelle; Cicnor; Climara Duo; Climen; Climodien; Dilena; Emmenovis; Estalis Sequi; Estalis; Estracomb; Femoston 1/5; Femoston 2/10; Kliogest; Nuvelle; Progyluton; Trisequens; Russia: Climen (Климен); Climodien (Климодиен); Cyclo-Progynova (Цикло-прогинова); Divina (Дивина); Diviseq (Дивисек); Divitren (Дивитрен); Femoston (Фемостон); Femoston 1/5 (Фемостон 1/5); Gynodian Depot (Гинодиан Депо); Indivina (Индивина); Klimonorm (Климонорм); Pausogest (Паузогест); Triaklim (Триаклим); Trisequens (Трисеквенс); South Africa: Activelle; Angeliq; Climen; Divina; Estracombi; Estro-Pause N; Evorel Conti; Evorel Sequi; Femoston; Kliogest; Mixogen; Postoval; Prefesta; Primodian Depot; Trisequens; Trivina; Singapore: Activelle; Climen; Estracomb; Femoston; Kliogest; Progyluton; Trisequens; Spain: Ablacton¤; Absorlent Plus; Activelle; Auroclim; Climen; Climodien; Clisin; Dinatrofon¤; Duofemme; Emenovister¤; Endomina Plus; Estalis Sequi; Estalis; Estandron Prolongado¤; Estracomb; Gynodian Depot¤; Merigest Sequi; Merigest; Mevaren; Nuvelle; Perifem; Primodian Depot¤; Primosiston Fuerte¤; Progyluton; Topasel; Trisequens; Sweden: Activelle; Climodien; Cyclabil; Divina Plus; Divina; Estalis Sekvens; Estalis; Estracomb¤; Evorel Micronor; Femanor; Femasekvens; Indivina; Kliogest; Novofem; Totelle Sekvens; Totelle; Trisekvens; Trivina; Switzerland: Activelle; Alpicort F; Climen; Cyclacur; Diviseq; Estalis Sequi; Estalis; Estandron Prolongatum¤; Estracomb; Estragest; Fem 7 Combi; Femoston Conti; Femoston; Gravibinon¤; Gynodian Depot; Indivina; Kliogest N; Linoladiol¤; Mericomb; Merigest; Novofem; OestroTabs Plus Cyclic¤; Primodian Depot¤; Primosiston¤; Systen Conti; Systen Sequi; Triaval; Trisequens; Tyliculine¤; Thailand: Activelle; Climen; Cyclo-Progynova; Duoton; Indivina; Klimonorm; Kliogest¤; Primodian Depot; Trisequens¤; United Kingdom: Adgyn Combi¤; Angeliq; Climagest; Climesse; Clinorette; Cyclo-Progynova 1 mg; Cyclo-Progynova 2 mg; Elleste Duet Conti; Elleste-Duet; Estracombi; Estrapak¤; Evorel Conti; Evorel Pak¤; Evorel Sequi; Femapak; Femoston Conti; Femoston; FemSeven Conti; FemSeven Sequi; FemTab Continuous¤; FemTab Sequi; Hormonin; Indivina; Kliofem; Kliovance; Novofem; Nuvelle Continuous; Nuvelle TS¤; Nuvelle; Tridestra; Trisequens; United States: Activella; Andro/Fem¤; ClimaraPro; CombiPatch; Deladumone¤; depAndrogyn¤; Depo-Testadiol; Depotestogen; Duo-Cyp¤; Duratestrin¤; Estra-Testrin¤; Lunelle¤; Prefest; T-E Cypionate¤; Test-Estro¤; Testaval 90/4¤; Valertest¤; Venezuela: Cliane; Climene; Estracomb; Estragest; Ginecosid; Gynodian Depot; Mesigyna; Primosiston; Progyluton

Brand Name Drug: Aggrenox
Active Ingredient Drug: extended-release dipyridamole/aspirin
Indication: Prevention of stroke in patients who have had a previous stroke or transient ischemic attack
Company Name: Boehringer Ingelheim Pharmaceuticals, Inc
Availability: Approved for marketing in the US on November 23, 1999

Introduction

Some 800,000 people in the US experience a stroke each year, with about 160,000 dying from the illness. About 80% of strokes are caused by a blockage of an artery in the neck or brain. Of those who survive, the risk of stroke recurrence during the next five years ranges from 30% to nearly 50%. More than 4 million Americans are living with the consequences of stroke today.

The new drug Aggrenox was approved by the FDA to help those survivors reduce their risk of a recurrence. Manufactured by Boehringer Ingelheim Pharmaceuticals, Inc., Aggrenox contains a mixture of low-dose aspirin and dipyridamole, two drugs that each have antiplatelet effects and whose power together is additive. The recommended dose is two tablets daily, each containing 25mg aspirin and 200 mg extended-release dipyridamole.

Aggrenox: How It Works

Aggrenox is an antithrombotic agent and reduces blood clotting by exerting antiplatelet activity. Dipyridamole inhibits the uptake of adenosine into platelets in a dose-dependent manner, stimulating platelet adenylate-cyclase and increasing platelet cyclic-3′,5′-adenosine monophosphate levels. Via this mechanism, platelet aggregation is inhibited in response to various stimuli such as platelet activating factor, collagen, and adenosine diphosphate.

Aspirin inhibits platelet aggregation by irreversible inhibition of platelet cyclo-oxygenase and thus inhibits the generation of thromboxane A2, a powerful inducer of platelet aggregation and vasoconstriction.

Clinical Study Results

Aggrenox was evaluated in a double-blind, placebo-controlled, 24-month study called the European Stroke Prevention Study 2 (ESPS2), the largest recurrent stroke prevention trial ever conducted. A total of 6,602 patients who had an ischemic stroke or transient ischemic attack (TIA) were randomized into one of four groups: Aggrenox 25 mg aspirin/200 mg dipyridamole, aspirin 25 mg alone, 200 mg dipyridamole alone, or placebo. Treatment was administered twice daily (morning and evening).

Aggrenox reduced the risk of stroke by 22.1% compared to aspirin alone, by 24.4% compared to dipyridamole alone, and by 36.8% compared to placebo – all statistically significant findings. Compared to placebo, aspirin and dipyridamole each reduced the risk of stroke significantly (18% and 16% reductions, respectively), but had a greater effect when combined.

Aggrenox reduced the risk of stroke or death (combined) by 12.1% compared to aspirin alone, by 10.3% compared to dipyridamole alone, and by 24.2% compared to placebo. The rate of all-cause mortality was similar between the four treatment groups. Aggrenox also reduced the risk of TIA by 36% compared to placebo. The same findings persisted when patients were studied by age group.

What the Patient Should Know

Adverse effects associated with Aggrenox treatment included headache, bleeding, and gastrointestinal complaints. Since Aggrenox contains aspirin, it should be avoided in patients with severe hepatic insufficiency, severe renal failure, a history of active peptic ulcer, and bleeding disorders. Patients who consume three or more alcoholic beverages per day should be cautioned about the bleeding risks involved while taking aspirin. Dipyridamole has a vasodilatory effect and may cause chest pain in patients with underlying coronary artery disease, so it should be used with caution in this group. Since both aspirin and dipyridamole interact with a variety of other drugs, patient should inform their healthcare providers about other medications they may be taking.

Brand Name Drug: Penlac Nail Lacquer
Active Ingredient Drug: ciclopirox
Indication: Topical treatment of onchomycosis (nail fungus)
Company Name: Dermik Laboratories, a division of Aventis Pharmaceuticals
Availability: Approved by the FDA on December 27, 1999 and made available in the US in March 2000

Introduction

Millions of Americans, particularly those between the ages of 40 and 60, suffer from onchomycosis, a persistent fungal infection of the nails. It occurs when dermatophyte fungi, usually Trichophyton rubrum, invade the nail bed. Men and the elderly are afflicted most often, although the infection can strike all ages and women as well.

Onchomycosis of the toenails occurs four times more frequently than that of the fingernails, due in large part to the moist environment in shoes that promotes dermatophyte proliferation. In addition to causing embarrassment for its sufferers, onchomycosis can also cause discomfort and pain, particularly with walking, as the infection pushes up the infected nail. Nail fungus can lead to more serious infections in diabetics.

Until recently, such infections have been treated using oral preparations, such as terbinafine and itraconazole, but many patients cannot or prefer not to take these drugs. Penlac Nail Lacquer (ciclopirox) is now available in the US for these patients – the first topical agent approved in the US for this disorder. The lacquer was approved by the FDA on December 27, 1999 and made available in March 2000. Ciclopirox nail lacquer has been available for several years in Germany under the brand name Batrafen.

Manufactured by Dermik Laboratories, a division of Aventis Pharmaceuticals, Penlac is applied in the same manner as nail polish and should be used once daily, preferably at bedtime or eight hours before washing.

How It Works

Penlac Nail Lacquer Topical Solution 8% contains ciclopirox, a synthetic broad-spectrum antifungal agent that inhibits the growth of dermatophytes. In vitro studies suggest that ciclopirox may act by chelation of polyvalent cations, resulting in the inhibition of metal-dependent enzymes that are responsible for the degradation of peroxides within the fungal cell.

Penlac Nail Lacquer (ciclopirox): Clinical Study Results

The efficacy of Penlac Nail Lacquer (ciclopirox) for the treatment of onchomycosis was established in two double-blind, placebo-controlled studies in the US. The research is expected to be published later this year. One study included 219 patients (study 312), while the other involved 235 patients (study 313); all patients had onchomycosis of the great toenails without lunula involvement. Patients were treated with either Penlac or placebo every day for 48 weeks, with monthly removal of the unattached, infected toenail by the investigators.

At 48 weeks, 5.5% of patients in study 312 and 8.5% of patients in study 313 who were treated with Penlac achieved a complete cure (defined as a clear nail with negative mycology), compared to 0.9% and 0% of placebo patients, respectively. The corresponding rates for an almost-clear outcome (10% or less nail involvement and negative mycology) were 6.5% and 12% for Penlac patients, compared to 0.9% and 0.9% for placebo patients, respectively. Negative mycology alone was achieved by 29% of the Penlac patients in study 312 and 36% of Penlac patients in study 313, compared to 11% and 9% of placebo patients, respectively.

What the Patient Should Know

The most common side effect reported by patients using Penlac was redness at the nail fold. Some patients reported a change in nail shape, ingrown toenail, and nail discoloration. Patients who experience signs of increased irritation (redness, itching, burning, blistering, swelling, or oozing) should inform their healthcare professionals. Penlac Nail Lacquer is for external use only.

Daily applications of Penlac should be made over the previous coat and removed with alcohol every seven days. Removal of the unattached, infected nail should be performed by a healthcare professional as frequently as monthly to obtain maximum benefit of the product. Patients should also trim their nails weekly. Six months of treatment may be required before initial improvement of symptoms is noticed; full treatment time may be as long as 48 weeks.

Patients should not use nail polish or other cosmetic nail products on nails treated with Penlac. Because no studies have been conducted to determine whether Penlac might reduce the effectiveness of systemic antifungal agents for onchomycosis, the concomitant use of Penlac and systemic antifungal agents is not recommended.

Brand Name: AndroGel
Active Ingredient: testosterone
Indication: Topical testosterone replacement for men with low testosterone
Company Name: Unimed Pharmaceuticals, Inc.
Availability: Approved by FDA February 28, 2000

Introduction

An estimated 4 to 5 million men experience the effects of low testosterone – also known as hypogonadism – including a diminished interest in sex, impotence, reduced lean body mass, decreased bone density, and low mood and energy levels. Testosterone replacement has most commonly been achieved using painful deep muscle injections and potentially irritating transdermal patches.

A new form of testosterone replacement will soon be available in the US in the form of a gel: AndroGel 1%. Manufactured by Unimed Pharmaceuticals, Inc., a subsidiary of Solvay Pharmaceuticals, Inc., AndroGel was approved by the FDA on February 28, 2000, and is expected to be available with a prescription in the US by mid-summer. AndroGel is a clear colorless gel that men apply once daily to their shoulders, upper arms, and/or abdomen. The gel dries within a few minutes of application.

How It Works

Upon application to the skin, AndroGel is absorbed through the skin, which serves as a reservoir for the hormone. The testosterone slowly enters the circulation, and normal testosterone levels (298-1043 ng/dl) are restored within a few hours. Absorption of testosterone into the blood continues for the entire 24-hour dosing interval.

AndroGel: Clinical Study Results

The results of a clinical study demonstrating the efficacy of AndroGel will be presented at the 82nd Annual Meeting of the Endocrine Society in June 2000 in Toronto. AndroGel 1% was evaluated in a multicenter, randomized, parallel-group, active-controlled, 180-day trial in 227 hypogonadal men. The study was conducted in 2 phases. During the initial treatment period (days 1-90), 73 patients were randomized to AndroGel 5 G daily (to deliver 50 mg testosterone), 78 patients to AndroGel 10 G daily (to deliver 100 mg testosterone), and 76 patients to a non-scrotal testosterone transdermal system (5 mg daily). The study was double-blind for dose of AndroGel but open-label for active control. Patients who were originally randomized to AndroGel and who had single-sample serum testosterone levels above or below the normal range on day 60 were titrated to 7.5 G daily (to deliver 75 mg testosterone) on day 91. During the extended treatment period (days 91-180), 51 patients continued on AndroGel 5 G daily, 52 patients continued on AndroGel 10 G daily, 41 patients continued on a non-scrotal testosterone transdermal system (5 mg daily), and 40 patients received AndroGel 7.5 G daily.

Mean peak, trough, and average serum testosterone concentrations within the normal range (298-1043 ng/dl) were achieved on the first day of treatment with doses of 5 G and 10 G. In patients continuing on AndroGel 5 G and 10 G, these mean testosterone levels were maintained within the normal range for the 180-day duration of the study. Testosterone concentrations were maintained as long as the patient continued to apply the prescribed AndroGel treatment properly. On treatment day 180, the 7.5 G dose was found to produce mean concentrations intermediate to those produced by 5 G and 10 G of AndroGel. Of 129 hypogonadal men who were appropriately titrated with AndroGel and who had sufficient data for analysis, 87% achieved an average serum testosterone level within the normal range on treatment day 180.

AndroGel 5 G/day and 10 G/day resulted in significant increases over time in total body mass and total body lean mass, while total body fat mass and the percent body fat decreased significantly. These changes were maintained for 180 days of treatment. Changes in the 7.5 G dose group were similar. Bone mineral density in both hip and spine increased significantly from baseline to day 180 with 10 G AndroGel.

AndroGel treatment at 5 G/day and 10 G/day for 90 days produced significant improvement in libido (measured by sexual motivation, sexual activity, and enjoyment of sexual activity as assessed by patient responses to a questionnaire). The degree of penile erection, as subjectively estimated by the patients, increased with AndroGel treatment, as did the subjective score for “satisfactory duration of erection.” AndroGel treatment at 5 G/day and 10 G/day produced positive effects on mood and fatigue. Similar changes were seen after 180 days of treatment and in the group treated with the 7.5 G dose.

What the Patient Should Know

The most commonly reported side effects associated with AndroGel were acne and a skin reaction at the application site. Seven patients experienced a prostate disorder, most often enlargement of the prostate. Nine patients had abnormal lab test results.

After applying AndroGel, men should avoid bathing or showering for at least 5-6 hours. AndroGel should not be applied to the scrotum.

AndroGel is contraindicated in men with breast or prostate cancer. Geriatric patients may be at risk for prostatic hyperplasia and cancer.

Vigorous skin-to-skin contact may transfer testosterone from the treated individual to an untreated individual and increase serum testosterone levels in the untreated person. This can be prevented if the treated individual wears a shirt after applying AndroGel. Residual testosterone can be removed from the skin with soap and water.

AndroGel is not indicated for use in women. Pregnant women should avoid skin contact with AndroGel application sites in men, since testosterone may harm the fetus.

Brand Name Drug: Mobic
Active Ingredient Drug: meloxicam
Indication: Treatment of osteoarthritis
Company Name: Boehringer Ingelheim Pharmaceuticals, Inc. and Abbott Laboratories
Availability: Approved by the FDA on April 14, 2000

Introduction

As the population ages, the need for effective pain relief from osteoarthritis – which currently affects 80% of Americans over age 65 — is expected to increase. Millions of people are still searching for an effective treatment they can tolerate. Often arthritis patients try several medications and find they are not effective or cause side effects that make tolerating the medication difficult. Some patients keep searching, while others simply give up.

Mobic (meloxicam) tablets provide a new alternative for patients – when beginning therapy or when other treatments are discontinued. The FDA approved the use of Mobic for the once-daily treatment of osteoarthritis on April 14, 2000. The drug will be co-marketed by Boehringer Ingelheim Pharmaceuticals, Inc. and Abbott Laboratories. Mobic is a member of the family of COX-2 inhibitors. The recommended starting dose is 7.5 mg/day, increasing the dosage to a maximum of 15 mg/day in patients who require it.

How It Works

Mobic is an NSAID that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of meloxicam may be related to prostaglandin synthetase (cyclooxygenase-2) inhibition.

Mobic (meloxicam): Clinical Study Results

Mobic was evaluated for the treatment of osteoarthritis of the knee and hip in a double-blind controlled trial in the US of 464 patients treated for 12 weeks. Mobic (3.75 mg, 7.5 mg, and 15 mg) was compared with placebo. Patients who received Mobic 7.5 mg/day and 15 mg/day showed significant improvement in investigator’s and patient’s global assessments, patient pain assessment, and total WOMAC score (which addresses pain, function, and stiffness).

The use of Mobic for managing the signs and symptoms of osteoarthritis was also assessed in six double-blind active controlled trials outside the US involving 9,589 patients treated for 4 weeks to 6 months. Mobic (meloxicam) 7.5 mg/day and 15 mg/day showed efficacy comparable to piroxicam 20 mg/day and diclofenac SR 100 mg/day and consistent with the efficacy demonstrated in the US trial.

However, Mobic was found to be better tolerated than both drugs. In one study, the incidence of adverse events was significantly lower in the Mobic group (22.5%) compared with the piroxicam group (27.9%), mainly due to the significantly lower incidence of adverse gastrointestinal events in the Mobic group than in the piroxicam group (10.3% vs. 15.4%). Individual GI events occurred significantly less often with Mobic than piroxicam, including dyspepsia (3.4% vs. 5.8%), nausea/vomiting (2.5% vs. 3.4%), and abdominal pain (2.1% vs. 3.6%). There were 16 patients with perforations, ulcerations, or bleeding of the upper GI tract in the piroxicam group compared with seven in the Mobic group.

In another study, significantly fewer adverse events were reported by patients receiving Mobic compared to diclofenac. This was attributable to fewer GI adverse events (13%) compared to diclofenac (19%). Of the most common GI adverse events, there was significantly less dyspepsia, nausea and vomiting, abdominal pain, and diarrhea with Mobic (meloxicam) compared to diclofenac. Five patients on Mobic experienced a perforation, ulcer or bleed vs. seven on diclofenac. No endoscopically verified ulcer complication was detected in the Mobic group, compared to four with diclofenac.

What the Patient Should Know

Patients who have a known allergy to meloxicam, aspirin, or other traditional NSAIDs should not use Mobic tablets, nor should women who are, or may be, pregnant. As with all NSAIDs, Mobic has the potential to cause gastrointestinal bleeding, particularly in patients with bleeding disorders and those taking anticoagulants such as warfarin. Therefore, patients should be educated about the signs and symptoms of such bleeding and advised to seek medical attention promptly should it occur.

The most common side effects associated with Mobic are diarrhea, abdominal pain, and dyspepsia. Patients should also report any skin rash, unexplained weight gain, or edema to their physicians.

Mobic (meloxicam) should be used with caution in patients with hepatic or renal impairment, and in those with fluid retention, hypertension, or heart failure (since some patients taking Mobic have experienced fluid retention and edema). Mobic may interact with ACE inhibitors, furosemide, and lithium. Patients taking these drugs should inform their physicians.

Brand Name: Tamiflu
Active Ingredient: oseltamivir phosphate
Indication: Treatment of influenza A and B
Company Name: Hoffmann-La Roche Inc. and Gilead Sciences, Inc.
Availability: Approved for marketing in the US in October 1999

Introduction

Some 40 million Americans develop the flu every year, putting about 300,000 in the hospital. Up to 40,000 people die from influenza or its complications annually. Moreover, hospitalization and deaths due to the flu are increased among the elderly and those with high-risk medical conditions. The economic costs of the flu are high as well: some $14.6 billion due to lost wages, decreased productivity, and physician visits.

Arriving just in time for this year’s flu season, Tamiflu (oseltamivir phosphate) is the first neuraminidase inhibitor available in pill form. It is indicated for the treatment of uncomplicated acute illness due to infection with influenza A and B (which includes all common strains of the virus) in adults who have been symptomatic for no more than two days. Unlike over-the-counter medications that treat only the symptoms of the flu, Tamiflu actually targets the influenza virus and stops it from replicating. The recommended oral dose is 75 mg twice daily for five days.

How It Works

The neuraminidase protein is one of two major surface structures on the influenza virus and is virtually the same from one common strain of influenza to the next. The influenza virus needs neuraminidase to replicate and spread to other cells. In vitro studies showed that Tamiflu works by binding to the neuraminidase site and inhibiting its action, thus preventing replication of the influenza virus and its ability to spread from cell to cell.

Tamiflu (oseltamivir phosphate): Clinical Study Results

The efficacy of Tamiflu was demonstrated in two phase III double-blinded placebo-controlled trials, one conducted in the US and one outside the US. Eligible patients had a fever of more than 100 degrees F and at least one respiratory symptom (cough, nasal symptoms, or sore throat) and at least one systemic symptom (myalgia, chills/sweats, malaise, fatigue, or headache), and influenza known to be circulating in the community. Of 849 influenza-infected patients, 95% had influenza A, 3% had influenza B, and 2% had an unknown type.

Tamiflu administration commenced within 40 hours of onset of symptoms. Subjects participating in the trials were required to assess their symptoms as none, mild, moderate, or severe. Time to improvement was defined as the interval between the initiation of treatment to the time when all symptoms could be described as none or mild. In both studies, influenza-infected patients who received 75 mg of Tamiflu twice daily for five days showed a 1.3 day reduction in time to improvement of symptoms when compared to patients receiving placebo. The results were similar among men and women and in the elderly.

Recent studies have demonstrated that Tamiflu may be able to prevent infection with influenza A and B. However, the drug is not approved for this indication at this time.

What the Patient Should Know

Nausea and vomiting were the most common adverse events reported in patients taking Tamiflu, and to a lesser extent, bronchitis, insomnia, and vertigo. These events were generally mild and transient. Patients are advised to begin Tamiflu treatment as soon as possible after the initial appearance of symptoms. Finally, Tamiflu is not a substitute for a flu shot. Patients should continue receiving an annual flu shot according to immunization guidelines.